Author: "Doherty, J.A." - Searchworks@Jio Institute Digital Library Search Results

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151 results on '"Doherty, J.A."'

1. Prognostic gene expression signature for high-grade serous ovarian cancer

Author: Bowtell, D., Chenevix-Trench, G., Green, A., Webb, P., DeFazio, A., Gertig, D., Traficante, N., Fereday, S., Moore, S., Hung, J., Harrap, K., Sadkowsky, T., Pandeya, N., Malt, M., Mellon, A., Robertson, R., Vanden Bergh, T., Jones, M., Mackenzie, P., Maidens, J., Nattress, K., Chiew, Y.E., Stenlake, A., Sullivan, H., Alexander, B., Ashover, P., Brown, S., Corrish, T., Green, L., Jackman, L., Ferguson, K., Martin, K., Martyn, A., Ranieri, B., White, J., Jayde, V., Mamers, P., Bowes, L., Galletta, L., Giles, D., Hendley, J., Alsop, K., Schmidt, T., Shirley, H., Ball, C., Young, C., Viduka, S., Tran, Hoa, Bilic, Sanela, Glavinas, Lydia, Brooks, Julia, Stuart-Harris, R., Kirsten, F., Rutovitz, J., Clingan, P., Glasgow, A., Proietto, A., Braye, S., Otton, G., Shannon, J., Bonaventura, T., Stewart, J., Begbie, S., Friedlander, M., Bell, D., Baron-Hay, S., Ferrier,a, A., Gard, G., Nevell, D., Pavlakis, N., Valmadre, S., Young, B., Camaris, C., Crouch, R., Edwards, L., Hacker, N., Marsden, D., Robertson, G., Beale, P., Beith, J., Carter, J., Dalrymple, C., Houghton, R., Russell, P., Links, M., Grygiel, J., Hill, J., Brand, A., Byth, K., Jaworski, R., Harnett, P., Sharma, R., Wain, G., Ward, B., Papadimos, D., Crandon, A., Cummings, M., Horwood, K., Obermair, A., Perrin, L., Wyld, D., Nicklin, J., Davy, M., Oehler, M.K., Hall, C., Dodd, T., Healy, T., Pittman, K., Henderson, D., Miller, J., Pierdes, J., Blomfield, P., Challis, D., McIntosh, R., Parker, A., Brown, B., Rome, R., Allen, D., Grant, P., Hyde, S., Laurie, R., Robbie, M., Healy, D., Jobling, T., Manolitsas, T., McNealage, J., Rogers, P., Susil, B., Sumithran, E., Simpson, I., Phillips, K., Rischin, D., Fox, S., Johnson, D., Lade, S., Loughrey, M., O’Callaghan, N., Murray, W., Waring, P., Billson, V., Pyman, J., Neesham, D., Quinn, M., Underhill, C., Bell, R., Ng, L.F., Blum, R., Ganju, V., Hammond, I., Leung, Y., McCartney, A., Buck, M., Haviv, I., Purdie, D., Whiteman, D., Zeps, N., Millstein, J., Budden, T., Goode, E.L., Anglesio, M.S., Talhouk, A., Intermaggio, M.P., Leong, H.S., Chen, S., Elatre, W., Gilks, B., Nazeran, T., Volchek, M., Bentley, R.C., Wang, C., Chiu, D.S., Kommoss, S., Leung, S.C.Y., Senz, J., Lum, A., Chow, V., Sudderuddin, H., Mackenzie, R., George, J., Steed, H., Koziak, J.M., Köbel, M., McNeish, I.A., Goranova, T., Ennis, D., Macintyre, G., Silva De Silva, D., Ramón y Cajal, T., García-Donas, J., Hernando Polo, S., Rodriguez, G.C., Cushing-Haugen, K.L., Harris, H.R., Greene, C.S., Zelaya, R.A., Behrens, S., Fortner, R.T., Sinn, P., Herpel, E., Lester, J., Lubiński, J., Oszurek, O., Tołoczko, A., Cybulski, C., Menkiszak, J., Pearce, C.L., Pike, M.C., Tseng, C., Alsop, J., Rhenius, V., Song, H., Jimenez-Linan, M., Piskorz, A.M., Gentry-Maharaj, A., Karpinskyj, C., Widschwendter, M., Singh, N., Kennedy, C.J., Harnett, P.R., Gao, B., Johnatty, S.E., Sayer, R., Boros, J., Winham, S.J., Keeney, G.L., Kaufmann, S.H., Larson, M.C., Luk, H., Hernandez, B.Y., Thompson, P.J., Wilkens, L.R., Carney, M.E., Trabert, B., Lissowska, J., Brinton, L., Sherman, M.E., Bodelon, C., Hinsley, S., Lewsley, L.A., Glasspool, R., Banerjee, S.N., Stronach, E.A., Haluska, P., Ray-Coquard, I., Mahner, S., Winterhoff, B., Slamon, D., Levine, D.A., Kelemen, L.E., Benitez, J., Chang-Claude, J., Gronwald, J., Wu, A.H., Menon, U., Goodman, M.T., Schildkraut, J.M., Wentzensen, N., Brown, R., Berchuck, A., deFazio, A., Gayther, S.A., García, M.J., Henderson, M.J., Rossing, M.A., Beeghly-Fadiel, A., Fasching, P.A., Orsulic, S., Karlan, B.Y., Konecny, G.E., Huntsman, D.G., Bowtell, D.D., Brenton, J.D., Doherty, J.A., Pharoah, P.D.P., and Ramus, S.J.
Published: 2020
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2. Use of aspirin, other nonsteroidal anti-inflammatory drugs and acetaminophen and risk of endometrial cancer: the Epidemiology of Endometrial Cancer Consortium

Author: Webb, P.M., Na, R., Weiderpass, E., Adami, H.O., Anderson, K.E., Bertrand, K.A., Botteri, E., Brasky, T.M., Brinton, L.A., Chen, C., Doherty, J.A., Lu, L., McCann, S.E., Moysich, K.B., Olson, S., Petruzella, S., Palmer, J.R., Prizment, A.E., Schairer, C., Setiawan, V.W., Spurdle, A.B., Trabert, B., Wentzensen, N., Wilkens, L., Yang, H.P., Yu, H., Risch, H.A., and Jordan, S.J.
Published: 2019
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3. Lifetime ovulatory years and risk of epithelial ovarian cancer: a multinational pooled analysis.

Author: Fu, Z., Brooks, M.M., Irvin, S., Jordan, S., Aben, K.K.H., Anton-Culver, H., Bandera, E.V., Beckmann, M.W., Berchuck, A., Brooks-Wilson, A., Chang-Claude, J., Cook, L.S., Cramer, D.W, Cushing-Haugen, K.L., Doherty, J.A., Ekici, A.B., Fasching, P.A., Fortner, R.T., Gayther, S.A., Gentry-Maharaj, A., Giles, G.G., Goode, E.L., Goodman, M.T., Harris, H.R., Hein, A., Kaaks, R., Kiemeney, L.A., Köbel, M., Kotsopoulos, J., Le, N.D., Lee, A.W.C., Matsuo, K., McGuire, V., McLaughlin, J.R., Menon, U., Milne, R.L., Moysich, K.B., Pearce, C.L., Pike, M.C., Qin, B., Ramus, S.J., Riggan, M.J., Rothstein, J.H., Schildkraut, J.M., Sieh, W., Sutphen, R., Terry, K.L., Thompson, P.J., Titus, L., Altena, A.M. van, White, E., Whittemore, A.S., Wu, A.H., Zheng, W., Ziogas, Argyrios, Taylor, S.E., Tang, L., Songer, T., Wentzensen, N., Webb, P.M., Risch, H.A., Modugno, F., Fu, Z., Brooks, M.M., Irvin, S., Jordan, S., Aben, K.K.H., Anton-Culver, H., Bandera, E.V., Beckmann, M.W., Berchuck, A., Brooks-Wilson, A., Chang-Claude, J., Cook, L.S., Cramer, D.W, Cushing-Haugen, K.L., Doherty, J.A., Ekici, A.B., Fasching, P.A., Fortner, R.T., Gayther, S.A., Gentry-Maharaj, A., Giles, G.G., Goode, E.L., Goodman, M.T., Harris, H.R., Hein, A., Kaaks, R., Kiemeney, L.A., Köbel, M., Kotsopoulos, J., Le, N.D., Lee, A.W.C., Matsuo, K., McGuire, V., McLaughlin, J.R., Menon, U., Milne, R.L., Moysich, K.B., Pearce, C.L., Pike, M.C., Qin, B., Ramus, S.J., Riggan, M.J., Rothstein, J.H., Schildkraut, J.M., Sieh, W., Sutphen, R., Terry, K.L., Thompson, P.J., Titus, L., Altena, A.M. van, White, E., Whittemore, A.S., Wu, A.H., Zheng, W., Ziogas, Argyrios, Taylor, S.E., Tang, L., Songer, T., Wentzensen, N., Webb, P.M., Risch, H.A., and Modugno, F.
Abstract: Item does not contain fulltext, BACKGROUND: The role of ovulation in epithelial ovarian cancer (EOC) is supported by the consistent protective effects of parity and oral contraceptive use. Whether these factors protect through anovulation alone remains unclear. We explored the association between lifetime ovulatory years (LOY) and EOC. METHODS: LOY was calculated using 12 algorithms. Odds ratios (ORs) and 95% confidence intervals (CIs) estimated the association between LOY or LOY components and EOC among 26 204 control participants and 21 267 case patients from 25 studies. To assess whether LOY components act through ovulation suppression alone, we compared beta coefficients obtained from regression models with expected estimates assuming 1 year of ovulation suppression has the same effect regardless of source. RESULTS: LOY was associated with increased EOC risk (OR per year increase = 1.014, 95% CI = 1.009 to 1.020 to OR per year increase = 1.044, 95% CI = 1.041 to 1.048). Individual LOY components, except age at menarche, also associated with EOC. The estimated model coefficient for oral contraceptive use and pregnancies were 4.45 times and 12- to 15-fold greater than expected, respectively. LOY was associated with high-grade serous, low-grade serous, endometrioid, and clear cell histotypes (ORs per year increase = 1.054, 1.040, 1.065, and 1.098, respectively) but not mucinous tumors. Estimated coefficients of LOY components were close to expected estimates for high-grade serous but larger than expected for low-grade serous, endometrioid, and clear cell histotypes. CONCLUSIONS: LOY is positively associated with nonmucinous EOC. Differences between estimated and expected model coefficients for LOY components suggest factors beyond ovulation underlie the associations between LOY components and EOC in general and for non-HGSOC.
Published: 2023

4. Cross-Cancer Genome-Wide Association Study of Endometrial Cancer and Epithelial Ovarian Cancer Identifies Genetic Risk Regions Associated with Risk of Both Cancers.

Author: Glubb D.M., Thompson D.J., Aben K.K.H., Alsulimani A., Amant F., Annibali D., Attia J., Barricarte A., Beckmann M.W., Berchuck A., Bermisheva M., Bernardini M.Q., Bischof K., Bjorge L., Bodelon C., Brand A.H., Brenton J.D., Brinton L.A., Bruinsma F., Buchanan D.D., Burghaus S., Butzow R., Cai H., Carney M.E., Chanock S.J., Chen C., Chen X.Q., Chen Z., Cook L.S., Cunningham J.M., De Vivo I., deFazio A., Doherty J.A., Dork T., du Bois A., Dunning A.M., Durst M., Edwards T., Edwards R.P., Ekici A.B., Ewing A., Fasching P.A., Ferguson S., Flanagan J.M., Fostira F., Fountzilas G., Friedenreich C.M., Gao B., Gaudet M.M., Gawelko J., Gentry-Maharaj A., Giles G.G., Glasspool R., Goodman M.T., Gronwald J., Harris H.R., Harter P., Hein A., Heitz F., Hildebrandt M.A.T., Hillemanns P., Hogdall E., Hogdall C.K., Holliday E.G., Huntsman D.G., Huzarski T., Jakubowska A., Jensen A., Jones M.E., Karlan B.Y., Karnezis A., Kelley J.L., Khusnutdinova E., Killeen J.L., Kjaer S.K., Klapdor R., Kobel M., Konopka B., Konstantopoulou I., Kopperud R.K., Koti M., Kraft P., Kupryjanczyk J., Lambrechts D., Larson M.C., Le Marchand L., Lele S., Lester J., Li A.J., Liang D., Liebrich C., Lipworth L., Lissowska J., Lu L., Lu K.H., Macciotta A., Mattiello A., May T., McAlpine J.N., McGuire V., McNeish I.A., Menon U., Modugno F., Moysich K.B., Nevanlinna H., Odunsi K., Olsson H., Orsulic S., Osorio A., Palli D., Park-Simon T.-W., Pearce C.L., Pejovic T., Permuth J.B., Podgorska A., Ramus S.J., Rebbeck T.R., Riggan M.J., Risch H.A., Rothstein J.H., Runnebaum I.B., Scott R.J., Sellers T.A., Senz J., Setiawan V.W., Siddiqui N., Sieh W., Spiewankiewicz B., Sutphen R., Swerdlow A.J., Szafron L.M., Teo S.H., Thompson P.J., Thomsen L.C.V., Titus L., Tone A., Tumino R., Turman C., Vanderstichele A., Edwards D.V., Vergote I., Vierkant R.A., Wang Z., Wang-Gohrke S., Webb P.M., White E., Whittemore A.S., Winham S.J., Wu X., Wu A.H., Yannoukakos D., Spurdle A.B., O'Mara T.A., Glubb D.M., Thompson D.J., Aben K.K.H., Alsulimani A., Amant F., Annibali D., Attia J., Barricarte A., Beckmann M.W., Berchuck A., Bermisheva M., Bernardini M.Q., Bischof K., Bjorge L., Bodelon C., Brand A.H., Brenton J.D., Brinton L.A., Bruinsma F., Buchanan D.D., Burghaus S., Butzow R., Cai H., Carney M.E., Chanock S.J., Chen C., Chen X.Q., Chen Z., Cook L.S., Cunningham J.M., De Vivo I., deFazio A., Doherty J.A., Dork T., du Bois A., Dunning A.M., Durst M., Edwards T., Edwards R.P., Ekici A.B., Ewing A., Fasching P.A., Ferguson S., Flanagan J.M., Fostira F., Fountzilas G., Friedenreich C.M., Gao B., Gaudet M.M., Gawelko J., Gentry-Maharaj A., Giles G.G., Glasspool R., Goodman M.T., Gronwald J., Harris H.R., Harter P., Hein A., Heitz F., Hildebrandt M.A.T., Hillemanns P., Hogdall E., Hogdall C.K., Holliday E.G., Huntsman D.G., Huzarski T., Jakubowska A., Jensen A., Jones M.E., Karlan B.Y., Karnezis A., Kelley J.L., Khusnutdinova E., Killeen J.L., Kjaer S.K., Klapdor R., Kobel M., Konopka B., Konstantopoulou I., Kopperud R.K., Koti M., Kraft P., Kupryjanczyk J., Lambrechts D., Larson M.C., Le Marchand L., Lele S., Lester J., Li A.J., Liang D., Liebrich C., Lipworth L., Lissowska J., Lu L., Lu K.H., Macciotta A., Mattiello A., May T., McAlpine J.N., McGuire V., McNeish I.A., Menon U., Modugno F., Moysich K.B., Nevanlinna H., Odunsi K., Olsson H., Orsulic S., Osorio A., Palli D., Park-Simon T.-W., Pearce C.L., Pejovic T., Permuth J.B., Podgorska A., Ramus S.J., Rebbeck T.R., Riggan M.J., Risch H.A., Rothstein J.H., Runnebaum I.B., Scott R.J., Sellers T.A., Senz J., Setiawan V.W., Siddiqui N., Sieh W., Spiewankiewicz B., Sutphen R., Swerdlow A.J., Szafron L.M., Teo S.H., Thompson P.J., Thomsen L.C.V., Titus L., Tone A., Tumino R., Turman C., Vanderstichele A., Edwards D.V., Vergote I., Vierkant R.A., Wang Z., Wang-Gohrke S., Webb P.M., White E., Whittemore A.S., Winham S.J., Wu X., Wu A.H., Yannoukakos D., Spurdle A.B., and O'Mara T.A.
Abstract: BACKGROUND: Accumulating evidence suggests a relationship between endometrial cancer and ovarian cancer. Independent genome-wide association studies (GWAS) for endometrial cancer and ovarian cancer have identified 16 and 27 risk regions, respectively, four of which overlap between the two cancers. We aimed to identify joint endometrial and ovarian cancer risk loci by performing a meta-analysis of GWAS summary statistics from these two cancers. METHOD(S): Using LDScore regression, we explored the genetic correlation between endometrial cancer and ovarian cancer. To identify loci associated with the risk of both cancers, we implemented a pipeline of statistical genetic analyses (i.e., inverse-variance meta-analysis, colocalization, and M-values) and performed analyses stratified by subtype. Candidate target genes were then prioritized using functional genomic data. RESULT(S): Genetic correlation analysis revealed significant genetic correlation between the two cancers (rG = 0.43, P = 2.66 x 10-5). We found seven loci associated with risk for both cancers (PBonferroni < 2.4 x 10-9). In addition, four novel subgenome-wide regions at 7p22.2, 7q22.1, 9p12, and 11q13.3 were identified (P < 5 x 10-7). Promoter-associated HiChIP chromatin loops from immortalized endometrium and ovarian cell lines and expression quantitative trait loci data highlighted candidate target genes for further investigation. CONCLUSION(S): Using cross-cancer GWAS meta-analysis, we have identified several joint endometrial and ovarian cancer risk loci and candidate target genes for future functional analysis. IMPACT: Our research highlights the shared genetic relationship between endometrial cancer and ovarian cancer. Further studies in larger sample sets are required to confirm our findings.Copyright ©2020 American Association for Cancer Research.
Published: 2022

5. Polygenic risk modeling for prediction of epithelial ovarian cancer risk

Author: Dareng, E.O., Tyrer, J.P., Barnes, D.R., Jones, M.R., Yang, X, Aben, K.K.H., Adank, M.A., Agata, S., Andrulis, I.L., Anton-Culver, H., Antonenkova, N.N., Aravantinos, G., Arun, B.K., Augustinsson, A., Balmaña, J., Bandera, E.V., Barkardottir, R.B., Barrowdale, D., Beckmann, M.W., Beeghly-Fadiel, A., Benitez, J., Bermisheva, M., Bernardini, M.Q., Bjorge, L., Black, A., Bogdanova, N.V., Bonanni, B., Borg, A., Brenton, J.D., Budzilowska, A., Butzow, R., Buys, S.S., Cai, H., Caligo, M.A., Campbell, I., Cannioto, R., Cassingham, H., Chang-Claude, J., Chanock, S.J., Chen, K., Chiew, Y.E., Chung, W.K., Claes, K.B.M., Colonna, S., Cook, L.S., Couch, F.J., Daly, M.B., Dao, F., Davies, E., Hoya, M. de la, Putter, R. de, Dennis, J., DePersia, A., Devilee, P., Diez, O., Ding, Y.C., Doherty, J.A., Domchek, S.M., Dörk, T., Bois, A. du, Dürst, M., Eccles, D.M., Eliassen, H.A., Engel, C., Evans, G.D., Fasching, P.A., Flanagan, J.M., Fortner, R.T., Machackova, E., Friedman, E., Ganz, P.A., Garber, J., Gensini, F., Giles, G.G., Glendon, G., Godwin, A.K., Goodman, M.T., Greene, M.H., Gronwald, J., Hahnen, E., Haiman, C.A., Håkansson, N., Hamann, U., Hansen, T.V., Harris, H.R., Hartman, M, Heitz, F., Hildebrandt, M.A., Høgdall, E., Høgdall, C.K., Hopper, J.L., Huang, R.Y., Huff, C., Hulick, P.J., Huntsman, D.G., Imyanitov, E.N., Isaacs, C., Jakubowska, A., James, P.A., Kiemeney, L.A.L.M., Altena, A.M. van, Janavicius, R., Antoniou, A.C., Pharoah, P.D., Dareng, E.O., Tyrer, J.P., Barnes, D.R., Jones, M.R., Yang, X, Aben, K.K.H., Adank, M.A., Agata, S., Andrulis, I.L., Anton-Culver, H., Antonenkova, N.N., Aravantinos, G., Arun, B.K., Augustinsson, A., Balmaña, J., Bandera, E.V., Barkardottir, R.B., Barrowdale, D., Beckmann, M.W., Beeghly-Fadiel, A., Benitez, J., Bermisheva, M., Bernardini, M.Q., Bjorge, L., Black, A., Bogdanova, N.V., Bonanni, B., Borg, A., Brenton, J.D., Budzilowska, A., Butzow, R., Buys, S.S., Cai, H., Caligo, M.A., Campbell, I., Cannioto, R., Cassingham, H., Chang-Claude, J., Chanock, S.J., Chen, K., Chiew, Y.E., Chung, W.K., Claes, K.B.M., Colonna, S., Cook, L.S., Couch, F.J., Daly, M.B., Dao, F., Davies, E., Hoya, M. de la, Putter, R. de, Dennis, J., DePersia, A., Devilee, P., Diez, O., Ding, Y.C., Doherty, J.A., Domchek, S.M., Dörk, T., Bois, A. du, Dürst, M., Eccles, D.M., Eliassen, H.A., Engel, C., Evans, G.D., Fasching, P.A., Flanagan, J.M., Fortner, R.T., Machackova, E., Friedman, E., Ganz, P.A., Garber, J., Gensini, F., Giles, G.G., Glendon, G., Godwin, A.K., Goodman, M.T., Greene, M.H., Gronwald, J., Hahnen, E., Haiman, C.A., Håkansson, N., Hamann, U., Hansen, T.V., Harris, H.R., Hartman, M, Heitz, F., Hildebrandt, M.A., Høgdall, E., Høgdall, C.K., Hopper, J.L., Huang, R.Y., Huff, C., Hulick, P.J., Huntsman, D.G., Imyanitov, E.N., Isaacs, C., Jakubowska, A., James, P.A., Kiemeney, L.A.L.M., Altena, A.M. van, Janavicius, R., Antoniou, A.C., and Pharoah, P.D.
Abstract: Item does not contain fulltext, Polygenic risk scores (PRS) for epithelial ovarian cancer (EOC) have the potential to improve risk stratification. Joint estimation of Single Nucleotide Polymorphism (SNP) effects in models could improve predictive performance over standard approaches of PRS construction. Here, we implemented computationally efficient, penalized, logistic regression models (lasso, elastic net, stepwise) to individual level genotype data and a Bayesian framework with continuous shrinkage, "select and shrink for summary statistics" (S4), to summary level data for epithelial non-mucinous ovarian cancer risk prediction. We developed the models in a dataset consisting of 23,564 non-mucinous EOC cases and 40,138 controls participating in the Ovarian Cancer Association Consortium (OCAC) and validated the best models in three populations of different ancestries: prospective data from 198,101 women of European ancestries; 7,669 women of East Asian ancestries; 1,072 women of African ancestries, and in 18,915 BRCA1 and 12,337 BRCA2 pathogenic variant carriers of European ancestries. In the external validation data, the model with the strongest association for non-mucinous EOC risk derived from the OCAC model development data was the S4 model (27,240 SNPs) with odds ratios (OR) of 1.38 (95% CI: 1.28-1.48, AUC: 0.588) per unit standard deviation, in women of European ancestries; 1.14 (95% CI: 1.08-1.19, AUC: 0.538) in women of East Asian ancestries; 1.38 (95% CI: 1.21-1.58, AUC: 0.593) in women of African ancestries; hazard ratios of 1.36 (95% CI: 1.29-1.43, AUC: 0.592) in BRCA1 pathogenic variant carriers and 1.49 (95% CI: 1.35-1.64, AUC: 0.624) in BRCA2 pathogenic variant carriers. Incorporation of the S4 PRS in risk prediction models for ovarian cancer may have clinical utility in ovarian cancer prevention programs.
Published: 2022

6. Copy Number Variants Are Ovarian Cancer Risk Alleles at Known and Novel Risk Loci

Author: DeVries, A.A.F., Dennis, J., Tyrer, J.P., Peng, P.C., Coetzee, S.G., Reyes, A.L., Plummer, J.T., Davis, B.D., Chen, S.S., Dezem, F.S., Aben, K.K.H., Anton-Culver, H., Antonenkova, N.N., Beckmann, M.W., Beeghly-Fadiel, A., Berchuck, A., Bogdanova, N.V., Bogdanova-Markov, N., Brenton, J.D., Butzow, R., Campbell, I., Chang-Claude, J., Chenevix-Trench, G., Cook, L.S., Defazio, A., Doherty, J.A., Dörk, T., Eccles, D.M., Eliassen, A.H., Fasching, P.A., Fortner, R.T., Giles, G.G., Goode, E.L., Goodman, M.T., Gronwald, J., Håkansson, N., Hildebrandt, M.A., Huff, C., Huntsman, D.G., Jensen, A., Kar, S., Karlan, B.Y., Khusnutdinova, E.K., Kiemeney, L.A.L.M., Kjaer, S.K., Kupryjanczyk, J., Labrie, M., Lambrechts, D., Le, N.D., Lubiński, J., May, T., Menon, U., Milne, R.L., Modugno, F., Monteiro, Ana, Moysich, K.B., Odunsi, K., Olsson, H., Pearce, C.L., Pejovic, T., Ramus, S.J., Riboli, E., Riggan, M.J., Romieu, I., Sandler, D.P., Schildkraut, J.M., Setiawan, V.W., Sieh, W., Song, H., Sutphen, R., Terry, K.L., Thompson, P.J., Titus, L., Tworoger, S.S., Nieuwenhuysen, E. Van, Edwards, D.V., Webb, P.M., Wentzensen, N., Whittemore, A.S., Wolk, A., Wu, A.H., Ziogas, Argyrios, Freedman, M.L., Lawrenson, K., Pharoah, P.D., Easton, D.F., Gayther, S.A., Jones, M.R., DeVries, A.A.F., Dennis, J., Tyrer, J.P., Peng, P.C., Coetzee, S.G., Reyes, A.L., Plummer, J.T., Davis, B.D., Chen, S.S., Dezem, F.S., Aben, K.K.H., Anton-Culver, H., Antonenkova, N.N., Beckmann, M.W., Beeghly-Fadiel, A., Berchuck, A., Bogdanova, N.V., Bogdanova-Markov, N., Brenton, J.D., Butzow, R., Campbell, I., Chang-Claude, J., Chenevix-Trench, G., Cook, L.S., Defazio, A., Doherty, J.A., Dörk, T., Eccles, D.M., Eliassen, A.H., Fasching, P.A., Fortner, R.T., Giles, G.G., Goode, E.L., Goodman, M.T., Gronwald, J., Håkansson, N., Hildebrandt, M.A., Huff, C., Huntsman, D.G., Jensen, A., Kar, S., Karlan, B.Y., Khusnutdinova, E.K., Kiemeney, L.A.L.M., Kjaer, S.K., Kupryjanczyk, J., Labrie, M., Lambrechts, D., Le, N.D., Lubiński, J., May, T., Menon, U., Milne, R.L., Modugno, F., Monteiro, Ana, Moysich, K.B., Odunsi, K., Olsson, H., Pearce, C.L., Pejovic, T., Ramus, S.J., Riboli, E., Riggan, M.J., Romieu, I., Sandler, D.P., Schildkraut, J.M., Setiawan, V.W., Sieh, W., Song, H., Sutphen, R., Terry, K.L., Thompson, P.J., Titus, L., Tworoger, S.S., Nieuwenhuysen, E. Van, Edwards, D.V., Webb, P.M., Wentzensen, N., Whittemore, A.S., Wolk, A., Wu, A.H., Ziogas, Argyrios, Freedman, M.L., Lawrenson, K., Pharoah, P.D., Easton, D.F., Gayther, S.A., and Jones, M.R.
Abstract: Item does not contain fulltext, BACKGROUND: Known risk alleles for epithelial ovarian cancer (EOC) account for approximately 40% of the heritability for EOC. Copy number variants (CNVs) have not been investigated as EOC risk alleles in a large population cohort. METHODS: Single nucleotide polymorphism array data from 13 071 EOC cases and 17 306 controls of White European ancestry were used to identify CNVs associated with EOC risk using a rare admixture maximum likelihood test for gene burden and a by-probe ratio test. We performed enrichment analysis of CNVs at known EOC risk loci and functional biofeatures in ovarian cancer-related cell types. RESULTS: We identified statistically significant risk associations with CNVs at known EOC risk genes; BRCA1 (PEOC = 1.60E-21; OREOC = 8.24), RAD51C (Phigh-grade serous ovarian cancer [HGSOC] = 5.5E-4; odds ratio [OR]HGSOC = 5.74 del), and BRCA2 (PHGSOC = 7.0E-4; ORHGSOC = 3.31 deletion). Four suggestive associations (P < .001) were identified for rare CNVs. Risk-associated CNVs were enriched (P < .05) at known EOC risk loci identified by genome-wide association study. Noncoding CNVs were enriched in active promoters and insulators in EOC-related cell types. CONCLUSIONS: CNVs in BRCA1 have been previously reported in smaller studies, but their observed frequency in this large population-based cohort, along with the CNVs observed at BRCA2 and RAD51C gene loci in EOC cases, suggests that these CNVs are potentially pathogenic and may contribute to the spectrum of disease-causing mutations in these genes. CNVs are likely to occur in a wider set of susceptibility regions, with potential implications for clinical genetic testing and disease prevention.
Published: 2022

7. Iam hiQ—a novel pair of accuracy indices for imputed genotypes

Author: Rosenberger, A., Tozzi, V., Bickeböller, H., Hung, R.J., Christiani, D.C., Caporaso, N.E., Liu, G., Bojesen, S.E., Le Marchand, L., Albanes, D., Aldrich, M.C., Tardon, A., Fernández-Tardón, G., Rennert, G., Field, J.K., Davies, M., Liloglou, T., Kiemeney, L.A., Lazarus, P., Haugen, A., Zienolddiny, S., Lam, S., Schabath, M.B., Andrew, A.S., Duell, E.J., Arnold, S.M., Brunnström, H., Melander, O., Goodman, G.E., Chen, C., Doherty, J.A., Teare, M.D., Cox, A., Woll, P.J., Risch, A., Muley, T.R., Johansson, M., Brennan, P., Landi, M.T., Shete, S.S., and Amos, C.I.
Abstract: Background\ud \ud Imputation of untyped markers is a standard tool in genome-wide association studies to close the gap between directly genotyped and other known DNA variants. However, high accuracy with which genotypes are imputed is fundamental. Several accuracy measures have been proposed and some are implemented in imputation software, unfortunately diversely across platforms. In the present paper, we introduce Iam hiQ, an independent pair of accuracy measures that can be applied to dosage files, the output of all imputation software. Iam (imputation accuracy measure) quantifies the average amount of individual-specific versus population-specific genotype information in a linear manner. hiQ (heterogeneity in quantities of dosages) addresses the inter-individual heterogeneity between dosages of a marker across the sample at hand.\ud \ud \ud \ud Results\ud \ud Applying both measures to a large case–control sample of the International Lung Cancer Consortium (ILCCO), comprising 27,065 individuals, we found meaningful thresholds for Iam and hiQ suitable to classify markers of poor accuracy. We demonstrate how Manhattan-like plots and moving averages of Iam and hiQ can be useful to identify regions enriched with less accurate imputed markers, whereas these regions would by missed when applying the accuracy measure info (implemented in IMPUTE2).\ud \ud \ud \ud Conclusion\ud \ud We recommend using Iam hiQ additional to other accuracy scores for variant filtering before stepping into the analysis of imputed GWAS data.
Published: 2022

8. Pleiotropy-guided transcriptome imputation from normal and tumor tissues identifies candidate susceptibility genes for breast and ovarian cancer

Author: Kar, S.P., Considine, D.P.C., Tyrer, J.P., Plummer, J.T., Chen, S., Dezem, F.S., Barbeira, A.N., Rajagopal, P.S., Rosenow, W.T., Moreno, F., Bodelon, C., Chang-Claude, J., Chenevix-Trench, G., Defazio, A., Dörk, T., Ekici, A.B., Ewing, A., Fountzilas, G., Goode, E.L., Hartman, M, Heitz, F., Hillemanns, P., Høgdall, E., Høgdall, C.K., Huzarski, T., Jensen, A., Karlan, B.Y., Khusnutdinova, E., Kiemeney, L.A.L.M., Kjaer, S.K., Klapdor, R., Köbel, M., Li, J., Liebrich, C., May, T., Olsson, H., Permuth, J.B., Peterlongo, P., Radice, P., Ramus, S.J., Riggan, M.J., Risch, H.A., Saloustros, E., Simard, J., Szafron, L.M., Titus, L., Thompson, C.L., Vierkant, R.A., Winham, S.J., Zheng, W., Doherty, J.A., Berchuck, A., Lawrenson, K., Im, H.K., Manichaikul, A.W., Pharoah, P.D., Gayther, S.A., Schildkraut, J.M., Kar, S.P., Considine, D.P.C., Tyrer, J.P., Plummer, J.T., Chen, S., Dezem, F.S., Barbeira, A.N., Rajagopal, P.S., Rosenow, W.T., Moreno, F., Bodelon, C., Chang-Claude, J., Chenevix-Trench, G., Defazio, A., Dörk, T., Ekici, A.B., Ewing, A., Fountzilas, G., Goode, E.L., Hartman, M, Heitz, F., Hillemanns, P., Høgdall, E., Høgdall, C.K., Huzarski, T., Jensen, A., Karlan, B.Y., Khusnutdinova, E., Kiemeney, L.A.L.M., Kjaer, S.K., Klapdor, R., Köbel, M., Li, J., Liebrich, C., May, T., Olsson, H., Permuth, J.B., Peterlongo, P., Radice, P., Ramus, S.J., Riggan, M.J., Risch, H.A., Saloustros, E., Simard, J., Szafron, L.M., Titus, L., Thompson, C.L., Vierkant, R.A., Winham, S.J., Zheng, W., Doherty, J.A., Berchuck, A., Lawrenson, K., Im, H.K., Manichaikul, A.W., Pharoah, P.D., Gayther, S.A., and Schildkraut, J.M.
Abstract: Contains fulltext : 237689.pdf (Publisher’s version ) (Open Access), Familial, sequencing, and genome-wide association studies (GWASs) and genetic correlation analyses have progressively unraveled the shared or pleiotropic germline genetics of breast and ovarian cancer. In this study, we aimed to leverage this shared germline genetics to improve the power of transcriptome-wide association studies (TWASs) to identify candidate breast cancer and ovarian cancer susceptibility genes. We built gene expression prediction models using the PrediXcan method in 681 breast and 295 ovarian tumors from The Cancer Genome Atlas and 211 breast and 99 ovarian normal tissue samples from the Genotype-Tissue Expression project and integrated these with GWAS meta-analysis data from the Breast Cancer Association Consortium (122,977 cases/105,974 controls) and the Ovarian Cancer Association Consortium (22,406 cases/40,941 controls). The integration was achieved through application of a pleiotropy-guided conditional/conjunction false discovery rate (FDR) approach in the setting of a TWASs. This identified 14 candidate breast cancer susceptibility genes spanning 11 genomic regions and 8 candidate ovarian cancer susceptibility genes spanning 5 genomic regions at conjunction FDR < 0.05 that were >1 Mb away from known breast and/or ovarian cancer susceptibility loci. We also identified 38 candidate breast cancer susceptibility genes and 17 candidate ovarian cancer susceptibility genes at conjunction FDR < 0.05 at known breast and/or ovarian susceptibility loci. The 22 genes identified by our cross-cancer analysis represent promising candidates that further elucidate the role of the transcriptome in mediating germline breast and ovarian cancer risk.
Published: 2021

9. Refined cut-off for TP53 immunohistochemistry improves prediction of TP53 mutation status in ovarian mucinous tumors: implications for outcome analyses.

Author: Friedlander M., Russell P., Links M., Grygiel J., Hill J., Byth K., Jaworski R., Harnett P., Wain G., Ward B., Papadimos D., Crandon A., Cummings M., Horwood K., Obermair A., Perrin L., Wyld D., Nicklin J., Davy M., Oehler M.K., Hall C., Dodd T., Healy T., Pittman K., Henderson D., Miller J., Pierdes J., Blomfield P., Challis D., McIntosh R., Parker A., Brown B., Rome R., Allen D., Grant P., Hyde S., Laurie R., Robbie M., Healy D., Jobling T., Manolitsas T., McNealage J., Rogers P., Susil B., Sumithran E., Simpson I., Phillips K., Rischin D., Fox S., Johnson D., Lade S., Loughrey M., O'Callaghan N., Murray W., Waring P., Billson V., Pyman J., Neesham D., Quinn M., Underhill C., Bell R., Ng L.F., Blum R., Ganju V., Hammond I., Leung Y., McCartney A., Buck M., Haviv I., Purdie D., Whiteman D., Zeps N., Kaufmann S., Meagher N.S., Ramus S.J., Campbell I., Cheasley D., Wakefield M.J., Ryland G.L., Allan P.E., Alsop K., Ananda S., Anglesio M.S., Au-Yeung G., Bohm M., Bowtell D.D.L., Brand A., Chenevix-Trench G., Christie M., Chiew Y.-E., Churchman M., DeFazio A., Dudley R., Fairweather N., Fereday S., Fox S.B., Gilks C.B., Gourley C., Hacker N.F., Hadley A.M., Hendley J., Ho G.-Y., Huntsman D.G., Hunter S.M., Jobling T.W., Kalli K.R., Kaufmann S.H., Kennedy C.J., Kobel M., Le Page C., McNally O.M., McAlpine J.N., Mileshkin L., Jan Pyman, Rahimi K., Samimi G., Sharma R., Stephens A.N., Traficante N., Antill Y.C., Scott C.L., Campbell I.G., Gorringe K.L., Kang E.Y., LePage C., da Cunha Torres M., Rowley S., Salazar C., Xing Z., Allan P., Mes-Masson A.-M., Provencher D.M., Kelemen L.E., Fasching P.A., Doherty J.A., Goodman M.T., Goode E.L., Deen S., Pharoah P.D.P., Brenton J.D., Sieh W., Mateoiu C., Sundfeldt K., Cook L.S., Le N.D., Bowtell D., Green A., Webb P., Gertig D., Moore S., Hung J., Harrap K., Sadkowsky T., Pandeya N., Malt M., Mellon A., Robertson R., Bergh T.V., Jones M., Mackenzie P., Maidens J., Nattress K., Chiew Y.E., Stenlake A., Sullivan H., Alexander B., Ashover P., Brown S., Corrish T., Green L., Jackman L., Ferguson K., Martin K., Martyn A., Ranieri B., White J., Jayde V., Mamers P., Bowes L., Galletta L., Giles D., Schmidt T., Shirley H., Ball C., Young C., Viduka S., Tran H., Bilic S., Glavinas L., Brooks J., Stuart-Harris R., Kirsten F., Rutovitz J., Clingan P., Glasgow A., Proietto A., Braye S., Otton G., Shannon J., Bonaventura T., Stewart J., Begbie S., Bell D., Baron-Hay S., Ferrier A., Gard G., Nevell D., Pavlakis N., Valmadre S., Young B., Camaris C., Crouch R., Edwards L., Hacker N., Marsden D., Robertson G., Beale P., Beith J., Carter J., Dalrymple C., Houghton R., Friedlander M., Russell P., Links M., Grygiel J., Hill J., Byth K., Jaworski R., Harnett P., Wain G., Ward B., Papadimos D., Crandon A., Cummings M., Horwood K., Obermair A., Perrin L., Wyld D., Nicklin J., Davy M., Oehler M.K., Hall C., Dodd T., Healy T., Pittman K., Henderson D., Miller J., Pierdes J., Blomfield P., Challis D., McIntosh R., Parker A., Brown B., Rome R., Allen D., Grant P., Hyde S., Laurie R., Robbie M., Healy D., Jobling T., Manolitsas T., McNealage J., Rogers P., Susil B., Sumithran E., Simpson I., Phillips K., Rischin D., Fox S., Johnson D., Lade S., Loughrey M., O'Callaghan N., Murray W., Waring P., Billson V., Pyman J., Neesham D., Quinn M., Underhill C., Bell R., Ng L.F., Blum R., Ganju V., Hammond I., Leung Y., McCartney A., Buck M., Haviv I., Purdie D., Whiteman D., Zeps N., Kaufmann S., Meagher N.S., Ramus S.J., Campbell I., Cheasley D., Wakefield M.J., Ryland G.L., Allan P.E., Alsop K., Ananda S., Anglesio M.S., Au-Yeung G., Bohm M., Bowtell D.D.L., Brand A., Chenevix-Trench G., Christie M., Chiew Y.-E., Churchman M., DeFazio A., Dudley R., Fairweather N., Fereday S., Fox S.B., Gilks C.B., Gourley C., Hacker N.F., Hadley A.M., Hendley J., Ho G.-Y., Huntsman D.G., Hunter S.M., Jobling T.W., Kalli K.R., Kaufmann S.H., Kennedy C.J., Kobel M., Le Page C., McNally O.M., McAlpine J.N., Mileshkin L., Jan Pyman, Rahimi K., Samimi G., Sharma R., Stephens A.N., Traficante N., Antill Y.C., Scott C.L., Campbell I.G., Gorringe K.L., Kang E.Y., LePage C., da Cunha Torres M., Rowley S., Salazar C., Xing Z., Allan P., Mes-Masson A.-M., Provencher D.M., Kelemen L.E., Fasching P.A., Doherty J.A., Goodman M.T., Goode E.L., Deen S., Pharoah P.D.P., Brenton J.D., Sieh W., Mateoiu C., Sundfeldt K., Cook L.S., Le N.D., Bowtell D., Green A., Webb P., Gertig D., Moore S., Hung J., Harrap K., Sadkowsky T., Pandeya N., Malt M., Mellon A., Robertson R., Bergh T.V., Jones M., Mackenzie P., Maidens J., Nattress K., Chiew Y.E., Stenlake A., Sullivan H., Alexander B., Ashover P., Brown S., Corrish T., Green L., Jackman L., Ferguson K., Martin K., Martyn A., Ranieri B., White J., Jayde V., Mamers P., Bowes L., Galletta L., Giles D., Schmidt T., Shirley H., Ball C., Young C., Viduka S., Tran H., Bilic S., Glavinas L., Brooks J., Stuart-Harris R., Kirsten F., Rutovitz J., Clingan P., Glasgow A., Proietto A., Braye S., Otton G., Shannon J., Bonaventura T., Stewart J., Begbie S., Bell D., Baron-Hay S., Ferrier A., Gard G., Nevell D., Pavlakis N., Valmadre S., Young B., Camaris C., Crouch R., Edwards L., Hacker N., Marsden D., Robertson G., Beale P., Beith J., Carter J., Dalrymple C., and Houghton R.
Abstract: TP53 mutations are implicated in the progression of mucinous borderline tumors (MBOT) to mucinous ovarian carcinomas (MOC). Optimized immunohistochemistry (IHC) for TP53 has been established as a proxy for the TP53 mutation status in other ovarian tumor types. We aimed to confirm the ability of TP53 IHC to predict TP53 mutation status in ovarian mucinous tumors and to evaluate the association of TP53 mutation status with survival among patients with MBOT and MOC. Tumor tissue from an initial cohort of 113 women with MBOT/MOC was stained with optimized IHC for TP53 using tissue microarrays (75.2%) or full sections (24.8%) and interpreted using established criteria as normal or abnormal (overexpression, complete absence, or cytoplasmic). Cases were considered concordant if abnormal IHC staining predicted deleterious TP53 mutations. Discordant tissue microarray cases were re-evaluated on full sections and interpretational criteria were refined. The initial cohort was expanded to a total of 165 MBOT and 424 MOC for the examination of the association of survival with TP53 mutation status, assessed either by TP53 IHC and/or sequencing. Initially, 82/113 (72.6%) cases were concordant using the established criteria. Refined criteria for overexpression to account for intratumoral heterogeneity and terminal differentiation improved concordance to 93.8% (106/113). In the expanded cohort, 19.4% (32/165) of MBOT showed evidence for TP53 mutation and this was associated with a higher risk of recurrence, disease-specific death, and all-cause mortality (overall survival: HR = 4.6, 95% CI 1.5-14.3, p = 0.0087). Within MOC, 61.1% (259/424) harbored a TP53 mutation, but this was not associated with survival (overall survival, p = 0.77). TP53 IHC is an accurate proxy for TP53 mutation status with refined interpretation criteria accounting for intratumoral heterogeneity and terminal differentiation in ovarian mucinous tumors. TP53 mutation status is an important biomarker to identify MB
Published: 2021

10. Prognostic gene expression signature for high-grade serous ovarian cancer

Author: Millstein, J., primary, Budden, T., additional, Goode, E.L., additional, Anglesio, M.S., additional, Talhouk, A., additional, Intermaggio, M.P., additional, Leong, H.S., additional, Chen, S., additional, Elatre, W., additional, Gilks, B., additional, Nazeran, T., additional, Volchek, M., additional, Bentley, R.C., additional, Wang, C., additional, Chiu, D.S., additional, Kommoss, S., additional, Leung, S.C.Y., additional, Senz, J., additional, Lum, A., additional, Chow, V., additional, Sudderuddin, H., additional, Mackenzie, R., additional, George, J., additional, Fereday, S., additional, Hendley, J., additional, Traficante, N., additional, Steed, H., additional, Koziak, J.M., additional, Köbel, M., additional, McNeish, I.A., additional, Goranova, T., additional, Ennis, D., additional, Macintyre, G., additional, Silva De Silva, D., additional, Ramón y Cajal, T., additional, García-Donas, J., additional, Hernando Polo, S., additional, Rodriguez, G.C., additional, Cushing-Haugen, K.L., additional, Harris, H.R., additional, Greene, C.S., additional, Zelaya, R.A., additional, Behrens, S., additional, Fortner, R.T., additional, Sinn, P., additional, Herpel, E., additional, Lester, J., additional, Lubiński, J., additional, Oszurek, O., additional, Tołoczko, A., additional, Cybulski, C., additional, Menkiszak, J., additional, Pearce, C.L., additional, Pike, M.C., additional, Tseng, C., additional, Alsop, J., additional, Rhenius, V., additional, Song, H., additional, Jimenez-Linan, M., additional, Piskorz, A.M., additional, Gentry-Maharaj, A., additional, Karpinskyj, C., additional, Widschwendter, M., additional, Singh, N., additional, Kennedy, C.J., additional, Sharma, R., additional, Harnett, P.R., additional, Gao, B., additional, Johnatty, S.E., additional, Sayer, R., additional, Boros, J., additional, Winham, S.J., additional, Keeney, G.L., additional, Kaufmann, S.H., additional, Larson, M.C., additional, Luk, H., additional, Hernandez, B.Y., additional, Thompson, P.J., additional, Wilkens, L.R., additional, Carney, M.E., additional, Trabert, B., additional, Lissowska, J., additional, Brinton, L., additional, Sherman, M.E., additional, Bodelon, C., additional, Hinsley, S., additional, Lewsley, L.A., additional, Glasspool, R., additional, Banerjee, S.N., additional, Stronach, E.A., additional, Haluska, P., additional, Ray-Coquard, I., additional, Mahner, S., additional, Winterhoff, B., additional, Slamon, D., additional, Levine, D.A., additional, Kelemen, L.E., additional, Benitez, J., additional, Chang-Claude, J., additional, Gronwald, J., additional, Wu, A.H., additional, Menon, U., additional, Goodman, M.T., additional, Schildkraut, J.M., additional, Wentzensen, N., additional, Brown, R., additional, Berchuck, A., additional, Chenevix-Trench, G., additional, deFazio, A., additional, Gayther, S.A., additional, García, M.J., additional, Henderson, M.J., additional, Rossing, M.A., additional, Beeghly-Fadiel, A., additional, Fasching, P.A., additional, Orsulic, S., additional, Karlan, B.Y., additional, Konecny, G.E., additional, Huntsman, D.G., additional, Bowtell, D.D., additional, Brenton, J.D., additional, Doherty, J.A., additional, Pharoah, P.D.P., additional, Ramus, S.J., additional, Bowtell, D., additional, Green, A., additional, Webb, P., additional, DeFazio, A., additional, Gertig, D., additional, Moore, S., additional, Hung, J., additional, Harrap, K., additional, Sadkowsky, T., additional, Pandeya, N., additional, Malt, M., additional, Mellon, A., additional, Robertson, R., additional, Vanden Bergh, T., additional, Jones, M., additional, Mackenzie, P., additional, Maidens, J., additional, Nattress, K., additional, Chiew, Y.E., additional, Stenlake, A., additional, Sullivan, H., additional, Alexander, B., additional, Ashover, P., additional, Brown, S., additional, Corrish, T., additional, Green, L., additional, Jackman, L., additional, Ferguson, K., additional, Martin, K., additional, Martyn, A., additional, Ranieri, B., additional, White, J., additional, Jayde, V., additional, Mamers, P., additional, Bowes, L., additional, Galletta, L., additional, Giles, D., additional, Alsop, K., additional, Schmidt, T., additional, Shirley, H., additional, Ball, C., additional, Young, C., additional, Viduka, S., additional, Tran, Hoa, additional, Bilic, Sanela, additional, Glavinas, Lydia, additional, Brooks, Julia, additional, Stuart-Harris, R., additional, Kirsten, F., additional, Rutovitz, J., additional, Clingan, P., additional, Glasgow, A., additional, Proietto, A., additional, Braye, S., additional, Otton, G., additional, Shannon, J., additional, Bonaventura, T., additional, Stewart, J., additional, Begbie, S., additional, Friedlander, M., additional, Bell, D., additional, Baron-Hay, S., additional, Ferrier,a, A., additional, Gard, G., additional, Nevell, D., additional, Pavlakis, N., additional, Valmadre, S., additional, Young, B., additional, Camaris, C., additional, Crouch, R., additional, Edwards, L., additional, Hacker, N., additional, Marsden, D., additional, Robertson, G., additional, Beale, P., additional, Beith, J., additional, Carter, J., additional, Dalrymple, C., additional, Houghton, R., additional, Russell, P., additional, Links, M., additional, Grygiel, J., additional, Hill, J., additional, Brand, A., additional, Byth, K., additional, Jaworski, R., additional, Harnett, P., additional, Wain, G., additional, Ward, B., additional, Papadimos, D., additional, Crandon, A., additional, Cummings, M., additional, Horwood, K., additional, Obermair, A., additional, Perrin, L., additional, Wyld, D., additional, Nicklin, J., additional, Davy, M., additional, Oehler, M.K., additional, Hall, C., additional, Dodd, T., additional, Healy, T., additional, Pittman, K., additional, Henderson, D., additional, Miller, J., additional, Pierdes, J., additional, Blomfield, P., additional, Challis, D., additional, McIntosh, R., additional, Parker, A., additional, Brown, B., additional, Rome, R., additional, Allen, D., additional, Grant, P., additional, Hyde, S., additional, Laurie, R., additional, Robbie, M., additional, Healy, D., additional, Jobling, T., additional, Manolitsas, T., additional, McNealage, J., additional, Rogers, P., additional, Susil, B., additional, Sumithran, E., additional, Simpson, I., additional, Phillips, K., additional, Rischin, D., additional, Fox, S., additional, Johnson, D., additional, Lade, S., additional, Loughrey, M., additional, O’Callaghan, N., additional, Murray, W., additional, Waring, P., additional, Billson, V., additional, Pyman, J., additional, Neesham, D., additional, Quinn, M., additional, Underhill, C., additional, Bell, R., additional, Ng, L.F., additional, Blum, R., additional, Ganju, V., additional, Hammond, I., additional, Leung, Y., additional, McCartney, A., additional, Buck, M., additional, Haviv, I., additional, Purdie, D., additional, Whiteman, D., additional, and Zeps, N., additional
Published: 2020
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11. Mendelian Randomization and mediation analysis of leukocyte telomere length and risk of lung and head and neck cancers

Author: Kachuri, L. Saarela, O. Bojesen, S.E. Davey Smith, G. Liu, G. Landi, M.T. Caporaso, N.E. Christiani, D.C. Johansson, M. Panico, S. Overvad, K. Trichopoulou, A. Vineis, P. Scelo, G. Zaridze, D. Wu, X. Albanes, D. Diergaarde, B. Lagiou, P. Macfarlane, G.J. Aldrich, M.C. Tardón, A. Rennert, G. Olshan, A.F. Weissler, M.C. Chen, C. Goodman, G.E. Doherty, J.A. Ness, A.R. Bickeböller, H. Wichmann, H.-E. Risch, A. Field, J.K. Teare, M.D. Kiemeney, L.A. Van Der Heijden, E.H.F.M. Carroll, J.C. Haugen, A. Zienolddiny, S. Skaug, V. Wünsch-Filho, V. Tajara, E.H. Ayoub Moysés, R. Daumas Nunes, F. Lam, S. Eluf-Neto, J. Lacko, M. Peters, W.H.M. Le Marchand, L. Duell, E.J. Andrew, A.S. Franceschi, S. Schabath, M.B. Manjer, J. Arnold, S. Lazarus, P. Mukeriya, A. Swiatkowska, B. Janout, V. Holcatova, I. Stojsic, J. Mates, D. Lissowska, J. Boccia, S. Lesseur, C. Zong, X. McKay, J.D. Brennan, P. Amos, C.I. Hung, R.J.
Abstract: Background: Evidence from observational studies of telomere length (TL) has been conflicting regarding its direction of association with cancer risk. We investigated the causal relevance of TL for lung and head and neck cancers using Mendelian Randomization (MR) and mediation analyses. Methods: We developed a novel genetic instrument for TL in chromosome 5p15.33, using variants identified through deep-sequencing, that were genotyped in 2051 cancer-free subjects. Next, we conducted an MR analysis of lung (16 396 cases, 13 013 controls) and head and neck cancer (4415 cases, 5013 controls) using eight genetic instruments for TL. Lastly, the 5p15.33 instrument and distinct 5p15.33 lung cancer risk loci were evaluated using two-sample mediation analysis, to quantify their direct and indirect, telomere-mediated, effects. Results: The multi-allelic 5p15.33 instrument explained 1.49-2.00% of TL variation in our data (p = 2.6 × 10-9). The MR analysis estimated that a 1000 base-pair increase in TL increases risk of lung cancer [odds ratio (OR) = 1.41, 95% confidence interval (CI): 1.20-1.65] and lung adenocarcinoma (OR = 1.92, 95% CI: 1.51-2.22), but not squamous lung carcinoma (OR = 1.04, 95% CI: 0.83-1.29) or head and neck cancers (OR = 0.90, 95% CI: 0.70-1.05). Mediation analysis of the 5p15.33 instrument indicated an absence of direct effects on lung cancer risk (OR = 1.00, 95% CI: 0.95-1.04). Analysis of distinct 5p15.33 susceptibility variants estimated that TL mediates up to 40% of the observed associations with lung cancer risk. Conclusions: Our findings support a causal role for long telomeres in lung cancer aetiology, particularly for adenocarcinoma, and demonstrate that telomere maintenance partially mediates the lung cancer susceptibility conferred by 5p15.33 loci. © 2018 The Author(s) 2018; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.
Published: 2019

12. Mendelian Randomization and mediation analysis of leukocyte telomere length and risk of lung and head and neck cancers

Author: Kachuri, L., Saarela, O., Bojesen, S.E., Smith, G., Liu, G., Landi, M.T., Caporaso, N.E., Christiani, D.C., Johansson, M., Panico, S., Overvad, K., Trichopoulou, A., Vineis, P., Scelo, G., Zaridze, D., Wu, X., Albanes, D., Diergaarde, B., Lagiou, P., Macfarlane, G.J., Aldrich, M.C., Tardon, A., Rennert, G., Olshan, A.F., Weissler, M.C., Chen, C, Goodman, G.E., Doherty, J.A., Ness, A.R., Bickeboller, H., Wichmann, H.E., Risch, A., Field, J.K., Teare, M.D., Kiemeney, L.A.L.M., Heijden, E. van der, Carroll, J.C., Haugen, A., Zienolddiny, S., Skaug, V., Wunsch-Filho, V., Tajara, E.H., Moyses, R. Ayoub, Nunes, F. Daumas, Lam, S., Eluf-Neto, J., Lacko, M., Peters, W.H.M., Marchand, L. Le, Duell, E.J., Andrew, A.S., Franceschi, S., Schabath, M.B., Manjer, J., Arnold, S, Lazarus, P., Mukeriya, A., Swiatkowska, B., Janout, V., Holcatova, I., Stojsic, J., Mates, D., Lissowska, J., Boccia, S., Lesseur, C., Zong, X., McKay, J.D., Brennan, P., Amos, C.I., Hung, R.J., Kachuri, L., Saarela, O., Bojesen, S.E., Smith, G., Liu, G., Landi, M.T., Caporaso, N.E., Christiani, D.C., Johansson, M., Panico, S., Overvad, K., Trichopoulou, A., Vineis, P., Scelo, G., Zaridze, D., Wu, X., Albanes, D., Diergaarde, B., Lagiou, P., Macfarlane, G.J., Aldrich, M.C., Tardon, A., Rennert, G., Olshan, A.F., Weissler, M.C., Chen, C, Goodman, G.E., Doherty, J.A., Ness, A.R., Bickeboller, H., Wichmann, H.E., Risch, A., Field, J.K., Teare, M.D., Kiemeney, L.A.L.M., Heijden, E. van der, Carroll, J.C., Haugen, A., Zienolddiny, S., Skaug, V., Wunsch-Filho, V., Tajara, E.H., Moyses, R. Ayoub, Nunes, F. Daumas, Lam, S., Eluf-Neto, J., Lacko, M., Peters, W.H.M., Marchand, L. Le, Duell, E.J., Andrew, A.S., Franceschi, S., Schabath, M.B., Manjer, J., Arnold, S, Lazarus, P., Mukeriya, A., Swiatkowska, B., Janout, V., Holcatova, I., Stojsic, J., Mates, D., Lissowska, J., Boccia, S., Lesseur, C., Zong, X., McKay, J.D., Brennan, P., Amos, C.I., and Hung, R.J.
Abstract: Contains fulltext : 208363.pdf (publisher's version ) (Closed access), BACKGROUND: Evidence from observational studies of telomere length (TL) has been conflicting regarding its direction of association with cancer risk. We investigated the causal relevance of TL for lung and head and neck cancers using Mendelian Randomization (MR) and mediation analyses. METHODS: We developed a novel genetic instrument for TL in chromosome 5p15.33, using variants identified through deep-sequencing, that were genotyped in 2051 cancer-free subjects. Next, we conducted an MR analysis of lung (16 396 cases, 13 013 controls) and head and neck cancer (4415 cases, 5013 controls) using eight genetic instruments for TL. Lastly, the 5p15.33 instrument and distinct 5p15.33 lung cancer risk loci were evaluated using two-sample mediation analysis, to quantify their direct and indirect, telomere-mediated, effects. RESULTS: The multi-allelic 5p15.33 instrument explained 1.49-2.00% of TL variation in our data (p = 2.6 x 10-9). The MR analysis estimated that a 1000 base-pair increase in TL increases risk of lung cancer [odds ratio (OR) = 1.41, 95% confidence interval (CI): 1.20-1.65] and lung adenocarcinoma (OR = 1.92, 95% CI: 1.51-2.22), but not squamous lung carcinoma (OR = 1.04, 95% CI: 0.83-1.29) or head and neck cancers (OR = 0.90, 95% CI: 0.70-1.05). Mediation analysis of the 5p15.33 instrument indicated an absence of direct effects on lung cancer risk (OR = 1.00, 95% CI: 0.95-1.04). Analysis of distinct 5p15.33 susceptibility variants estimated that TL mediates up to 40% of the observed associations with lung cancer risk. CONCLUSIONS: Our findings support a causal role for long telomeres in lung cancer aetiology, particularly for adenocarcinoma, and demonstrate that telomere maintenance partially mediates the lung cancer susceptibility conferred by 5p15.33 loci.
Published: 2019

13. A comprehensive gene-environment interaction analysis in Ovarian Cancer using genome-wide significant common variants.

Author: Kjaer S.K., Bandera E.V., Cook L.S., Cramer D.W., Milne R.L., Winham S.J., Modugno F., Mukherjee B., Pearce C.L., Pharoah P.D.P., Pike M.C., Huntsman D., Hogdall E., Trabert B., Wentzensen N., Le N.D., Schildkraut J.M., Harris H.R., Chang-Claude J., Thompson P.J., Kim S., Wang M., Tyrer J.P., Jensen A., Wiensch A., Liu G., Lee A.W., Ness R.B., Salvatore M., Tworoger S.S., Whittemore A.S., Anton-Culver H., Sieh W., Olson S.H., Berchuck A., Goode E.L., Goodman M.T., Doherty J.A., Chenevix-Trench G., Rossing M.A., Webb P.M., Giles G.G., Terry K.L., Ziogas A., Fortner R.T., Menon U., Gayther S.A., Wu A.H., Song H., Brooks-Wilson A., Kjaer S.K., Bandera E.V., Cook L.S., Cramer D.W., Milne R.L., Winham S.J., Modugno F., Mukherjee B., Pearce C.L., Pharoah P.D.P., Pike M.C., Huntsman D., Hogdall E., Trabert B., Wentzensen N., Le N.D., Schildkraut J.M., Harris H.R., Chang-Claude J., Thompson P.J., Kim S., Wang M., Tyrer J.P., Jensen A., Wiensch A., Liu G., Lee A.W., Ness R.B., Salvatore M., Tworoger S.S., Whittemore A.S., Anton-Culver H., Sieh W., Olson S.H., Berchuck A., Goode E.L., Goodman M.T., Doherty J.A., Chenevix-Trench G., Rossing M.A., Webb P.M., Giles G.G., Terry K.L., Ziogas A., Fortner R.T., Menon U., Gayther S.A., Wu A.H., Song H., and Brooks-Wilson A.
Abstract: As a follow-up to genome-wide association analysis of common variants associated with ovarian carcinoma (cancer), our study considers seven well-known ovarian cancer risk factors and their interactions with 28 genome-wide significant common genetic variants. The interaction analyses were based on data from 9971 ovarian cancer cases and 15,566 controls from 17 case-control studies. Likelihood ratio and Wald tests for multiplicative interaction and for relative excess risk due to additive interaction were used. The top multiplicative interaction was noted between oral contraceptive pill (OCP) use (ever vs. never) and rs13255292 (p value = 3.48 x 10-4). Among women with the TT genotype for this variant, the odds ratio for OCP use was 0.53 (95% CI = 0.46-0.60) compared to 0.71 (95%CI = 0.66-0.77) for women with the CC genotype. When stratified by duration of OCP use, women with 1-5 years of OCP use exhibited differential protective benefit across genotypes. However, no interaction on either the multiplicative or additive scale was found to be statistically significant after multiple testing correction. The results suggest that OCP use may offer increased benefit for women who are carriers of the T allele in rs13255292. On the other hand, for women carrying the C allele in this variant, longer (5+ years) use of OCP may reduce the impact of carrying the risk allele of this SNP. Replication of this finding is needed. The study presents a comprehensive analytic framework for conducting gene-environment analysis in ovarian cancer.Copyright © 2018 UICC
Published: 2019

14. Genetic modifiers of radon-induced lung cancer risk: a genome-wide interaction study in former uranium miners

Author: Rosenberger, A., Hung, R.J., Christiani, D.C., Caporaso, N.E., Liu, G., Bojesen, S.E., Marchand, L. Le, Haiman, C.A., Albanes, D., Aldrich, M.C., Tardon, A., Fernandez-Tardon, G., Rennert, G., Field, J.K., Kiemeney, B., Lazarus, P., Haugen, A., Zienolddiny, S., Lam, S., Schabath, M.B., Andrew, A.S., Brunnsstom, H., Goodman, G.E., Doherty, J.A., Chen, C, Teare, M.D., Wichmann, H.E., Manz, J., Risch, A., Muley, T.R., Johansson, M., Brennan, P., Landi, M.T., Amos, C.I., Pesch, B., Johnen, G., Bruning, T., Bickeboller, H., Gomolka, M., Rosenberger, A., Hung, R.J., Christiani, D.C., Caporaso, N.E., Liu, G., Bojesen, S.E., Marchand, L. Le, Haiman, C.A., Albanes, D., Aldrich, M.C., Tardon, A., Fernandez-Tardon, G., Rennert, G., Field, J.K., Kiemeney, B., Lazarus, P., Haugen, A., Zienolddiny, S., Lam, S., Schabath, M.B., Andrew, A.S., Brunnsstom, H., Goodman, G.E., Doherty, J.A., Chen, C, Teare, M.D., Wichmann, H.E., Manz, J., Risch, A., Muley, T.R., Johansson, M., Brennan, P., Landi, M.T., Amos, C.I., Pesch, B., Johnen, G., Bruning, T., Bickeboller, H., and Gomolka, M.
Abstract: Item does not contain fulltext, PURPOSE: Radon is a risk factor for lung cancer and uranium miners are more exposed than the general population. A genome-wide interaction analysis was carried out to identify genomic loci, genes or gene sets that modify the susceptibility to lung cancer given occupational exposure to the radioactive gas radon. METHODS: Samples from 28 studies provided by the International Lung Cancer Consortium were pooled with samples of former uranium miners collected by the German Federal Office of Radiation Protection. In total, 15,077 cases and 13,522 controls, all of European ancestries, comprising 463 uranium miners were compared. The DNA of all participants was genotyped with the OncoArray. We fitted single-marker and in multi-marker models and performed an exploratory gene-set analysis to detect cumulative enrichment of significance in sets of genes. RESULTS: We discovered a genome-wide significant interaction of the marker rs12440014 within the gene CHRNB4 (OR = 0.26, 95% CI 0.11-0.60, p = 0.0386 corrected for multiple testing). At least suggestive significant interaction of linkage disequilibrium blocks was observed at the chromosomal regions 18q21.23 (p = 1.2 x 10(-6)), 5q23.2 (p = 2.5 x 10(-6)), 1q21.3 (p = 3.2 x 10(-6)), 10p13 (p = 1.3 x 10(-5)) and 12p12.1 (p = 7.1 x 10(-5)). Genes belonging to the Gene Ontology term "DNA dealkylation involved in DNA repair" (GO:0006307; p = 0.0139) or the gene family HGNC:476 "microRNAs" (p = 0.0159) were enriched with LD-blockwise significance. CONCLUSION: The well-established association of the genomic region 15q25 to lung cancer might be influenced by exposure to radon among uranium miners. Furthermore, lung cancer susceptibility is related to the functional capability of DNA damage signaling via ubiquitination processes and repair of radiation-induced double-strand breaks by the single-strand annealing mechanism.
Published: 2018

15. rs495139 in the TYMS-ENOSF1 Region and Risk of Ovarian Carcinoma of Mucinous Histology

Author: Kelemen, L.E., Earp, M., Fridley, B.L., Chenevix-Trench, G., Fasching, P.A., Beckmann, M.W., Ekici, A.B., Hein, A., Lambrechts, D., Lambrechts, S., Nieuwenhuysen, E. Van, Vergote, I., Rossing, M.A., Doherty, J.A., Chang-Claude, J., Behrens, S., Moysich, K.B., Cannioto, R., Lele, S., Odunsi, K., Goodman, M.T., Shvetsov, Y.B., Thompson, P.J., Wilkens, L.R., Dork, T., Antonenkova, N., Bogdanova, N., Hillemanns, P., Runnebaum, I.B., Bois, A. du, Harter, P., Heitz, F., Schwaab, I., Butzow, R., Pelttari, L.M., Nevanlinna, H., Modugno, F., Edwards, R.P., Kelley, J.L., Ness, R.B., Karlan, B.Y., Lester, J., Orsulic, S., Walsh, C., Kjaer, S.K., Jensen, A., Cunningham, J.M., Vierkant, R.A., Giles, G.G., Bruinsma, F., Southey, M.C., Hildebrandt, M.A., Liang, D., Lu, K., Wu, X., Sellers, T.A., Levine, D.A., Schildkraut, J.M., Iversen, E.S., Terry, K.L., Cramer, D.W, Tworoger, S.S., Poole, E.M., Bandera, E.V., Olson, S.H., Orlow, I., Thomsen, L.C., Bjorge, L., Krakstad, C., Tangen, I.L., Kiemeney, L.A.L.M., Aben, K.K.H., Massuger, L.F., Altena, A.M. van, Pejovic, T., Bean, Y., Kellar, M., Cook, L.S., Le, N.D., Brooks-Wilson, A., Gronwald, J., Cybulski, C., Jakubowska, A., Lubinski, J., Wentzensen, N., Brinton, L.A., Lissowska, J., Hogdall, E., Engelholm, S.A., Hogdall, C., Lundvall, L., Nedergaard, L., Pharoah, P.D., Dicks, E., Song, H., Tyrer, J.P., McNeish, I., Siddiqui, N., Carty, K., Goode, E.L., Berchuck, A., Kelemen, L.E., Earp, M., Fridley, B.L., Chenevix-Trench, G., Fasching, P.A., Beckmann, M.W., Ekici, A.B., Hein, A., Lambrechts, D., Lambrechts, S., Nieuwenhuysen, E. Van, Vergote, I., Rossing, M.A., Doherty, J.A., Chang-Claude, J., Behrens, S., Moysich, K.B., Cannioto, R., Lele, S., Odunsi, K., Goodman, M.T., Shvetsov, Y.B., Thompson, P.J., Wilkens, L.R., Dork, T., Antonenkova, N., Bogdanova, N., Hillemanns, P., Runnebaum, I.B., Bois, A. du, Harter, P., Heitz, F., Schwaab, I., Butzow, R., Pelttari, L.M., Nevanlinna, H., Modugno, F., Edwards, R.P., Kelley, J.L., Ness, R.B., Karlan, B.Y., Lester, J., Orsulic, S., Walsh, C., Kjaer, S.K., Jensen, A., Cunningham, J.M., Vierkant, R.A., Giles, G.G., Bruinsma, F., Southey, M.C., Hildebrandt, M.A., Liang, D., Lu, K., Wu, X., Sellers, T.A., Levine, D.A., Schildkraut, J.M., Iversen, E.S., Terry, K.L., Cramer, D.W, Tworoger, S.S., Poole, E.M., Bandera, E.V., Olson, S.H., Orlow, I., Thomsen, L.C., Bjorge, L., Krakstad, C., Tangen, I.L., Kiemeney, L.A.L.M., Aben, K.K.H., Massuger, L.F., Altena, A.M. van, Pejovic, T., Bean, Y., Kellar, M., Cook, L.S., Le, N.D., Brooks-Wilson, A., Gronwald, J., Cybulski, C., Jakubowska, A., Lubinski, J., Wentzensen, N., Brinton, L.A., Lissowska, J., Hogdall, E., Engelholm, S.A., Hogdall, C., Lundvall, L., Nedergaard, L., Pharoah, P.D., Dicks, E., Song, H., Tyrer, J.P., McNeish, I., Siddiqui, N., Carty, K., Goode, E.L., and Berchuck, A.
Abstract: Contains fulltext : 195643.pdf (publisher's version ) (Open Access), Thymidylate synthase (TYMS) is a crucial enzyme for DNA synthesis. TYMS expression is regulated by its antisense mRNA, ENOSF1. Disrupted regulation may promote uncontrolled DNA synthesis and tumor growth. We sought to replicate our previously reported association between rs495139 in the TYMS-ENOSF1 3' gene region and increased risk of mucinous ovarian carcinoma (MOC) in an independent sample. Genotypes from 24,351 controls to 15,000 women with invasive OC, including 665 MOC, were available. We estimated per-allele odds ratios (OR) and 95% confidence intervals (CI) using unconditional logistic regression, and meta-analysis when combining these data with our previous report. The association between rs495139 and MOC was not significant in the independent sample (OR = 1.09; 95% CI = 0.97(-)1.22; p = 0.15; N = 665 cases). Meta-analysis suggested a weak association (OR = 1.13; 95% CI = 1.03(-)1.24; p = 0.01; N = 1019 cases). No significant association with risk of other OC histologic types was observed (p = 0.05 for tumor heterogeneity). In expression quantitative trait locus (eQTL) analysis, the rs495139 allele was positively associated with ENOSF1 mRNA expression in normal tissues of the gastrointestinal system, particularly esophageal mucosa (r = 0.51, p = 1.7 x 10(-28)), and nonsignificantly in five MOC tumors. The association results, along with inconclusive tumor eQTL findings, suggest that a true effect of rs495139 might be small.
Published: 2018

16. Identification of nine new susceptibility loci for endometrial cancer.

Author: Fung J., Chanock S.J., Chen C., Chen M.M., Ashton K., Milne R.L., Mints M., Montgomery G.W., Nassir R., Olsson H., Orlow I., Otton G., Palles C., Perry J.R.B., Peto J., Pooler L., Prescott J., Proietto T., Rebbeck T.R., Risch H.A., Rogers P.A.W., Rubner M., Runnebaum I., Sacerdote C., Sarto G.E., Schumacher F., Scott R.J., Setiawan V.W., Shah M., Sheng X., Shu X.-O., Southey M.C., Swerdlow A.J., Tham E., Trovik J., Turman C., Tyrer J.P., Vachon C., VanDen Berg D., Vanderstichele A., Wang Z., Webb P.M., Wentzensen N., Werner H.M.J., Winham S.J., Wolk A., Xia L., Xiang Y.-B., Yang H.P., Yu H., Zheng W., Pharoah P.D.P., Dunning A.M., Kraft P., De Vivo I., Tomlinson I., Easton D.F., Spurdle A.B., Thompson D.J., Jones A., O'Mara T.A., Glubb D.M., Amant F., Annibali D., Attia J., Auer P.L., Beckmann M.W., Black A., Bolla M.K., Brauch H., Brenner H., Brinton L., Buchanan D.D., Burwinkel B., Cheng T.H.T., Clarke C.L., Clendenning M., Cook L.S., Couch F.J., Cox A., Crous-Bous M., Czene K., Day F., Dennis J., Depreeuw J., Doherty J.A., Dork T., Dowdy S.C., Durst M., Ekici A.B., Fasching P.A., Fridley B.L., Friedenreich C.M., Fritschi L., Chang-Claude J., Garcia-Closas M., Gaudet M.M., Giles G.G., Goode E.L., Gorman M., Haiman C.A., Hall P., Hankison S.E., Healey C.S., Hein A., Hillemanns P., Hodgson S., Hoivik E.A., Holliday E.G., Hopper J.L., Hunter D.J., Krakstad C., Kristensen V.N., Lambrechts D., Marchand L.L., Liang X., Lindblom A., Lissowska J., Long J., Lu L., Magliocco A.M., Martin L., McEvoy M., Meindl A., Michailidou K., Fung J., Chanock S.J., Chen C., Chen M.M., Ashton K., Milne R.L., Mints M., Montgomery G.W., Nassir R., Olsson H., Orlow I., Otton G., Palles C., Perry J.R.B., Peto J., Pooler L., Prescott J., Proietto T., Rebbeck T.R., Risch H.A., Rogers P.A.W., Rubner M., Runnebaum I., Sacerdote C., Sarto G.E., Schumacher F., Scott R.J., Setiawan V.W., Shah M., Sheng X., Shu X.-O., Southey M.C., Swerdlow A.J., Tham E., Trovik J., Turman C., Tyrer J.P., Vachon C., VanDen Berg D., Vanderstichele A., Wang Z., Webb P.M., Wentzensen N., Werner H.M.J., Winham S.J., Wolk A., Xia L., Xiang Y.-B., Yang H.P., Yu H., Zheng W., Pharoah P.D.P., Dunning A.M., Kraft P., De Vivo I., Tomlinson I., Easton D.F., Spurdle A.B., Thompson D.J., Jones A., O'Mara T.A., Glubb D.M., Amant F., Annibali D., Attia J., Auer P.L., Beckmann M.W., Black A., Bolla M.K., Brauch H., Brenner H., Brinton L., Buchanan D.D., Burwinkel B., Cheng T.H.T., Clarke C.L., Clendenning M., Cook L.S., Couch F.J., Cox A., Crous-Bous M., Czene K., Day F., Dennis J., Depreeuw J., Doherty J.A., Dork T., Dowdy S.C., Durst M., Ekici A.B., Fasching P.A., Fridley B.L., Friedenreich C.M., Fritschi L., Chang-Claude J., Garcia-Closas M., Gaudet M.M., Giles G.G., Goode E.L., Gorman M., Haiman C.A., Hall P., Hankison S.E., Healey C.S., Hein A., Hillemanns P., Hodgson S., Hoivik E.A., Holliday E.G., Hopper J.L., Hunter D.J., Krakstad C., Kristensen V.N., Lambrechts D., Marchand L.L., Liang X., Lindblom A., Lissowska J., Long J., Lu L., Magliocco A.M., Martin L., McEvoy M., Meindl A., and Michailidou K.
Abstract: Endometrial cancer is the most commonly diagnosed cancer of the female reproductive tract in developed countries. Through genome-wide association studies (GWAS), we have previously identified eight risk loci for endometrial cancer. Here, we present an expanded meta-analysis of 12,906 endometrial cancer cases and 108,979 controls (including new genotype data for 5624 cases) and identify nine novel genome-wide significant loci, including a locus on 12q24.12 previously identified by meta-GWAS of endometrial and colorectal cancer. At five loci, expression quantitative trait locus (eQTL) analyses identify candidate causal genes; risk alleles at two of these loci associate with decreased expression of genes, which encode negative regulators of oncogenic signal transduction proteins (SH2B3 (12q24.12) and NF1 (17q11.2)). In summary, this study has doubled the number of known endometrial cancer risk loci and revealed candidate causal genes for future study.Copyright © 2018, The Author(s).
Published: 2018

17. Cigarette smoking is associated with adverse survival among women with ovarian cancer: Results from a pooled analysis of 19 studies

Author: Praestegaard, C., Jensen, A., Jensen, S.M., Nielsen, T.S., Webb, P.M., Nagle, C.M., Defazio, A., Hogdall, E., Rossing, M.A., Doherty, J.A., Wicklund, K.G., Goodman, M.T., Modugno, F., Moysich, K., Ness, R.B., Edwards, R., Matsuo, K., Hosono, S., Goode, E.L., Winham, S.J., Fridley, B.L., Cramer, D.W, Terry, K.L., Schildkraut, J.M., Berchuck, A., Bandera, E.V., Paddock, L.E., Massuger, L.F.A.G., Wentzensen, N., Pharoah, P., Song, H., Whittemore, A., McGuire, V., Sieh, W., Rothstein, J., Anton-Culver, H., Ziogas, A., Menon, U., Gayther, S.A., Ramus, S.J., Gentry-Maharaj, A., Wu, A.H., Pearce, C.L., Pike, M., Lee, A.W., Sutphen, R., Chang-Claude, J., Risch, H.A., Kjaer, S.K., Praestegaard, C., Jensen, A., Jensen, S.M., Nielsen, T.S., Webb, P.M., Nagle, C.M., Defazio, A., Hogdall, E., Rossing, M.A., Doherty, J.A., Wicklund, K.G., Goodman, M.T., Modugno, F., Moysich, K., Ness, R.B., Edwards, R., Matsuo, K., Hosono, S., Goode, E.L., Winham, S.J., Fridley, B.L., Cramer, D.W, Terry, K.L., Schildkraut, J.M., Berchuck, A., Bandera, E.V., Paddock, L.E., Massuger, L.F.A.G., Wentzensen, N., Pharoah, P., Song, H., Whittemore, A., McGuire, V., Sieh, W., Rothstein, J., Anton-Culver, H., Ziogas, A., Menon, U., Gayther, S.A., Ramus, S.J., Gentry-Maharaj, A., Wu, A.H., Pearce, C.L., Pike, M., Lee, A.W., Sutphen, R., Chang-Claude, J., Risch, H.A., and Kjaer, S.K.
Abstract: Contains fulltext : 174714.pdf (publisher's version ) (Closed access), Cigarette smoking is associated with an increased risk of developing mucinous ovarian tumors but whether it is associated with ovarian cancer survival overall or for the different histotypes is unestablished. Furthermore, it is unknown whether the association between cigarette smoking and survival differs according to strata of ovarian cancer stage at diagnosis. In a large pooled analysis, we evaluated the association between various measures of cigarette smoking and survival among women with epithelial ovarian cancer. We obtained data from 19 case-control studies in the Ovarian Cancer Association Consortium (OCAC), including 9,114 women diagnosed with ovarian cancer. Cox regression models were used to estimate adjusted study-specific hazard ratios (HRs), which were combined into pooled hazard ratios (pHR) with corresponding 95% confidence intervals (CIs) under random effects models. Overall, 5,149 (57%) women died during a median follow-up period of 7.0 years. Among women diagnosed with ovarian cancer, both current (pHR = 1.17, 95% CI: 1.08-1.28) and former smokers (pHR = 1.10, 95% CI: 1.02-1.18) had worse survival compared with never smoking women. In histotype-stratified analyses, associations were observed for mucinous (current smoking: pHR = 1.91, 95% CI: 1.01-3.65) and serous histotypes (current smoking: pHR = 1.11, 95% CI: 1.00-1.23; former smoking: pHR = 1.12, 95% CI: 1.04-1.20). Further, our results suggested that current smoking has a greater impact on survival among women with localized than disseminated disease. The identification of cigarette smoking as a modifiable factor associated with survival has potential clinical importance as a focus area to improve ovarian cancer prognosis.
Published: 2017

18. Identification of 12 new susceptibility loci for different histotypes of epithelial ovarian cancer

Author: Phelan, C.M., Kuchenbaecker, K.B., Tyrer, J.P., Kar, S.P., Lawrenson, K., Winham, S.J., Dennis, J., Pirie, A., Riggan, M.J., Chornokur, G., Earp, M.A., Lyra, P.C., Jr., Lee, J.M., Coetzee, S., Beesley, J., McGuffog, L., Soucy, P., Dicks, E., Lee, A., Barrowdale, D., Lecarpentier, J., Leslie, G., Aalfs, C.M., Aben, K.K.H., Adams, M., Adlard, J., Andrulis, I.L., Anton-Culver, H., Antonenkova, N., Aravantinos, G., Arnold, N., Arun, B.K., Arver, B., Azzollini, J., Balmana, J., Banerjee, S.N., Barjhoux, L., Barkardottir, R.B., Bean, Y., Beckmann, M.W., Beeghly-Fadiel, A., Benitez, J., Bermisheva, M., Bernardini, M.Q., Birrer, M.J., Bjorge, L., Black, A., Blankstein, K., Blok, M.J., Bodelon, C., Bogdanova, N., Bojesen, A., Bonanni, B., Borg, A., Bradbury, A.R., Brenton, J.D., Brewer, C., Brinton, L., Broberg, P., Brooks-Wilson, A., Bruinsma, F., Brunet, J., Buecher, B., Butzow, R., Buys, S.S., Caldes, T., Caligo, M.A., Campbell, I., Cannioto, R., Carney, M.E., Cescon, T., Chan, S.B., Chang-Claude, J., Chanock, S., Chen, X.Q., Chiew, Y.E., Chiquette, J., Chung, W.K., Claes, K.B., Conner, T., Cook, L.S., Cook, J., Cramer, D.W, Cunningham, J.M., D'Aloisio, A.A., Daly, M.B., Damiola, F., Damirovna, S.D., Dansonka-Mieszkowska, A., Dao, F., Davidson, R., Defazio, A., Delnatte, C., Doheny, K.F., Diez, O., Ding, Y.C., Doherty, J.A., Domchek, S.M., Dorfling, C.M., Dork, T., Mensenkamp, A.R., Kiemeney, L.A.L.M., Massuger, L.F.A.G., Altena, A.M. van, et al., Phelan, C.M., Kuchenbaecker, K.B., Tyrer, J.P., Kar, S.P., Lawrenson, K., Winham, S.J., Dennis, J., Pirie, A., Riggan, M.J., Chornokur, G., Earp, M.A., Lyra, P.C., Jr., Lee, J.M., Coetzee, S., Beesley, J., McGuffog, L., Soucy, P., Dicks, E., Lee, A., Barrowdale, D., Lecarpentier, J., Leslie, G., Aalfs, C.M., Aben, K.K.H., Adams, M., Adlard, J., Andrulis, I.L., Anton-Culver, H., Antonenkova, N., Aravantinos, G., Arnold, N., Arun, B.K., Arver, B., Azzollini, J., Balmana, J., Banerjee, S.N., Barjhoux, L., Barkardottir, R.B., Bean, Y., Beckmann, M.W., Beeghly-Fadiel, A., Benitez, J., Bermisheva, M., Bernardini, M.Q., Birrer, M.J., Bjorge, L., Black, A., Blankstein, K., Blok, M.J., Bodelon, C., Bogdanova, N., Bojesen, A., Bonanni, B., Borg, A., Bradbury, A.R., Brenton, J.D., Brewer, C., Brinton, L., Broberg, P., Brooks-Wilson, A., Bruinsma, F., Brunet, J., Buecher, B., Butzow, R., Buys, S.S., Caldes, T., Caligo, M.A., Campbell, I., Cannioto, R., Carney, M.E., Cescon, T., Chan, S.B., Chang-Claude, J., Chanock, S., Chen, X.Q., Chiew, Y.E., Chiquette, J., Chung, W.K., Claes, K.B., Conner, T., Cook, L.S., Cook, J., Cramer, D.W, Cunningham, J.M., D'Aloisio, A.A., Daly, M.B., Damiola, F., Damirovna, S.D., Dansonka-Mieszkowska, A., Dao, F., Davidson, R., Defazio, A., Delnatte, C., Doheny, K.F., Diez, O., Ding, Y.C., Doherty, J.A., Domchek, S.M., Dorfling, C.M., Dork, T., Mensenkamp, A.R., Kiemeney, L.A.L.M., Massuger, L.F.A.G., Altena, A.M. van, and et al.
Abstract: Contains fulltext : 174141.pdf (publisher's version ) (Closed access), To identify common alleles associated with different histotypes of epithelial ovarian cancer (EOC), we pooled data from multiple genome-wide genotyping projects totaling 25,509 EOC cases and 40,941 controls. We identified nine new susceptibility loci for different EOC histotypes: six for serous EOC histotypes (3q28, 4q32.3, 8q21.11, 10q24.33, 18q11.2 and 22q12.1), two for mucinous EOC (3q22.3 and 9q31.1) and one for endometrioid EOC (5q12.3). We then performed meta-analysis on the results for high-grade serous ovarian cancer with the results from analysis of 31,448 BRCA1 and BRCA2 mutation carriers, including 3,887 mutation carriers with EOC. This identified three additional susceptibility loci at 2q13, 8q24.1 and 12q24.31. Integrated analyses of genes and regulatory biofeatures at each locus predicted candidate susceptibility genes, including OBFC1, a new candidate susceptibility gene for low-grade and borderline serous EOC.
Published: 2017

19. Obesity, metabolic factors and risk of different histological types of lung cancer: A Mendelian randomization study

Author: Carreras-Torres, R., Johansson, M., Haycock, P.C., Wade, K.H., Relton, C.L., Martin, R.M., Smith, G., Albanes, D., Aldrich, M.C., Andrew, A., Arnold, S.M., Bickeboller, H., Bojesen, S.E., Brunnstrom, H., Manjer, J., Bruske, I., Caporaso, N.E., Chen, C., Christiani, D.C., Christian, W.J., Doherty, J.A., Duell, E.J., Field, J.K., Davies, M.P., Marcus, M.W., Goodman, G.E., Grankvist, K., Haugen, A., Hong, Y.C., Kiemeney, L.A.L.M., Heijden, E. van der, Kraft, P., Johansson, M.B., Lam, S., Landi, M.T., Lazarus, P., Marchand, L. Le, Liu, G., Melander, O., Park, S.L., Rennert, G., Risch, A., Haura, E.B., Scelo, G., Zaridze, D., Mukeriya, A., Savic, M., Lissowska, J., Swiatkowska, B., Janout, V., Holcatova, I., Mates, D., Schabath, M.B., Shen, H., Tardon, A., Teare, M.D., Woll, P., Tsao, M.S., Wu, X., Yuan, J.M., Hung, R.J., Amos, C.I., McKay, J., Brennan, P., Carreras-Torres, R., Johansson, M., Haycock, P.C., Wade, K.H., Relton, C.L., Martin, R.M., Smith, G., Albanes, D., Aldrich, M.C., Andrew, A., Arnold, S.M., Bickeboller, H., Bojesen, S.E., Brunnstrom, H., Manjer, J., Bruske, I., Caporaso, N.E., Chen, C., Christiani, D.C., Christian, W.J., Doherty, J.A., Duell, E.J., Field, J.K., Davies, M.P., Marcus, M.W., Goodman, G.E., Grankvist, K., Haugen, A., Hong, Y.C., Kiemeney, L.A.L.M., Heijden, E. van der, Kraft, P., Johansson, M.B., Lam, S., Landi, M.T., Lazarus, P., Marchand, L. Le, Liu, G., Melander, O., Park, S.L., Rennert, G., Risch, A., Haura, E.B., Scelo, G., Zaridze, D., Mukeriya, A., Savic, M., Lissowska, J., Swiatkowska, B., Janout, V., Holcatova, I., Mates, D., Schabath, M.B., Shen, H., Tardon, A., Teare, M.D., Woll, P., Tsao, M.S., Wu, X., Yuan, J.M., Hung, R.J., Amos, C.I., McKay, J., and Brennan, P.
Abstract: Contains fulltext : 174154.pdf (publisher's version ) (Open Access), BACKGROUND: Assessing the relationship between lung cancer and metabolic conditions is challenging because of the confounding effect of tobacco. Mendelian randomization (MR), or the use of genetic instrumental variables to assess causality, may help to identify the metabolic drivers of lung cancer. METHODS AND FINDINGS: We identified genetic instruments for potential metabolic risk factors and evaluated these in relation to risk using 29,266 lung cancer cases (including 11,273 adenocarcinomas, 7,426 squamous cell and 2,664 small cell cases) and 56,450 controls. The MR risk analysis suggested a causal effect of body mass index (BMI) on lung cancer risk for two of the three major histological subtypes, with evidence of a risk increase for squamous cell carcinoma (odds ratio (OR) [95% confidence interval (CI)] = 1.20 [1.01-1.43] and for small cell lung cancer (OR [95%CI] = 1.52 [1.15-2.00]) for each standard deviation (SD) increase in BMI [4.6 kg/m2]), but not for adenocarcinoma (OR [95%CI] = 0.93 [0.79-1.08]) (Pheterogeneity = 4.3x10-3). Additional analysis using a genetic instrument for BMI showed that each SD increase in BMI increased cigarette consumption by 1.27 cigarettes per day (P = 2.1x10-3), providing novel evidence that a genetic susceptibility to obesity influences smoking patterns. There was also evidence that low-density lipoprotein cholesterol was inversely associated with lung cancer overall risk (OR [95%CI] = 0.90 [0.84-0.97] per SD of 38 mg/dl), while fasting insulin was positively associated (OR [95%CI] = 1.63 [1.25-2.13] per SD of 44.4 pmol/l). Sensitivity analyses including a weighted-median approach and MR-Egger test did not detect other pleiotropic effects biasing the main results. CONCLUSIONS: Our results are consistent with a causal role of fasting insulin and low-density lipoprotein cholesterol in lung cancer etiology, as well as for BMI in squamous cell and small cell carcinoma. The latter relation may be mediated by a previously unrecognized
Published: 2017

20. History of Comorbidities and Survival of Ovarian Cancer Patients, Results from the Ovarian Cancer Association Consortium

Author: Minlikeeva, A.N., Freudenheim, J.L., Eng, K.H., Cannioto, R.A., Friel, G., Szender, J.B., Segal, B., Odunsi, K., Mayor, P., Diergaarde, B., Zsiros, E., Kelemen, L.E., Kobel, M., Steed, H., Defazio, A., Jordan, S.J., Fasching, P.A., Beckmann, M.W., Risch, H.A., Rossing, M.A., Doherty, J.A., Chang-Claude, J., Goodman, M.T., Dork, T., Edwards, R., Modugno, F., Ness, R.B., Matsuo, K., Mizuno, M., Karlan, B.Y., Goode, E.L., Kjaer, S.K., Hogdall, E., Schildkraut, J.M., Terry, K.L., Cramer, D.W, Bandera, E.V., Paddock, L.E., Kiemeney, L.A.L.M., Massuger, L.F.A.G., Sutphen, R., Anton-Culver, H., Ziogas, A., Menon, U., Gayther, S.A., Ramus, S.J., Gentry-Maharaj, A., Pearce, C.L., Wu, A.H., Kupryjanczyk, J., Jensen, A., Webb, P.M., Moysich, K.B., Minlikeeva, A.N., Freudenheim, J.L., Eng, K.H., Cannioto, R.A., Friel, G., Szender, J.B., Segal, B., Odunsi, K., Mayor, P., Diergaarde, B., Zsiros, E., Kelemen, L.E., Kobel, M., Steed, H., Defazio, A., Jordan, S.J., Fasching, P.A., Beckmann, M.W., Risch, H.A., Rossing, M.A., Doherty, J.A., Chang-Claude, J., Goodman, M.T., Dork, T., Edwards, R., Modugno, F., Ness, R.B., Matsuo, K., Mizuno, M., Karlan, B.Y., Goode, E.L., Kjaer, S.K., Hogdall, E., Schildkraut, J.M., Terry, K.L., Cramer, D.W, Bandera, E.V., Paddock, L.E., Kiemeney, L.A.L.M., Massuger, L.F.A.G., Sutphen, R., Anton-Culver, H., Ziogas, A., Menon, U., Gayther, S.A., Ramus, S.J., Gentry-Maharaj, A., Pearce, C.L., Wu, A.H., Kupryjanczyk, J., Jensen, A., Webb, P.M., and Moysich, K.B.
Abstract: Contains fulltext : 177359.pdf (publisher's version ) (Closed access), Background: Comorbidities can affect survival of ovarian cancer patients by influencing treatment efficacy. However, little evidence exists on the association between individual concurrent comorbidities and prognosis in ovarian cancer patients.Methods: Among patients diagnosed with invasive ovarian carcinoma who participated in 23 studies included in the Ovarian Cancer Association Consortium, we explored associations between histories of endometriosis; asthma; depression; osteoporosis; and autoimmune, gallbladder, kidney, liver, and neurological diseases and overall and progression-free survival. Using Cox proportional hazards regression models adjusted for age at diagnosis, stage of disease, histology, and study site, we estimated pooled HRs and 95% confidence intervals to assess associations between each comorbidity and ovarian cancer outcomes.Results: None of the comorbidities were associated with ovarian cancer outcome in the overall sample nor in strata defined by histologic subtype, weight status, age at diagnosis, or stage of disease (local/regional vs. advanced).Conclusions: Histories of endometriosis; asthma; depression; osteoporosis; and autoimmune, gallbladder, kidney, liver, or neurologic diseases were not associated with ovarian cancer overall or progression-free survival.Impact: These previously diagnosed chronic diseases do not appear to affect ovarian cancer prognosis. Cancer Epidemiol Biomarkers Prev; 26(9); 1470-3. (c)2017 AACR.
Published: 2017

21. Pelvic Inflammatory Disease and the Risk of Ovarian Cancer and Borderline Ovarian Tumors: A Pooled Analysis of 13 Case-Control Studies

Author: Rasmussen, C.B., Kjaer, S.K., Albieri, V., Bandera, E.V., Doherty, J.A., Hogdall, E., Webb, P.M., Jordan, S.J., Rossing, M.A., Wicklund, K.G., Goodman, M.T., Modugno, F., Moysich, K.B., Ness, R.B., Edwards, R.P., Schildkraut, J.M., Berchuck, A., Olson, S.H., Kiemeney, L.A.L.M., Massuger, L.F.A.G., Narod, S.A., Phelan, C.M., Anton-Culver, H., Ziogas, A., Wu, A.H., Pearce, C.L., Risch, H.A., Jensen, A., Rasmussen, C.B., Kjaer, S.K., Albieri, V., Bandera, E.V., Doherty, J.A., Hogdall, E., Webb, P.M., Jordan, S.J., Rossing, M.A., Wicklund, K.G., Goodman, M.T., Modugno, F., Moysich, K.B., Ness, R.B., Edwards, R.P., Schildkraut, J.M., Berchuck, A., Olson, S.H., Kiemeney, L.A.L.M., Massuger, L.F.A.G., Narod, S.A., Phelan, C.M., Anton-Culver, H., Ziogas, A., Wu, A.H., Pearce, C.L., Risch, H.A., and Jensen, A.
Abstract: Contains fulltext : 169777.pdf (publisher's version ) (Closed access), Inflammation has been implicated in ovarian carcinogenesis. However, studies investigating the association between pelvic inflammatory disease (PID) and ovarian cancer risk are few and inconsistent. We investigated the association between PID and the risk of epithelial ovarian cancer according to tumor behavior and histotype. We pooled data from 13 case-control studies, conducted between 1989 and 2009, from the Ovarian Cancer Association Consortium (OCAC), including 9,162 women with ovarian cancers, 2,354 women with borderline tumors, and 14,736 control participants. Study-specific odds ratios were estimated and subsequently combined into a pooled odds ratio using a random-effects model. A history of PID was associated with an increased risk of borderline tumors (pooled odds ratio (pOR) = 1.32, 95% confidence interval (CI): 1.10, 1.58). Women with at least 2 episodes of PID had a 2-fold increased risk of borderline tumors (pOR = 2.14, 95% CI: 1.08, 4.24). No association was observed between PID and ovarian cancer risk overall (pOR = 0.99, 95% CI: 0.83, 1.19); however, a statistically nonsignificantly increased risk of low-grade serous tumors (pOR = 1.48, 95% CI: 0.92, 2.38) was noted. In conclusion, PID was associated with an increased risk of borderline ovarian tumors, particularly among women who had had multiple episodes of PID. Although our results indicated a histotype-specific association with PID, the association of PID with ovarian cancer risk is still somewhat uncertain and requires further investigation.
Published: 2017

22. History of hypertension, heart disease, and diabetes and ovarian cancer patient survival: evidence from the ovarian cancer association consortium

Author: Minlikeeva, A.N., Freudenheim, J.L., Cannioto, R.A., Szender, J.B., Eng, K.H., Modugno, F., Ness, R.B., LaMonte, M.J., Friel, G., Segal, B.H., Odunsi, K., Mayor, P., Zsiros, E., Schmalfeldt, B., Klapdor, R., Drk, T., Hillemanns, P., Kelemen, L.E., Kbel, M., Steed, H., Fazio, A. de, Jordan, S.J., Nagle, C.M., Risch, H.A., Rossing, M.A., Doherty, J.A., Goodman, M.T., Edwards, R., Matsuo, K., Mizuno, M., Karlan, B.Y., Kjaer, S.K., Hogdall, E., Jensen, A., Schildkraut, J.M., Terry, K.L., Cramer, D.W, Bandera, E.V., Paddock, L.E., Kiemeney, L.A.L.M., Massuger, L.F.A.G., Kupryjanczyk, J., Berchuck, A., Chang-Claude, J., Diergaarde, B., Webb, P.M., Moysich, K.B., Minlikeeva, A.N., Freudenheim, J.L., Cannioto, R.A., Szender, J.B., Eng, K.H., Modugno, F., Ness, R.B., LaMonte, M.J., Friel, G., Segal, B.H., Odunsi, K., Mayor, P., Zsiros, E., Schmalfeldt, B., Klapdor, R., Drk, T., Hillemanns, P., Kelemen, L.E., Kbel, M., Steed, H., Fazio, A. de, Jordan, S.J., Nagle, C.M., Risch, H.A., Rossing, M.A., Doherty, J.A., Goodman, M.T., Edwards, R., Matsuo, K., Mizuno, M., Karlan, B.Y., Kjaer, S.K., Hogdall, E., Jensen, A., Schildkraut, J.M., Terry, K.L., Cramer, D.W, Bandera, E.V., Paddock, L.E., Kiemeney, L.A.L.M., Massuger, L.F.A.G., Kupryjanczyk, J., Berchuck, A., Chang-Claude, J., Diergaarde, B., Webb, P.M., and Moysich, K.B.
Abstract: Contains fulltext : 174140.pdf (publisher's version ) (Closed access), PURPOSE: Survival following ovarian cancer diagnosis is generally low; understanding factors related to prognosis could be important to optimize treatment. The role of previously diagnosed comorbidities and use of medications for those conditions in relation to prognosis for ovarian cancer patients has not been studied extensively, particularly according to histological subtype. METHODS: Using pooled data from fifteen studies participating in the Ovarian Cancer Association Consortium, we examined the associations between history of hypertension, heart disease, diabetes, and medications taken for these conditions and overall survival (OS) and progression-free survival (PFS) among patients diagnosed with invasive epithelial ovarian carcinoma. We used Cox proportional hazards regression models adjusted for age and stage to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) overall and within strata of histological subtypes. RESULTS: History of diabetes was associated with increased risk of mortality (n = 7,674; HR = 1.12; 95% CI = 1.01-1.25). No significant mortality associations were observed for hypertension (n = 6,482; HR = 0.95; 95% CI = 0.88-1.02) or heart disease (n = 4,252; HR = 1.05; 95% CI = 0.87-1.27). No association of these comorbidities was found with PFS in the overall study population. However, among patients with endometrioid tumors, hypertension was associated with lower risk of progression (n = 339, HR = 0.54; 95% CI = 0.35-0.84). Comorbidity was not associated with OS or PFS for any of the other histological subtypes. Ever use of beta blockers, oral antidiabetic medications, and insulin was associated with increased mortality, HR = 1.20; 95% CI = 1.03-1.40, HR = 1.28; 95% CI = 1.05-1.55, and HR = 1.63; 95% CI = 1.20-2.20, respectively. Ever use of diuretics was inversely associated with mortality, HR = 0.71; 95% CI = 0.53-0.94. CONCLUSIONS: Histories of hypertension, diabetes, and use of diuretics, beta blockers, insulin, and oral antidi
Published: 2017

23. Large-scale association analysis identifies new lung cancer susceptibility loci and heterogeneity in genetic susceptibility across histological subtypes

Author: McKay, J.D., Hung, R.J., Han, Y., Zong, X., Carreras-Torres, R., Christiani, D.C., Caporaso, N., Johansson, M., Li, Y., Byun, J.Y., Dunning, A., Pooley, K.A., Qian, D.C., Liu, G., Bojesen, S.E., Wu, X., Marchand, L. le, Albanes, D., Bickeböller, H., Aldrich, M.C., Bush, W.S., Tardon, A., Rennert, G., Teare, M.D., Field, J.K., Kiemeney, L.A., Lazarus, P., Haugen, A., Schabath, M.B., Andrew, A.S., Shen, H., Hong, Y.C., Yuan, J.M., Bertazzi, P.A., Pesatori, A.C., Ye, Y., Diao, N., Su, L., Zhang, R., Brhane, Y., Leighl, N., Johansen, J.S., Mellemgaard, A., Saliba, W., Haiman, C.A., Wilkens, L.R., Fernandez-Somoano, A., Fernandez-Tardon, G., Heijden, H.F.M. van der, Kim, J.H., Hu, Z, Davies, M., Brunnström, H., Manjer, J., Melander, O., Muller, D., Overvad, K., Trichopoulou, A., Tumino, R., Doherty, J.A., Barnett, M.P., Chen, C., Goodman, G.E., Cox, A, Taylor, F., Woll, P.J., Brüske, I., Wichmann, H.E., Manz, J., Muley, T.R., Risch, A., Rosenberger, A., Grankvist, K., Shepherd, F.A., Tsao, M.S., Haura, E.B., Bolca, C., Holcatova, I., Janout, V., Kontic, M., Lissowska, J., Mukeria, A., Ognjanovic, S., Orlowski, T.M., Scelo, G., Swiatkowska, B., Zaridze, D., Bakke, P., Skaug, V., Zienolddiny, S., Duell, E.J., Butler, L.M., Koh, W.P., Gao, Y.T., Houlston, R.S., McLaughlin, J., Stevens, V.L., Joubert, P., Lamontagne, M., Nickle, D.C., Obeidat, M., Timens, W., Zhu, B, Kachuri, L., Artigas, M.S., Tobin, M.D., Wain, L.V., Rafnar, T., Thorgeirsson, T.E., Reginsson, G.W., Stefansson, K., Hancock, D.B., Bierut, L.J., Spitz, M.R., Gaddis, N.C., Lutz, S.M., Kamal, A., Pikielny, C., Zhu, D., Lindströem, S., Jiang, X., Tyndale, R.F., Chenevix-Trench, G., Beesley, J., Bossé, Y., Chanock, S., Brennan, P., Landi, M.T., Amos, C.I., McKay, J.D., Hung, R.J., Han, Y., Zong, X., Carreras-Torres, R., Christiani, D.C., Caporaso, N., Johansson, M., Li, Y., Byun, J.Y., Dunning, A., Pooley, K.A., Qian, D.C., Liu, G., Bojesen, S.E., Wu, X., Marchand, L. le, Albanes, D., Bickeböller, H., Aldrich, M.C., Bush, W.S., Tardon, A., Rennert, G., Teare, M.D., Field, J.K., Kiemeney, L.A., Lazarus, P., Haugen, A., Schabath, M.B., Andrew, A.S., Shen, H., Hong, Y.C., Yuan, J.M., Bertazzi, P.A., Pesatori, A.C., Ye, Y., Diao, N., Su, L., Zhang, R., Brhane, Y., Leighl, N., Johansen, J.S., Mellemgaard, A., Saliba, W., Haiman, C.A., Wilkens, L.R., Fernandez-Somoano, A., Fernandez-Tardon, G., Heijden, H.F.M. van der, Kim, J.H., Hu, Z, Davies, M., Brunnström, H., Manjer, J., Melander, O., Muller, D., Overvad, K., Trichopoulou, A., Tumino, R., Doherty, J.A., Barnett, M.P., Chen, C., Goodman, G.E., Cox, A, Taylor, F., Woll, P.J., Brüske, I., Wichmann, H.E., Manz, J., Muley, T.R., Risch, A., Rosenberger, A., Grankvist, K., Shepherd, F.A., Tsao, M.S., Haura, E.B., Bolca, C., Holcatova, I., Janout, V., Kontic, M., Lissowska, J., Mukeria, A., Ognjanovic, S., Orlowski, T.M., Scelo, G., Swiatkowska, B., Zaridze, D., Bakke, P., Skaug, V., Zienolddiny, S., Duell, E.J., Butler, L.M., Koh, W.P., Gao, Y.T., Houlston, R.S., McLaughlin, J., Stevens, V.L., Joubert, P., Lamontagne, M., Nickle, D.C., Obeidat, M., Timens, W., Zhu, B, Kachuri, L., Artigas, M.S., Tobin, M.D., Wain, L.V., Rafnar, T., Thorgeirsson, T.E., Reginsson, G.W., Stefansson, K., Hancock, D.B., Bierut, L.J., Spitz, M.R., Gaddis, N.C., Lutz, S.M., Kamal, A., Pikielny, C., Zhu, D., Lindströem, S., Jiang, X., Tyndale, R.F., Chenevix-Trench, G., Beesley, J., Bossé, Y., Chanock, S., Brennan, P., Landi, M.T., and Amos, C.I.
Abstract: Contains fulltext : 177377.pdf (Publisher’s version ) (Closed access)
Published: 2017

24. Enrichment of putative PAX8 target genes at serous epithelial ovarian cancer susceptibility loci

Author: Kar, S.P., Adler, E., Tyrer, J., Hazelett, D., Anton-Culver, H., Bandera, E.V., Beckmann, M.W., Berchuck, A., Bogdanova, N., Brinton, L., Butzow, R., Campbell, I., Carty, K., Chang-Claude, J., Cook, L.S., Cramer, D.W, Cunningham, J.M., Dansonka-Mieszkowska, A., Doherty, J.A., Dork, T., Durst, M., Eccles, D., Fasching, P.A., Flanagan, J., Gentry-Maharaj, A., Glasspool, R., Goode, E.L., Goodman, M.T., Gronwald, J., Heitz, F., Hildebrandt, M.A.T., Hogdall, E., Hogdall, C.K., Huntsman, D.G., Jensen, A., Karlan, B.Y., Kelemen, L.E., Kiemeney, L.A.L.M., Kjaer, S.K., Kupryjanczyk, J., Lambrechts, D., Levine, D.A., Li, Q., Lissowska, J., Lu, K.H., Lubinski, J., Massuger, L.F.A.G., McGuire, V., McNeish, I., Menon, U., Modugno, F., Monteiro, A.N., Moysich, K.B., Ness, R.B., Nevanlinna, H., Paul, J., Pearce, C.L., Pejovic, T., Permuth, J.B., Phelan, C., Pike, M.C., Poole, E.M., Ramus, S.J., Risch, H.A., Rossing, M.A., Salvesen, H.B., Schildkraut, J.M., Sellers, T.A., Sherman, M., Siddiqui, N., Sieh, W., Song, H., Southey, M., Terry, K.L., Tworoger, S.S., Walsh, C., Wentzensen, N., Whittemore, A.S., Wu, A.H., Yang, H., Zheng, W., Ziogas, A., Freedman, M.L., Gayther, S.A., Pharoah, P.D., Lawrenson, K., Kar, S.P., Adler, E., Tyrer, J., Hazelett, D., Anton-Culver, H., Bandera, E.V., Beckmann, M.W., Berchuck, A., Bogdanova, N., Brinton, L., Butzow, R., Campbell, I., Carty, K., Chang-Claude, J., Cook, L.S., Cramer, D.W, Cunningham, J.M., Dansonka-Mieszkowska, A., Doherty, J.A., Dork, T., Durst, M., Eccles, D., Fasching, P.A., Flanagan, J., Gentry-Maharaj, A., Glasspool, R., Goode, E.L., Goodman, M.T., Gronwald, J., Heitz, F., Hildebrandt, M.A.T., Hogdall, E., Hogdall, C.K., Huntsman, D.G., Jensen, A., Karlan, B.Y., Kelemen, L.E., Kiemeney, L.A.L.M., Kjaer, S.K., Kupryjanczyk, J., Lambrechts, D., Levine, D.A., Li, Q., Lissowska, J., Lu, K.H., Lubinski, J., Massuger, L.F.A.G., McGuire, V., McNeish, I., Menon, U., Modugno, F., Monteiro, A.N., Moysich, K.B., Ness, R.B., Nevanlinna, H., Paul, J., Pearce, C.L., Pejovic, T., Permuth, J.B., Phelan, C., Pike, M.C., Poole, E.M., Ramus, S.J., Risch, H.A., Rossing, M.A., Salvesen, H.B., Schildkraut, J.M., Sellers, T.A., Sherman, M., Siddiqui, N., Sieh, W., Song, H., Southey, M., Terry, K.L., Tworoger, S.S., Walsh, C., Wentzensen, N., Whittemore, A.S., Wu, A.H., Yang, H., Zheng, W., Ziogas, A., Freedman, M.L., Gayther, S.A., Pharoah, P.D., and Lawrenson, K.
Abstract: Contains fulltext : 170527.pdf (publisher's version ) (Closed access), BACKGROUND: Genome-wide association studies (GWAS) have identified 18 loci associated with serous ovarian cancer (SOC) susceptibility but the biological mechanisms driving these findings remain poorly characterised. Germline cancer risk loci may be enriched for target genes of transcription factors (TFs) critical to somatic tumorigenesis. METHODS: All 615 TF-target sets from the Molecular Signatures Database were evaluated using gene set enrichment analysis (GSEA) and three GWAS for SOC risk: discovery (2196 cases/4396 controls), replication (7035 cases/21 693 controls; independent from discovery), and combined (9627 cases/30 845 controls; including additional individuals). RESULTS: The PAX8-target gene set was ranked 1/615 in the discovery (PGSEA<0.001; FDR=0.21), 7/615 in the replication (PGSEA=0.004; FDR=0.37), and 1/615 in the combined (PGSEA<0.001; FDR=0.21) studies. Adding other genes reported to interact with PAX8 in the literature to the PAX8-target set and applying an alternative to GSEA, interval enrichment, further confirmed this association (P=0.006). Fifteen of the 157 genes from this expanded PAX8 pathway were near eight loci associated with SOC risk at P<10-5 (including six with P<5 x 10-8). The pathway was also associated with differential gene expression after shRNA-mediated silencing of PAX8 in HeyA8 (PGSEA=0.025) and IGROV1 (PGSEA=0.004) SOC cells and several PAX8 targets near SOC risk loci demonstrated in vitro transcriptomic perturbation. CONCLUSIONS: Putative PAX8 target genes are enriched for common SOC risk variants. This finding from our agnostic evaluation is of particular interest given that PAX8 is well-established as a specific marker for the cell of origin of SOC.
Published: 2017

25. Identification of 12 new susceptibility loci for different histotypes of epithelial ovarian cancer

Author: Phelan, C. (Catherine), Kuchenbaecker, K.B. (Karoline), Tyrer, J.P. (Jonathan P.), Kar, S.P. (Siddhartha P.), Lawrenson, K. (Kate), Winham, S.J. (Stacey J.), Dennis, J. (Joe), Pirie, A. (Ailith), Riggan, M.J. (Marjorie J.), Chornokur, G. (Ganna), Earp, M.A. (Madalene A.), Lyra, P.C. (Paulo C.), Lee, J.M. (Janet M.), Coetzee, S. (Simon), Beesley, J. (Jonathan), McGuffog, L. (Lesley), Soucy, P. (Penny), Dicks, E. (Ed), Lee, A. (Andrew), Barrowdale, D. (Daniel), Lecarpentier, J. (Julie), Leslie, G. (Goska), Aalfs, C.M. (Cora), Aben, K.K.H. (Katja), Adams, M. (Marcia), Adlard, J.W. (Julian), Andrulis, I.L. (Irene), Anton-Culver, H. (Hoda), Antonenkova, N. (Natalia), Aravantinos, G. (Gerasimos), Arnold, N. (Norbert), Arun, B.K. (Banu), Arver, B. (Brita), Azzollini, J., Balmana, J. (Judith), Banerjee, S. (Susana), Barjhoux, L. (Laure), Barkardottir, R.B. (Rosa B.), Bean, Y. (Yukie), Beckmann, M.W. (Matthias), Beeghly-Fadiel, A. (Alicia), Benítez, J. (Javier), Bermisheva, M. (Marina), Bernardini, M.Q. (Marcus Q.), Birrer, M.J. (Michael J.), Bjorge, L. (Line), Black, A., Blankstein, K. (Kenneth), Blok, M.J. (Marinus), Bodelon, C. (Clara), Bogdanova, N. (Natalia), Bojesen, A. (Anders), Bonanni, B. (Bernardo), Borg, Å. (Åke), Bradbury, A.R. (Angela R.), Brenton, J.D. (James D.), Brewer, C. (Carole), Brinton, L.A. (Louise), Broberg, P. (Per), Brooks-Wilson, A. (Angela), Bruinsma, F. (Fiona), Brunet, J. (Joan), Buecher, B. (Bruno), Butzow, R. (Ralf), Buys, S.S. (Saundra), Caldes, T. (Trinidad), Caligo, M.A. (Maria A.), Campbell, I. (Ian), Cannioto, R. (Rikki), Carney, M.E. (Michael), Cescon, T. (Terence), Chan, S. (Salina), Chang-Claude, J. (Jenny), Chanock, S.J. (Stephen), Chen, X.Q. (Xiao Qing), Chiew, Y.-E. (Yoke-Eng), Chiquette, J. (Jocelyne), Chung, W. (Wendy), Claes, K. (Kathleen), Conner, T. (Thomas), Cook, L.S. (Linda S.), Cook, J. (Jackie), Cramer, D.W. (Daniel), Cunningham, J.M. (Julie), D'Aloisio, A.A. (Aimee A.), Daly, M.B. (Mary), Damiola, F. (Francesca), Damirovna, S.D. (Sakaeva Dina), Dansonka-Mieszkowska, A. (Agnieszka), Dao, F. (Fanny), Davidson, R. (Rosemarie), DeFazio, A. (Anna), Delnatte, C.D. (Capucine), Doheny, K.F. (Kimberly), Díez, O. (Orland), Ding, Y.C. (Yuan Chun), Doherty, J.A. (Jennifer), Domchek, S.M. (Susan), Dorfling, C.M. (Cecilia), Dörk, T. (Thilo), Dossus, L. (Laure), Duran, M. (Mercedes), Dürst, M. (Matthias), Dworniczak, B. (Bernd), Eccles, D. (Diana), Edwards, T. (Todd), Eeles, R. (Rosalind), Eilber, U. (Ursula), Ejlertsen, B. (Bent), Ekici, A.B. (Arif), Ellis, S. (Steve), Elvira, M. (Mingajeva), Eng, K.H. (Kevin H.), Engel, C. (Christoph), Evans, D.G. (Gareth), Fasching, P.A. (Peter), Ferguson, S. (Sarah), Ferrer, S.F., Flanagan, J.M. (James), Fogarty, Z.C. (Zachary C.), Fortner, R.T. (Renée T.), Fostira, F. (Florentia), Foulkes, W.D. (William D.), Fountzilas, G. (George), Fridley, B.L. (Brooke), Friebel, M.O.W. (Mark ), Friedman, E. (Eitan), Frost, D. (Debra), Ganz, P.A. (Patricia), Garber, J. (Judy), García, M.J. (María J.), Garcia-Barberan, V. (Vanesa), Gehrig, P.A. (Paola A.), Gentry-Maharaj, A. (Aleksandra), Gerdes, A-M. (Anne-Marie), Giles, G.G. (Graham G.), Glasspool, R. (Rosalind), Glendon, G. (Gord), Godwin, A.K. (Andrew K.), Radice, P. (Paolo), Goranova, T. (Teodora), Gore, M. (Martin), Greene, M.H. (Mark H.), Gronwald, J. (Jacek), Gruber, S.B. (Stephen), Hahnen, E. (Eric), Haiman, C.A. (Christopher), Håkansson, N. (Niclas), Hamann, U. (Ute), Hansen, T.V.O. (Thomas V.O.), Harrington, P.A. (Patricia A.), Harris, H.R. (Holly), Hauke, J. (Jan), Hein, A. (Alexander), Henderson, A. (Alex), Hildebrandt, M.A.T. (Michelle A.T.), Hillemanns, P. (Peter), Hodgson, S. (Shirley), Høgdall, C.K. (Claus), Høgdall, E. (Estrid), Hogervorst, F.B.L. (Frans B. L.), Holland, H. (Helene), Hooning, M.J. (Maartje J.), Hosking, K. (Karen), Huang, R.-Y. (Ruea-Yea), Hulick, P.J. (Peter), Hung, J. (Jillian), Hunter, D.J. (David J.), Huntsman, D.G. (David G.), Huzarski, T. (Tomasz), Imyanitov, E.N. (Evgeny), Isaacs, C. (Claudine), Iversen, E. (Erik), Izatt, L. (Louise), Izquierdo, A. (A.), Jakubowska, A. (Anna), James, P. (Paul), Janavicius, R. (Ramunas), Jernetz, M. (Mats), Jensen, A. (Allan), Jensen, U.B., John, E.M. (Esther), Johnatty, S.E. (Sharon), Jones, M.E. (Michael E.), Kannisto, P. (Päivi), Karlan, B.Y. (Beth), Karnezis, A. (Anthony), Kast, K. (Karin), Kennedy, C.J. (Catherine J.), Khusnutdinova, E.K. (Elza), Kiemeney, L.A.L.M. (Bart), Kiiski, J.I. (Johanna I.), Kim, S.-W. (Sung-Won), Kjaer, M. (Michael), Köbel, M. (Martin), Kopperud, R.K. (Reidun K.), Kruse, T.A. (Torben), Kupryjanczyk, J. (Jolanta), Kwong, A. (Ava), Laitman, Y. (Yael), Lambrechts, D. (Diether), Larrañaga, N. (Nerea), Larson, M.C. (Melissa), Lazaro, C. (Conxi), Le, N.D. (Nhu D.), Le Marchand, L. (Loic), Lee, J.W. (Jong Won), Lele, S.B. (Shashikant B.), Leminen, A. (Arto), Leroux, D. (Dominique), Lester, J. (Jenny), Lesueur, F. (Fabienne), Levine, D.A. (Douglas), Liang, D. (Dong), Liebrich, C. (Clemens), Lilyquist, J. (Jenna), Lipworth, L. (Loren), Lissowska, J. (Jolanta), Lu, K.H. (Karen), Lubinski, J. (Jan), Luccarini, C. (Craig), Lundvall, L. (Lene), Mai, P.L. (Phuong), Mendoza-Fandiño, G. (Gustavo), Manoukian, S. (Siranoush), Massuger, L.F. (Leon), May, T. (Taymaa), Mazoyer, S. (Sylvie), McAlpine, J.N. (Jessica N.), McGuire, V. (Valerie), McLaughlin, J. (John), McNeish, I. (Iain), Meijers-Heijboer, E.J. (Hanne), Meindl, A. (Alfons), Menon, U. (Usha), Mensenkamp, A.R. (Arjen R.), Merritt, M.A. (Melissa A.), Milne, R.L. (Roger), Mitchell, G. (Gillian), Modugno, F. (Francesmary), Moes-Sosnowska, J. (Joanna), Moffitt, M. (Melissa), Montagna, M. (Marco), Moysich, K.B. (Kirsten), Mulligan, A.M. (Anna Marie), Musinsky, J. (Jacob), Nathanson, K.L. (Katherine), Nedergaard, L. (Lotte), Ness, R.B. (Roberta), Neuhausen, S.L. (Susan), Nevanlinna, H. (Heli), Niederacher, D. (Dieter), Nussbaum, R. (Robert), Odunsi, K. (Kunle), Olah, E. (Edith), Olopade, O.I. (Olofunmilayo), Olsson, H. (Håkan), Olswold, C. (Curtis), O'Malley, D.M. (David M.), Ong, K.-R. (Kai-Ren), Onland-Moret, N.C. (Charlotte), Orr, N. (Nick), Orsulic, S. (Sandra), Osorio, A. (Ana), Palli, D. (Domenico), Papi, L. (Laura), Park-Simon, T.-W., Paul, J. (James), Pearce, C.L. (Celeste), Pedersen, I.S. (Inge Søkilde), Peeters, P.H.M., Peissel, B. (Bernard), Peixoto, A. (Ana), Pejovic, T. (Tanja), Pelttari, L.M. (Liisa M.), Permuth, J.B. (Jennifer B.), Peterlongo, P. (Paolo), Pezzani, L. (Lidia), Pfeiler, G. (Georg), Phillips, K.-A. (Kelly-Anne), Piedmonte, M. (Marion), Pike, M.C. (Malcolm), Piskorz, A.M. (Anna M.), Poblete, S.R. (Samantha R.), Pócza, T. (Tímea), Poole, E.M. (Elizabeth M.), Poppe, B. (Bruce), Porteous, M.E. (Mary), Prieur, F. (Fabienne), Prokofyeva, D. (Darya), Pugh, E. (Elizabeth), Pujana, M.A. (Miquel Angel), Pujol, P. (Pascal), Rantala, J. (Johanna), Rappaport-Fuerhauser, C. (Christine), Rennert, G. (Gad), Rhiem, K. (Kerstin), Rice, P. (Patricia), Richardson, A.L. (Andrea), Robson, M. (Mark), Rodriguez, G.C. (Gustavo), Rodríguez-Antona, C. (Cristina), Romm, J. (Jane), Rookus, M.A. (Matti), Rossing, M.A. (Mary Anne), Rothstein, J.H. (Joseph H.), Rudolph, A. (Anja), Runnebaum, I.B. (Ingo), Salvesen, H.B. (Helga), Sandler, D.P. (Dale P.), Schoemaker, M.J. (Minouk J.), Senter, L. (Leigha), Setiawan, V.W. (V. Wendy), Severi, G. (Gianluca), Sharma, P. (Priyanka), Shelford, T. (Tameka), Siddiqui, N. (Nadeem), Side, L. (Lucy), Sieh, W. (Weiva), Singer, C.F. (Christian), Sobol, H. (Hagay), Song, H. (Honglin), Southey, M.C. (Melissa), Spurdle, A.B. (Amanda), Stadler, Z. (Zsofia), Steinemann, D. (Doris), Stoppa-Lyonnet, D. (Dominique), Sucheston-Campbell, L.E. (Lara E.), Sukiennicki, G. (Grzegorz), Sutphen, R. (Rebecca), Sutter, C. (Christian), Swerdlow, A.J. (Anthony ), Szabo, C. (Csilla), Szafron, L. (Lukasz), Tan, Y.Y. (Yen Y.), Taylor, J.A. (Jack A.), Tea, M.-K., Teixeira, P.J., Teo, S.-H. (Soo-Hwang), Terry, K.L. (Kathryn L.), Thompson, P.J. (Pamela J.), Thomsen, L.C.V. (Liv Cecilie Vestrheim), Thull, D.L. (Darcy L.), Tihomirova, L. (Laima), Tinker, A.V. (Anna V.), Tischkowitz, M. (Marc), Tognazzo, S. (Silvia), Toland, A.E. (Amanda Ewart), Tone, A. (Alicia), Trabert, B. (Britton), Travis, S.P.L. (Simon), Trichopoulou, A. (Antonia), Tung, N. (Nadine), Tworoger, S. (Shelley), Van Altena, A.M. (Anne M.), Van Den Berg, D. (David), Van Der Hout, A.H. (Annemarie H.), Luijt, R.B. (Rob) van der, Van Heetvelde, M. (Mattias), Van Nieuwenhuysen, E. (Els), Rensburg, E.J. (Elizabeth) van, Vanderstichele, A. (Adriaan), Varon-Mateeva, R. (Raymonda), Vega, A. (Ana), Edwards, D.V. (Digna Velez), Vergote, I., Vierkant, R.A. (Robert), Vijai, J. (Joseph), Vratimos, A. (Athanassios), Walker, L.J. (Lisa), Walsh, C. (Christine), Wand, D. (Dorothea), Wang-Gohrke, S. (Shan), Wappenschmidt, B. (Barbara), Webb, P.M. (Penelope M.), Weinberg, C.R. (Clarice R.), Weitzel, J.N. (Jeffrey), Wentzensen, N. (N.), Whittemore, A.S. (Alice), Wijnen, J.T. (Juul), Wilkens, L.R. (Lynne), Wolk, K. (Kerstin), Woo, M. (Michelle), Wu, X. (Xifeng), Wu, A.H. (Anna), Yang, H.P. (Hannah), Yannoukakos, D. (Drakoulis), Ziogas, A. (Argyrios), Zorn, K.K. (Kristin K.), Narod, S.A. (Steven A.), Easton, D.F. (Douglas), Amos, W., Schildkraut, J.M. (Joellen), Ramus, S.J. (Susan), Ottini, L. (Laura), Goodman, M.T. (Marc), Park, S.K. (Sue K.), Kelemen, L.E. (Linda), Risch, H. (Harvey), Thomassen, M. (Mads), Offit, K. (Kenneth), Simard, J. (Jacques), Schmutzler, R.K. (Rita), Hazelett, D. (Dennis), Monteiro, A.N.A. (Alvaro N.), Couch, F.J. (Fergus), Berchuck, A. (Andrew), Chenevix-Trench, G. (Georgia), Goode, E.L. (Ellen), Sellers, T.F., Gayther, S.A. (Simon), Antoniou, A.C. (Antonis), Pharoah, P.D.P. (Paul), Phelan, C. (Catherine), Kuchenbaecker, K.B. (Karoline), Tyrer, J.P. (Jonathan P.), Kar, S.P. (Siddhartha P.), Lawrenson, K. (Kate), Winham, S.J. (Stacey J.), Dennis, J. (Joe), Pirie, A. (Ailith), Riggan, M.J. (Marjorie J.), Chornokur, G. (Ganna), Earp, M.A. (Madalene A.), Lyra, P.C. (Paulo C.), Lee, J.M. (Janet M.), Coetzee, S. (Simon), Beesley, J. (Jonathan), McGuffog, L. (Lesley), Soucy, P. (Penny), Dicks, E. (Ed), Lee, A. (Andrew), Barrowdale, D. (Daniel), Lecarpentier, J. (Julie), Leslie, G. (Goska), Aalfs, C.M. (Cora), Aben, K.K.H. (Katja), Adams, M. (Marcia), Adlard, J.W. (Julian), Andrulis, I.L. (Irene), Anton-Culver, H. (Hoda), Antonenkova, N. (Natalia), Aravantinos, G. (Gerasimos), Arnold, N. (Norbert), Arun, B.K. (Banu), Arver, B. (Brita), Azzollini, J., Balmana, J. (Judith), Banerjee, S. (Susana), Barjhoux, L. (Laure), Barkardottir, R.B. (Rosa B.), Bean, Y. (Yukie), Beckmann, M.W. (Matthias), Beeghly-Fadiel, A. (Alicia), Benítez, J. (Javier), Bermisheva, M. (Marina), Bernardini, M.Q. (Marcus Q.), Birrer, M.J. (Michael J.), Bjorge, L. (Line), Black, A., Blankstein, K. (Kenneth), Blok, M.J. (Marinus), Bodelon, C. (Clara), Bogdanova, N. (Natalia), Bojesen, A. (Anders), Bonanni, B. (Bernardo), Borg, Å. (Åke), Bradbury, A.R. (Angela R.), Brenton, J.D. (James D.), Brewer, C. (Carole), Brinton, L.A. (Louise), Broberg, P. (Per), Brooks-Wilson, A. (Angela), Bruinsma, F. (Fiona), Brunet, J. (Joan), Buecher, B. (Bruno), Butzow, R. (Ralf), Buys, S.S. (Saundra), Caldes, T. (Trinidad), Caligo, M.A. (Maria A.), Campbell, I. (Ian), Cannioto, R. (Rikki), Carney, M.E. (Michael), Cescon, T. (Terence), Chan, S. (Salina), Chang-Claude, J. (Jenny), Chanock, S.J. (Stephen), Chen, X.Q. (Xiao Qing), Chiew, Y.-E. (Yoke-Eng), Chiquette, J. (Jocelyne), Chung, W. (Wendy), Claes, K. (Kathleen), Conner, T. (Thomas), Cook, L.S. (Linda S.), Cook, J. (Jackie), Cramer, D.W. (Daniel), Cunningham, J.M. (Julie), D'Aloisio, A.A. (Aimee A.), Daly, M.B. (Mary), Damiola, F. (Francesca), Damirovna, S.D. (Sakaeva Dina), Dansonka-Mieszkowska, A. (Agnieszka), Dao, F. (Fanny), Davidson, R. (Rosemarie), DeFazio, A. (Anna), Delnatte, C.D. (Capucine), Doheny, K.F. (Kimberly), Díez, O. (Orland), Ding, Y.C. (Yuan Chun), Doherty, J.A. (Jennifer), Domchek, S.M. (Susan), Dorfling, C.M. (Cecilia), Dörk, T. (Thilo), Dossus, L. (Laure), Duran, M. (Mercedes), Dürst, M. (Matthias), Dworniczak, B. (Bernd), Eccles, D. (Diana), Edwards, T. (Todd), Eeles, R. (Rosalind), Eilber, U. (Ursula), Ejlertsen, B. (Bent), Ekici, A.B. (Arif), Ellis, S. (Steve), Elvira, M. (Mingajeva), Eng, K.H. (Kevin H.), Engel, C. (Christoph), Evans, D.G. (Gareth), Fasching, P.A. (Peter), Ferguson, S. (Sarah), Ferrer, S.F., Flanagan, J.M. (James), Fogarty, Z.C. (Zachary C.), Fortner, R.T. (Renée T.), Fostira, F. (Florentia), Foulkes, W.D. (William D.), Fountzilas, G. (George), Fridley, B.L. (Brooke), Friebel, M.O.W. (Mark ), Friedman, E. (Eitan), Frost, D. (Debra), Ganz, P.A. (Patricia), Garber, J. (Judy), García, M.J. (María J.), Garcia-Barberan, V. (Vanesa), Gehrig, P.A. (Paola A.), Gentry-Maharaj, A. (Aleksandra), Gerdes, A-M. (Anne-Marie), Giles, G.G. (Graham G.), Glasspool, R. (Rosalind), Glendon, G. (Gord), Godwin, A.K. (Andrew K.), Radice, P. (Paolo), Goranova, T. (Teodora), Gore, M. (Martin), Greene, M.H. (Mark H.), Gronwald, J. (Jacek), Gruber, S.B. (Stephen), Hahnen, E. (Eric), Haiman, C.A. (Christopher), Håkansson, N. (Niclas), Hamann, U. (Ute), Hansen, T.V.O. (Thomas V.O.), Harrington, P.A. (Patricia A.), Harris, H.R. (Holly), Hauke, J. (Jan), Hein, A. (Alexander), Henderson, A. (Alex), Hildebrandt, M.A.T. (Michelle A.T.), Hillemanns, P. (Peter), Hodgson, S. (Shirley), Høgdall, C.K. (Claus), Høgdall, E. (Estrid), Hogervorst, F.B.L. (Frans B. L.), Holland, H. (Helene), Hooning, M.J. (Maartje J.), Hosking, K. (Karen), Huang, R.-Y. (Ruea-Yea), Hulick, P.J. (Peter), Hung, J. (Jillian), Hunter, D.J. (David J.), Huntsman, D.G. (David G.), Huzarski, T. (Tomasz), Imyanitov, E.N. (Evgeny), Isaacs, C. (Claudine), Iversen, E. (Erik), Izatt, L. (Louise), Izquierdo, A. (A.), Jakubowska, A. (Anna), James, P. (Paul), Janavicius, R. (Ramunas), Jernetz, M. (Mats), Jensen, A. (Allan), Jensen, U.B., John, E.M. (Esther), Johnatty, S.E. (Sharon), Jones, M.E. (Michael E.), Kannisto, P. (Päivi), Karlan, B.Y. (Beth), Karnezis, A. (Anthony), Kast, K. (Karin), Kennedy, C.J. (Catherine J.), Khusnutdinova, E.K. (Elza), Kiemeney, L.A.L.M. (Bart), Kiiski, J.I. (Johanna I.), Kim, S.-W. (Sung-Won), Kjaer, M. (Michael), Köbel, M. (Martin), Kopperud, R.K. (Reidun K.), Kruse, T.A. (Torben), Kupryjanczyk, J. (Jolanta), Kwong, A. (Ava), Laitman, Y. (Yael), Lambrechts, D. (Diether), Larrañaga, N. (Nerea), Larson, M.C. (Melissa), Lazaro, C. (Conxi), Le, N.D. (Nhu D.), Le Marchand, L. (Loic), Lee, J.W. (Jong Won), Lele, S.B. (Shashikant B.), Leminen, A. (Arto), Leroux, D. (Dominique), Lester, J. (Jenny), Lesueur, F. (Fabienne), Levine, D.A. (Douglas), Liang, D. (Dong), Liebrich, C. (Clemens), Lilyquist, J. (Jenna), Lipworth, L. (Loren), Lissowska, J. (Jolanta), Lu, K.H. (Karen), Lubinski, J. 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(Charlotte), Orr, N. (Nick), Orsulic, S. (Sandra), Osorio, A. (Ana), Palli, D. (Domenico), Papi, L. (Laura), Park-Simon, T.-W., Paul, J. (James), Pearce, C.L. (Celeste), Pedersen, I.S. (Inge Søkilde), Peeters, P.H.M., Peissel, B. (Bernard), Peixoto, A. (Ana), Pejovic, T. (Tanja), Pelttari, L.M. (Liisa M.), Permuth, J.B. (Jennifer B.), Peterlongo, P. (Paolo), Pezzani, L. (Lidia), Pfeiler, G. (Georg), Phillips, K.-A. (Kelly-Anne), Piedmonte, M. (Marion), Pike, M.C. (Malcolm), Piskorz, A.M. (Anna M.), Poblete, S.R. (Samantha R.), Pócza, T. (Tímea), Poole, E.M. (Elizabeth M.), Poppe, B. (Bruce), Porteous, M.E. (Mary), Prieur, F. (Fabienne), Prokofyeva, D. (Darya), Pugh, E. (Elizabeth), Pujana, M.A. (Miquel Angel), Pujol, P. (Pascal), Rantala, J. (Johanna), Rappaport-Fuerhauser, C. (Christine), Rennert, G. (Gad), Rhiem, K. (Kerstin), Rice, P. (Patricia), Richardson, A.L. (Andrea), Robson, M. (Mark), Rodriguez, G.C. (Gustavo), Rodríguez-Antona, C. (Cristina), Romm, J. 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(Laima), Tinker, A.V. (Anna V.), Tischkowitz, M. (Marc), Tognazzo, S. (Silvia), Toland, A.E. (Amanda Ewart), Tone, A. (Alicia), Trabert, B. (Britton), Travis, S.P.L. (Simon), Trichopoulou, A. (Antonia), Tung, N. (Nadine), Tworoger, S. (Shelley), Van Altena, A.M. (Anne M.), Van Den Berg, D. (David), Van Der Hout, A.H. (Annemarie H.), Luijt, R.B. (Rob) van der, Van Heetvelde, M. (Mattias), Van Nieuwenhuysen, E. (Els), Rensburg, E.J. (Elizabeth) van, Vanderstichele, A. (Adriaan), Varon-Mateeva, R. (Raymonda), Vega, A. (Ana), Edwards, D.V. (Digna Velez), Vergote, I., Vierkant, R.A. (Robert), Vijai, J. (Joseph), Vratimos, A. (Athanassios), Walker, L.J. (Lisa), Walsh, C. (Christine), Wand, D. (Dorothea), Wang-Gohrke, S. (Shan), Wappenschmidt, B. (Barbara), Webb, P.M. (Penelope M.), Weinberg, C.R. (Clarice R.), Weitzel, J.N. (Jeffrey), Wentzensen, N. (N.), Whittemore, A.S. (Alice), Wijnen, J.T. (Juul), Wilkens, L.R. (Lynne), Wolk, K. (Kerstin), Woo, M. (Michelle), Wu, X. (Xifeng), Wu, A.H. (Anna), Yang, H.P. (Hannah), Yannoukakos, D. (Drakoulis), Ziogas, A. (Argyrios), Zorn, K.K. (Kristin K.), Narod, S.A. (Steven A.), Easton, D.F. (Douglas), Amos, W., Schildkraut, J.M. (Joellen), Ramus, S.J. (Susan), Ottini, L. (Laura), Goodman, M.T. (Marc), Park, S.K. (Sue K.), Kelemen, L.E. (Linda), Risch, H. (Harvey), Thomassen, M. (Mads), Offit, K. (Kenneth), Simard, J. (Jacques), Schmutzler, R.K. (Rita), Hazelett, D. (Dennis), Monteiro, A.N.A. (Alvaro N.), Couch, F.J. (Fergus), Berchuck, A. (Andrew), Chenevix-Trench, G. (Georgia), Goode, E.L. (Ellen), Sellers, T.F., Gayther, S.A. (Simon), Antoniou, A.C. (Antonis), and Pharoah, P.D.P. (Paul)
Abstract: To identify common alleles associated with different histotypes of epithelial ovarian cancer (EOC), we pooled data from multiple genome-wide genotyping projects totaling 25,509 EOC cases and 40,941 controls. We identified nine new susceptibility loci for different EOC histotypes: six for serous EOC histotypes (3q28, 4q32.3, 8q21.11, 10q24.33, 18q11.2 and 22q12.1), two for mucinous EOC (3q22.3 and 9q31.1) and one for endometrioid EOC (5q12.3). We then performed meta-analysis on the results for high-grade serous ovarian cancer with the results from analysis of 31,448 BRCA1 and BRCA2 mutation carriers, including 3,887 mutation carriers with EOC. This identified three additional susceptibility loci at 2q13, 8q24.1 and 12q24.31. Integrated analyses of genes and regulatory biofeatures at each locus predicted candidate susceptibility genes, including OBFC1, a new candidate susceptibility gene for low-grade and borderline serous EOC.
Published: 2017
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26. BRCA2 polymorphic stop codon K3326X and the risk of breast, prostate, and ovarian cancers

Author: Meeks, H.D., Song, H.L., Michailidou, K., Bolla, M.K., Dennis, J., Wang, Q., Barrowdale, D., Frost, D., McGuffog, L., Ellis, S., Feng, B.J., Buys, S.S., Hopper, J.L., Southey, M.C., Tesoriero, A., James, P.A., Bruinsma, F., Campbell, I.G., Broeks, A., Schmidt, M.K., Hogervorst, F.B.L., Beckman, M.W., Fasching, P.A., Fletcher, O., Johnson, N., Sawyer, E.J., Riboli, E., Banerjee, S., Menon, U., Tomlinson, I., Burwinkel, B., Hamann, U., Marme, F., Rudolph, A., Janavicius, R., Tihomirova, L., Tung, N., Garber, J., Cramer, D., Terry, K.L., Poole, E.M., Tworoger, S.S., Dorfling, C.M., Rensburg, E.J. van, Godwin, A.K., Guenel, P., Truong, T., Stoppa-Lyonnet, D., Damiola, F., Mazoyer, S., Sinilnikova, O.M., Isaacs, C., Maugard, C., Bojesen, S.E., Flyger, H., Gerdes, A.M., Hansen, T.V.O., Jensen, A., Kjaer, S.K., Hogdall, C., Hogdall, E., Pedersen, I.S., Thomassen, M., Benitez, J., Gonzalez-Neira, A., Osorio, A., Hoya, M. de la, Segura, P.P., Diez, O., Lazaro, C., Brunet, J., Anton-Culver, H., Eunjung, L., John, E.M., Neuhausen, S.L., Ding, Y.C., Castillo, D., Weitzel, J.N., Ganz, P.A., Nussbaum, R.L., Chan, S.B., Karlan, B.Y., Lester, J., Wu, A., Gayther, S., Ramus, S.J., Sieh, W., Whittermore, A.S., Monteiro, A.N.A., Phelan, C.M., Terry, M.B., Piedmonte, M., Offit, K., Robson, M., Levine, D., Moysich, K.B., Cannioto, R., Olson, S.H., Daly, M.B., Nathanson, K.L., Domchek, S.M., Lu, K.H., Liang, D., Hildebrant, M.A.T., Ness, R., Modugno, F., Pearce, L., Goodman, M.T., Thompson, P.J., Brenner, H., Butterbach, K., Meindl, A., Hahnen, E., Wappenschmidt, B., Brauch, H., Bruning, T., Blomqvist, C., Khan, S., Nevanlinna, H., Pelttari, L.M., Aittomaki, K., Butzow, R., Bogdanova, N.V., Dork, T., Lindblom, A., Margolin, S., Rantala, J., Kosma, V.M., Mannermaa, A., Lambrechts, D., Neven, P., Claes, K.B.M., Maerken, T. van, Chang-Claude, J., Flesch-Janys, D., Heitz, F., Varon-Mateeva, R., Peterlongo, P., Radice, P., Viel, A., Barile, M., Peissel, B., Manoukian, S., Montagna, M., Oliani, C., Peixoto, A., Teixeira, M.R., Collavoli, A., Hallberg, E., Olson, J.E., Goode, E.L., Hart, S.N., Shimelis, H., Cunningham, J.M., Giles, G.G., Milne, R.L., Healey, S., Tucker, K., Haiman, C.A., Henderson, B.E., Goldberg, M.S., Tischkowitz, M., Simard, J., Soucy, P., Eccles, D.M., N. le, Borresen-Dale, A.L., Kristensen, V., Salvesen, H.B., Bjorge, L., Bandera, E.V., Risch, H., Zheng, W., Beeghly-Fadiel, A., Cai, H., Pylkas, K., Tollenaar, R.A.E.M., Ouweland, A.M.W. van der, Andrulis, I.L., Knight, J.A., Narod, S., Devilee, P., Winqvist, R., Figueroa, J., Greene, M.H., Mai, P.L., Loud, J.T., Garcia-Closas, M., Schoemaker, M.J., Czene, K., Darabi, H., McNeish, I., Siddiquil, N., Glasspool, R., Kwong, A., Park, S.K., Teo, S.H., Yoon, S.Y., Matsuo, K., Hosono, S., Woo, Y.L., Gao, Y.T., Foretova, L., Singer, C.F., Rappaport-Feurhauser, C., Friedman, E., Laitman, Y., Rennert, G., Imyanitov, E.N., Hulick, P.J., Olopade, O.I., Senter, L., Olah, E., Doherty, J.A., Schildkraut, J., Koppert, L.B., Kiemeney, L.A., Massuger, L.F.A.G., Cook, L.S., Pejovic, T., Li, J.M., Borg, A., Ofverholm, A., Rossing, M.A., Wentzensen, N., Henriksson, K., Cox, A., Cross, S.S., Pasini, B.J., Shah, M., Kabisch, M., Torres, D., Jakubowska, A., Lubinski, J., Gronwald, J., Agnarsson, B.A., Kupryjanczyk, J., Moes-Sosnowska, J., Fostira, F., Konstantopoulou, I., Slager, S., Jones, M., Antoniou, A.C., Berchuck, A., Swerdlow, A., Chenevix-Trench, G., Dunning, A.M., Pharoah, P.D.P., Hall, P., Easton, D.F., Couch, F.J., Spurdle, A.B., Goldgar, D.E., EMBRACE, kConFab Investigators, Australia Ovarian Canc Study Grp, HEBON, GEMO Study Collaborators, OCGN, PRostate Canc Assoc Grp, Damage and Repair in Cancer Development and Cancer Treatment (DARE), Targeted Gynaecologic Oncology (TARGON), Clinical Genetics, Obstetrics & Gynecology, Surgery, and [ 1 ] Univ Utah, Huntsman Canc Inst, Canc Control & Populat Sci, Salt Lake City, UT USA [ 2 ] Univ Cambridge, Dept Oncol, Ctr Canc Genet Epidemiol, Cambridge, England [ 3 ] Univ Cambridge, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Cambridge, England [ 4 ] Univ Utah, Sch Med, Huntsman Canc Inst, Dept Dermatol, 2000 Circle Hope Dr, Salt Lake City, UT 84112 USA [ 5 ] Univ Utah, Sch Med, Dept Med, Huntsman Canc Inst, Salt Lake City, UT USA [ 6 ] Univ Melbourne, Melbourne Sch Populat & Global Hlth, Ctr Epidemiol & Biostat, Melbourne, Vic, Australia [ 7 ] Univ Melbourne, Dept Pathol, Melbourne, Vic, Australia [ 8 ] Univ Melbourne, Dept Pathol, Genet Epidemiol Lab, Parkville, Vic 3052, Australia [ 9 ] KConFab Kathleen Cuningham Consortium Res Familia, Peter MacCallum Canc Ctr, Melbourne, Vic, Australia [ 10 ] Peter MacCallum Canc Ctr, Familial Canc Ctr, Melbourne, Vic, Australia [ 11 ] Univ Melbourne, Dept Oncol, Melbourne, Vic, Australia [ 12 ] Canc Council Victoria, Canc Epidemiol Ctr, Melbourne, Vic, Australia [ 13 ] Univ Melbourne, Peter MacCallum Canc Ctr, Sir Peter MacCallum Dept Oncol, Parkville, Vic 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Hosp Cologne, Ctr Familial Breast & Ovarian Canc, Cologne, Germany [ 112 ] Univ Hosp Cologne, Dept Obstet & Gynaecol, Cologne, Germany [ 113 ] Dr Margarete Fischer Bosch Inst Clin Pharmacol, Auerbachstr 112, Stuttgart, Germany [ 114 ] Univ Tubingen, Tubingen, Germany [ 115 ] Ruhr Univ Bochum IPA, German Social Accid Insurance & Inst, Inst Prevent & Occupat Med, Bochum, Germany [ 116 ] Univ Helsinki, Dept Oncol, Helsinki, Finland [ 117 ] Helsinki Univ Hosp, Helsinki, Finland [ 118 ] Univ Helsinki, Dept Obstet & Gynecol, Helsinki, Finland [ 119 ] Univ Helsinki, Dept Clin Genet, Helsinki, Finland [ 120 ] Univ Helsinki, Dept Pathol, Helsinki, Finland [ 121 ] Hannover Med Sch, Gynaecol Res Unit, Hannover, Germany [ 122 ] Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden [ 123 ] Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden [ 124 ] Karolinska Univ Hosp, Dept Clin Genet, Stockholm, Sweden [ 125 ] Univ Eastern Finland, Inst Clin Med Pathol & Forens Med, Sch Med, Kuopio, Finland [ 126 ] Kuopio Univ Hosp, Dept Clin Pathol, Imaging Ctr, SF-70210 Kuopio, Finland [ 127 ] Kuopio Univ Hosp, Ctr Canc, SF-70210 Kuopio, Finland [ 128 ] VIB, VRC, Leuven, Belgium [ 129 ] Univ Leuven, Dept Oncol, Lab Translat Genet, Leuven, Belgium [ 130 ] Univ Hosp Leuven, Dept Oncol, Multidisciplinary Breast Ctr, Leuven, Belgium [ 131 ] Univ Ghent, Ctr Med Genet, B-9000 Ghent, Belgium [ 132 ] Univ Med Ctr Hamburg Eppendorf, Inst Med Biometr & Epidemiol, Hamburg, Germany [ 133 ] Univ Med Ctr Hamburg Eppendorf, Clin Canc Registry, Dept Canc Epidemiol, Hamburg, Germany [ 134 ] Kliniken Essen Mitte Evang Huyssens Stiftung Knap, Dept Gynecol & Gynecol Oncol, Essen, Germany [ 135 ] Dr Horst Schmidt Kliniken Wiesbaden, Dept Gynecol & Gynecol Oncol, Wiesbaden, Germany [ 136 ] Charite, Campus Virchov Klinikum, Inst Human Genet, Berlin, Germany [ 137 ] Fdn Ist FIRC Oncol Mol, IFOM, Milan, Italy [ 138 ] Fdn IRCCS Ist Nazl Tumori, Dept Prevent & Predict Med, Unit Mol Bases Genet Risk & Genet Testing, 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Athens, Greece [ 232 ] Duke Univ, Med Ctr, Dept Obstet & Gynecol, Durham, NC 27710 USA
Subjects: 0301 basic medicine, Oncology, Male, Cancer Research, endocrine system diseases, LOCI, Estrogen receptor, FAMILY-HISTORY, Prostate cancer, 0302 clinical medicine, Ovarian Neoplasms/pathology, Prostate, Risk Factors, Brjóstakrabbamein, Odds Ratio, skin and connective tissue diseases, Ovarian Neoplasms, Women's cancers Radboud Institute for Molecular Life Sciences [Radboudumc 17], Prostatic Neoplasms/genetics, Research Support, Non-U.S. Gov't, SINGLE-NUCLEOTIDE POLYMORPHISMS, Middle Aged, BRCA2 Protein/genetics, PANCREATIC-CANCER, 3. Good health, SUSCEPTIBILITY GENE, medicine.anatomical_structure, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], 030220 oncology & carcinogenesis, Codon, Terminator, Female, Risk Factors Substances, Adult, medicine.medical_specialty, Heterozygote, Breast Neoplasms, Blöðruhálskirtilskrabbamein, Breast Neoplasms/genetics, Biology, Polymorphism, Single Nucleotide, Risk Assessment, Article, Ovarian Neoplasms/genetics, 03 medical and health sciences, Breast cancer, SDG 3 - Good Health and Well-being, Research Support, N.I.H., Extramural, Internal medicine, Pancreatic cancer, Krabbameinsrannsóknir, medicine, Journal Article, Humans, Genetic Predisposition to Disease, Neoplasm Invasiveness, Lysine/genetics, Krabbamein, Aged, Gynecology, BRCA2 Protein, Proportional hazards model, Lysine, DNA RECOMBINATION, CONSORTIUM, GERM-LINE MUTATION, Prostatic Neoplasms, Odds ratio, Arfgengi, medicine.disease, ESTROGEN-RECEPTOR, 030104 developmental biology, Logistic Models, PTT12, Eggjastokkar, FANCONI-ANEMIA, Ovarian cancer
Abstract: Contains fulltext : 172007.pdf (Publisher’s version ) (Closed access) BACKGROUND: The K3326X variant in BRCA2 (BRCA2*c.9976A>T; p.Lys3326*; rs11571833) has been found to be associated with small increased risks of breast cancer. However, it is not clear to what extent linkage disequilibrium with fully pathogenic mutations might account for this association. There is scant information about the effect of K3326X in other hormone-related cancers. METHODS: Using weighted logistic regression, we analyzed data from the large iCOGS study including 76 637 cancer case patients and 83 796 control patients to estimate odds ratios (ORw) and 95% confidence intervals (CIs) for K3326X variant carriers in relation to breast, ovarian, and prostate cancer risks, with weights defined as probability of not having a pathogenic BRCA2 variant. Using Cox proportional hazards modeling, we also examined the associations of K3326X with breast and ovarian cancer risks among 7183 BRCA1 variant carriers. All statistical tests were two-sided. RESULTS: The K3326X variant was associated with breast (ORw = 1.28, 95% CI = 1.17 to 1.40, P = 5.9x10(-) (6)) and invasive ovarian cancer (ORw = 1.26, 95% CI = 1.10 to 1.43, P = 3.8x10(-3)). These associations were stronger for serous ovarian cancer and for estrogen receptor-negative breast cancer (ORw = 1.46, 95% CI = 1.2 to 1.70, P = 3.4x10(-5) and ORw = 1.50, 95% CI = 1.28 to 1.76, P = 4.1x10(-5), respectively). For BRCA1 mutation carriers, there was a statistically significant inverse association of the K3326X variant with risk of ovarian cancer (HR = 0.43, 95% CI = 0.22 to 0.84, P = .013) but no association with breast cancer. No association with prostate cancer was observed. CONCLUSIONS: Our study provides evidence that the K3326X variant is associated with risk of developing breast and ovarian cancers independent of other pathogenic variants in BRCA2. Further studies are needed to determine the biological mechanism of action responsible for these associations.
Published: 2016

27. The association between socioeconomic status and tumour stage at diagnosis of ovarian cancer: A pooled analysis of 18 case-control studies

Author: Praestegaard, C., Kjaer, S.K., Nielsen, T.S., Jensen, S.M., Webb, P.M., Nagle, C.M., Hogdall, E., Risch, H.A., Rossing, M.A., Doherty, J.A., Wicklund, K.G., Goodman, M.T., Modugno, F., Moysich, K., Ness, R.B., Edwards, R.P., Goode, E.L., Winham, S.J., Fridley, B.L., Cramer, D.W, Terry, K.L., Schildkraut, J.M., Berchuck, A., Bandera, E.V., Paddock, L., Kiemeney, L.A., Massuger, L.F., Wentzensen, N., Pharoah, P., Song, H., Whittemore, A.S., McGuire, V., Sieh, W., Rothstein, J., Anton-Culver, H., Ziogas, A., Menon, U., Gayther, S.A., Ramus, S.J., Gentry-Maharaj, A., Wu, A.H., Pearce, C.L., Pike, M.C., Lee, A.W., Chang-Claude, J., Jensen, A., Praestegaard, C., Kjaer, S.K., Nielsen, T.S., Jensen, S.M., Webb, P.M., Nagle, C.M., Hogdall, E., Risch, H.A., Rossing, M.A., Doherty, J.A., Wicklund, K.G., Goodman, M.T., Modugno, F., Moysich, K., Ness, R.B., Edwards, R.P., Goode, E.L., Winham, S.J., Fridley, B.L., Cramer, D.W, Terry, K.L., Schildkraut, J.M., Berchuck, A., Bandera, E.V., Paddock, L., Kiemeney, L.A., Massuger, L.F., Wentzensen, N., Pharoah, P., Song, H., Whittemore, A.S., McGuire, V., Sieh, W., Rothstein, J., Anton-Culver, H., Ziogas, A., Menon, U., Gayther, S.A., Ramus, S.J., Gentry-Maharaj, A., Wu, A.H., Pearce, C.L., Pike, M.C., Lee, A.W., Chang-Claude, J., and Jensen, A.
Abstract: Contains fulltext : 171697.pdf (publisher's version ) (Closed access), PURPOSE: Socioeconomic status (SES) is a known predictor of survival for several cancers and it has been suggested that SES differences affecting tumour stage at diagnosis may be the most important explanatory factor for this. However, only a limited number of studies have investigated SES differences in tumour stage at diagnosis of ovarian cancer. In a pooled analysis, we investigated whether SES as represented by level of education is predictive for advanced tumour stage at diagnosis of ovarian cancer, overall and by histotype. The effect of cigarette smoking and body mass index (BMI) on the association was also evaluated. METHODS: From 18 case-control studies, we obtained information on 10,601 women diagnosed with epithelial ovarian cancer. Study specific odds ratios (ORs) with corresponding 95% confidence intervals (CI) were obtained from logistic regression models and combined into a pooled odds ratio (pOR) using a random effects model. RESULTS: Overall, women who completed high school (pOR 1.15; 95% CI 1.03-1.28). The risk estimates for the different histotypes of ovarian cancer resembled that observed for ovarian cancers combined but did not reach statistical significance. Our results were unchanged when we included BMI and cigarette smoking. CONCLUSION: Lower level of education was associated with an increased risk of advanced tumour stage at diagnosis of ovarian cancer. The observed socioeconomic difference in stage at diagnosis of ovarian cancer calls for further studies on how to reduce this diagnostic delay.
Published: 2016

28. Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus

Author: Lawrenson, K., Kar, S., McCue, K., Kuchenbaeker, K., Michailidou, K., Tyrer, J., Beesley, J., Ramus, S.J., Li, Q., Delgado, M.K., Lee, J.M., Aittomaki, K., Andrulis, I.L., Anton-Culver, H., Arndt, V., Arun, B.K., Arver, B., Bandera, E.V., Barile, M., Barkardottir, R.B., Barrowdale, D., Beckmann, M.W., Benitez, J., Berchuck, A., Bisogna, M., Bjorge, L., Blomqvist, C., Blot, W., Bogdanova, N., Bojesen, A., Bojesen, S.E., Bolla, M.K., Bonanni, B., Borresen-Dale, A.L., Brauch, H., Brennan, P., Brenner, H., Bruinsma, F., Brunet, J., Buhari, S.A., Burwinkel, B., Butzow, R., Buys, S.S., Cai, Q., Caldes, T., Campbell, I., Canniotto, R., Chang-Claude, J., Chiquette, J., Choi, J.Y., Claes, K.B., Cook, L.S., Cox, A, Cramer, D.W, Cross, S.S., Cybulski, C., Czene, K., Daly, M.B., Damiola, F., Dansonka-Mieszkowska, A., Darabi, H., Dennis, J., Devilee, P., Diez, O., Doherty, J.A., Domchek, S.M., Dorfling, C.M., Dork, T., Dumont, M., Ehrencrona, H., Ejlertsen, B., Ellis, S., Engel, C., Lee, E., Evans, D.G., Fasching, P.A., Feliubadalo, L., Figueroa, J., Flesch-Janys, D., Fletcher, O., Flyger, H., Foretova, L., Fostira, F., Foulkes, W.D., Fridley, B.L., Friedman, E., Frost, D., Gambino, G., Ganz, P.A., Garber, J., Garcia-Closas, M., Gentry-Maharaj, A., Ghoussaini, M., Giles, G.G., Glasspool, R., Godwin, A.K., Goldberg, M.S., Goldgar, D.E., Gonzalez-Neira, A., Goode, E.L., Kiemeney, B., Massuger, L.F.A.G., Mensenkamp, A.R., et al., Lawrenson, K., Kar, S., McCue, K., Kuchenbaeker, K., Michailidou, K., Tyrer, J., Beesley, J., Ramus, S.J., Li, Q., Delgado, M.K., Lee, J.M., Aittomaki, K., Andrulis, I.L., Anton-Culver, H., Arndt, V., Arun, B.K., Arver, B., Bandera, E.V., Barile, M., Barkardottir, R.B., Barrowdale, D., Beckmann, M.W., Benitez, J., Berchuck, A., Bisogna, M., Bjorge, L., Blomqvist, C., Blot, W., Bogdanova, N., Bojesen, A., Bojesen, S.E., Bolla, M.K., Bonanni, B., Borresen-Dale, A.L., Brauch, H., Brennan, P., Brenner, H., Bruinsma, F., Brunet, J., Buhari, S.A., Burwinkel, B., Butzow, R., Buys, S.S., Cai, Q., Caldes, T., Campbell, I., Canniotto, R., Chang-Claude, J., Chiquette, J., Choi, J.Y., Claes, K.B., Cook, L.S., Cox, A, Cramer, D.W, Cross, S.S., Cybulski, C., Czene, K., Daly, M.B., Damiola, F., Dansonka-Mieszkowska, A., Darabi, H., Dennis, J., Devilee, P., Diez, O., Doherty, J.A., Domchek, S.M., Dorfling, C.M., Dork, T., Dumont, M., Ehrencrona, H., Ejlertsen, B., Ellis, S., Engel, C., Lee, E., Evans, D.G., Fasching, P.A., Feliubadalo, L., Figueroa, J., Flesch-Janys, D., Fletcher, O., Flyger, H., Foretova, L., Fostira, F., Foulkes, W.D., Fridley, B.L., Friedman, E., Frost, D., Gambino, G., Ganz, P.A., Garber, J., Garcia-Closas, M., Gentry-Maharaj, A., Ghoussaini, M., Giles, G.G., Glasspool, R., Godwin, A.K., Goldberg, M.S., Goldgar, D.E., Gonzalez-Neira, A., Goode, E.L., Kiemeney, B., Massuger, L.F.A.G., Mensenkamp, A.R., and et al.
Abstract: Contains fulltext : 172592.pdf (publisher's version ) (Open Access), A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 x 10(-20)), ER-negative BC (P=1.1 x 10(-13)), BRCA1-associated BC (P=7.7 x 10(-16)) and triple negative BC (P-diff=2 x 10(-5)). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 x 10(-3)) and ABHD8 (P<2 x 10(-3)). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3'-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk.
Published: 2016

29. No clinical utility of KRAS variant rs61764370 for ovarian or breast cancer

Author: Hollestelle, A., Baan, F.H. van der, Berchuck, A., Johnatty, S.E., Aben, K.K.H., Agnarsson, B.A., Aittomaki, K., Alducci, E., Andrulis, I.L., Anton-Culver, H., Antonenkova, N.N., Antoniou, A.C., Apicella, C., Arndt, V., Arnold, N., Arun, B.K., Arver, B., Ashworth, A., Baglietto, L., Balleine, R., Bandera, E.V., Barrowdale, D., Bean, Y.T., Beckmann, L., Beckmann, M.W., Benitez, J., Berger, A., Berger, R., Beuselinck, B., Bisogna, M., Bjorge, L., Blomqvist, C., Bogdanova, N.V., Bojesen, A., Bojesen, S.E., Bolla, M.K., Bonanni, B., Brand, J.S., Brauch, H., Brenner, H., Brinton, L., Brooks-Wilson, A., Bruinsma, F., Brunet, J., Bruning, T., Budzilowska, A., Bunker, C.H., Burwinkel, B., Butzow, R., Buys, S.S., Caligo, M.A., Campbell, I., Carter, J., Chang-Claude, J., Chanock, S.J., Claes, K.B., Collee, J.M., Cook, L.S., Couch, F.J., Cox, A, Cramer, D., Cross, S.S., Cunningham, J.M., Cybulski, C., Czene, K., Damiola, F., Dansonka-Mieszkowska, A., Darabi, H., Hoya, M. de la, Defazio, A., Dennis, J., Devilee, P., Dicks, E.M., Diez, O., Doherty, J.A., Domchek, S.M., Dorfling, C.M., Dork, T., Silva Idos, S., Bois, A. du, Dumont, M., Dunning, A.M., Duran, M., Easton, D.F., Eccles, D., Edwards, R.P., Ehrencrona, H., Ejlertsen, B., Ekici, A.B., Ellis, S.D., Engel, C., Eriksson, M., Fasching, P.A., Feliubadalo, L., Figueroa, J., Flesch-Janys, D., Fletcher, O., Fontaine, A., Fortuzzi, S., Fostira, F., Kiemeney, L.A.L.M., Massuger, L.F.A.G., Mensenkamp, A.R., et al., Hollestelle, A., Baan, F.H. van der, Berchuck, A., Johnatty, S.E., Aben, K.K.H., Agnarsson, B.A., Aittomaki, K., Alducci, E., Andrulis, I.L., Anton-Culver, H., Antonenkova, N.N., Antoniou, A.C., Apicella, C., Arndt, V., Arnold, N., Arun, B.K., Arver, B., Ashworth, A., Baglietto, L., Balleine, R., Bandera, E.V., Barrowdale, D., Bean, Y.T., Beckmann, L., Beckmann, M.W., Benitez, J., Berger, A., Berger, R., Beuselinck, B., Bisogna, M., Bjorge, L., Blomqvist, C., Bogdanova, N.V., Bojesen, A., Bojesen, S.E., Bolla, M.K., Bonanni, B., Brand, J.S., Brauch, H., Brenner, H., Brinton, L., Brooks-Wilson, A., Bruinsma, F., Brunet, J., Bruning, T., Budzilowska, A., Bunker, C.H., Burwinkel, B., Butzow, R., Buys, S.S., Caligo, M.A., Campbell, I., Carter, J., Chang-Claude, J., Chanock, S.J., Claes, K.B., Collee, J.M., Cook, L.S., Couch, F.J., Cox, A, Cramer, D., Cross, S.S., Cunningham, J.M., Cybulski, C., Czene, K., Damiola, F., Dansonka-Mieszkowska, A., Darabi, H., Hoya, M. de la, Defazio, A., Dennis, J., Devilee, P., Dicks, E.M., Diez, O., Doherty, J.A., Domchek, S.M., Dorfling, C.M., Dork, T., Silva Idos, S., Bois, A. du, Dumont, M., Dunning, A.M., Duran, M., Easton, D.F., Eccles, D., Edwards, R.P., Ehrencrona, H., Ejlertsen, B., Ekici, A.B., Ellis, S.D., Engel, C., Eriksson, M., Fasching, P.A., Feliubadalo, L., Figueroa, J., Flesch-Janys, D., Fletcher, O., Fontaine, A., Fortuzzi, S., Fostira, F., Kiemeney, L.A.L.M., Massuger, L.F.A.G., Mensenkamp, A.R., and et al.
Abstract: Contains fulltext : 167534.pdf (publisher's version ) (Closed access), OBJECTIVE: Clinical genetic testing is commercially available for rs61764370, an inherited variant residing in a KRAS 3' UTR microRNA binding site, based on suggested associations with increased ovarian and breast cancer risk as well as with survival time. However, prior studies, emphasizing particular subgroups, were relatively small. Therefore, we comprehensively evaluated ovarian and breast cancer risks as well as clinical outcome associated with rs61764370. METHODS: Centralized genotyping and analysis were performed for 140,012 women enrolled in the Ovarian Cancer Association Consortium (15,357 ovarian cancer patients; 30,816 controls), the Breast Cancer Association Consortium (33,530 breast cancer patients; 37,640 controls), and the Consortium of Modifiers of BRCA1 and BRCA2 (14,765 BRCA1 and 7904 BRCA2 mutation carriers). Results : We found no association with risk of ovarian cancer (OR=0.99, 95% CI 0.94-1.04, p=0.74) or breast cancer (OR=0.98, 95% CI 0.94-1.01, p=0.19) and results were consistent among mutation carriers (BRCA1, ovarian cancer HR=1.09, 95% CI 0.97-1.23, p=0.14, breast cancer HR=1.04, 95% CI 0.97-1.12, p=0.27; BRCA2, ovarian cancer HR=0.89, 95% CI 0.71-1.13, p=0.34, breast cancer HR=1.06, 95% CI 0.94-1.19, p=0.35). Null results were also obtained for associations with overall survival following ovarian cancer (HR=0.94, 95% CI 0.83-1.07, p=0.38), breast cancer (HR=0.96, 95% CI 0.87-1.06, p=0.38), and all other previously-reported associations. CONCLUSIONS: rs61764370 is not associated with risk of ovarian or breast cancer nor with clinical outcome for patients with these cancers. Therefore, genotyping this variant has no clinical utility related to the prediction or management of these cancers.
Published: 2016

30. Assessing the genetic architecture of epithelial ovarian cancer histological subtypes

Author: Cuellar-Partida, G., Lu, Y., Dixon, S.C., Fasching, P.A., Hein, A., Burghaus, S., Beckmann, M.W., Lambrechts, D., Nieuwenhuysen, E. Van, Vergote, I., Vanderstichele, A., Doherty, J.A., Rossing, M.A., Chang-Claude, J., Rudolph, A., Wang-Gohrke, S., Goodman, M.T., Bogdanova, N., Dork, T., Durst, M., Hillemanns, P., Runnebaum, I.B., Antonenkova, N., Butzow, R., Leminen, A., Nevanlinna, H., Pelttari, L.M., Edwards, R.P., Kelley, J.L., Modugno, F., Moysich, K.B., Ness, R.B., Cannioto, R., Hogdall, E., Hogdall, C., Jensen, A., Giles, G.G., Bruinsma, F., Kjaer, S.K., Hildebrandt, M.A.T., Liang, D., Lu, K.H., Wu, X., Bisogna, M., Dao, F., Levine, D.A., Cramer, D.W, Terry, K.L., Tworoger, S.S., Stampfer, M., Missmer, S., Bjorge, L., Salvesen, H.B., Kopperud, R.K., Bischof, K., Aben, K.K.H., Kiemeney, L.A.L.M., Massuger, L.F.A.G., Brooks-Wilson, A., Olson, S.H., McGuire, V., Rothstein, J.H., Sieh, W., Whittemore, A.S., Cook, L.S., Le, N.D., Gilks, C. Blake, Gronwald, J., Jakubowska, A., Lubinski, J., Kluz, T., Song, H., Tyrer, J.P., Wentzensen, N., Brinton, L., Trabert, B., Lissowska, J., McLaughlin, J.R., Narod, S.A., Phelan, C., Anton-Culver, H., Ziogas, A., Eccles, D., Campbell, I., Gayther, S.A., Gentry-Maharaj, A., Menon, U., Ramus, S.J., Wu, A.H., Dansonka-Mieszkowska, A., Kupryjanczyk, J., Timorek, A., Szafron, L., Cunningham, J.M., Fridley, B.L., Winham, S.J., Bandera, E.V., Poole, E.M., Morgan, T.K., Goode, E.L., Cuellar-Partida, G., Lu, Y., Dixon, S.C., Fasching, P.A., Hein, A., Burghaus, S., Beckmann, M.W., Lambrechts, D., Nieuwenhuysen, E. Van, Vergote, I., Vanderstichele, A., Doherty, J.A., Rossing, M.A., Chang-Claude, J., Rudolph, A., Wang-Gohrke, S., Goodman, M.T., Bogdanova, N., Dork, T., Durst, M., Hillemanns, P., Runnebaum, I.B., Antonenkova, N., Butzow, R., Leminen, A., Nevanlinna, H., Pelttari, L.M., Edwards, R.P., Kelley, J.L., Modugno, F., Moysich, K.B., Ness, R.B., Cannioto, R., Hogdall, E., Hogdall, C., Jensen, A., Giles, G.G., Bruinsma, F., Kjaer, S.K., Hildebrandt, M.A.T., Liang, D., Lu, K.H., Wu, X., Bisogna, M., Dao, F., Levine, D.A., Cramer, D.W, Terry, K.L., Tworoger, S.S., Stampfer, M., Missmer, S., Bjorge, L., Salvesen, H.B., Kopperud, R.K., Bischof, K., Aben, K.K.H., Kiemeney, L.A.L.M., Massuger, L.F.A.G., Brooks-Wilson, A., Olson, S.H., McGuire, V., Rothstein, J.H., Sieh, W., Whittemore, A.S., Cook, L.S., Le, N.D., Gilks, C. Blake, Gronwald, J., Jakubowska, A., Lubinski, J., Kluz, T., Song, H., Tyrer, J.P., Wentzensen, N., Brinton, L., Trabert, B., Lissowska, J., McLaughlin, J.R., Narod, S.A., Phelan, C., Anton-Culver, H., Ziogas, A., Eccles, D., Campbell, I., Gayther, S.A., Gentry-Maharaj, A., Menon, U., Ramus, S.J., Wu, A.H., Dansonka-Mieszkowska, A., Kupryjanczyk, J., Timorek, A., Szafron, L., Cunningham, J.M., Fridley, B.L., Winham, S.J., Bandera, E.V., Poole, E.M., Morgan, T.K., and Goode, E.L.
Abstract: Contains fulltext : 171782.pdf (publisher's version ) (Closed access), Epithelial ovarian cancer (EOC) is one of the deadliest common cancers. The five most common types of disease are high-grade and low-grade serous, endometrioid, mucinous and clear cell carcinoma. Each of these subtypes present distinct molecular pathogeneses and sensitivities to treatments. Recent studies show that certain genetic variants confer susceptibility to all subtypes while other variants are subtype-specific. Here, we perform an extensive analysis of the genetic architecture of EOC subtypes. To this end, we used data of 10,014 invasive EOC patients and 21,233 controls from the Ovarian Cancer Association Consortium genotyped in the iCOGS array (211,155 SNPs). We estimate the array heritability (attributable to variants tagged on arrays) of each subtype and their genetic correlations. We also look for genetic overlaps with factors such as obesity, smoking behaviors, diabetes, age at menarche and height. We estimated the array heritabilities of high-grade serous disease ([Formula: see text] = 8.8 +/- 1.1 %), endometrioid ([Formula: see text] = 3.2 +/- 1.6 %), clear cell ([Formula: see text] = 6.7 +/- 3.3 %) and all EOC ([Formula: see text] = 5.6 +/- 0.6 %). Known associated loci contributed approximately 40 % of the total array heritability for each subtype. The contribution of each chromosome to the total heritability was not proportional to chromosome size. Through bivariate and cross-trait LD score regression, we found evidence of shared genetic backgrounds between the three high-grade subtypes: serous, endometrioid and undifferentiated. Finally, we found significant genetic correlations of all EOC with diabetes and obesity using a polygenic prediction approach.
Published: 2016

31. Adult body mass index and risk of ovarian cancer by subtype: a Mendelian randomization study

Author: Dixon, S.C., Nagle, C.M., Thrift, A.P., Pharoah, P.D., Pearce, C.L., Zheng, W., Painter, J.N., Chenevix-Trench, G., Fasching, P.A., Beckmann, M.W., Lambrechts, D., Vergote, I., Lambrechts, S., Nieuwenhuysen, E. Van, Rossing, M.A., Doherty, J.A., Wicklund, K.G., Chang-Claude, J., Rudolph, A., Moysich, K.B., Odunsi, K., Goodman, M.T., Wilkens, L.R., Thompson, P.J., Shvetsov, Y.B., Dork, T., Park-Simon, T.W., Hillemanns, P., Bogdanova, N., Butzow, R., Nevanlinna, H., Pelttari, L.M., Leminen, A., Modugno, F., Ness, R.B., Edwards, R.P., Kelley, J.L., Heitz, F., Karlan, B.Y., Kjaer, S.K., Hogdall, E., Jensen, A., Goode, E.L., Fridley, B.L., Cunningham, J.M., Winham, S.J., Giles, G.G., Bruinsma, F., Milne, R.L., Southey, M.C., Hildebrandt, M.A.T., Wu, X., Lu, K.H., Liang, D., Levine, D.A., Bisogna, M., Schildkraut, J.M., Berchuck, A., Cramer, D.W, Terry, K.L., Bandera, E.V., Olson, S.H., Salvesen, H.B., Thomsen, L.C., Kopperud, R.K., Bjorge, L., Kiemeney, L.A.L.M., Massuger, L.F.A.G., Pejovic, T., Cook, L.S., Le, N.D., Swenerton, K.D., Brooks-Wilson, A., Kelemen, L.E., Lubinski, J., Huzarski, T., Gronwald, J., Menkiszak, J., Wentzensen, N., Brinton, L., Yang, H., Lissowska, J., Hogdall, C.K., Lundvall, L., Song, H., Tyrer, J.P., Campbell, I., Eccles, D., Paul, J., Glasspool, R., Siddiqui, N., Whittemore, A.S., Sieh, W., McGuire, V., Rothstein, J.H., Narod, S.A., Phelan, C., Risch, H.A., McLaughlin, J.R., Anton-Culver, H., et al., Dixon, S.C., Nagle, C.M., Thrift, A.P., Pharoah, P.D., Pearce, C.L., Zheng, W., Painter, J.N., Chenevix-Trench, G., Fasching, P.A., Beckmann, M.W., Lambrechts, D., Vergote, I., Lambrechts, S., Nieuwenhuysen, E. Van, Rossing, M.A., Doherty, J.A., Wicklund, K.G., Chang-Claude, J., Rudolph, A., Moysich, K.B., Odunsi, K., Goodman, M.T., Wilkens, L.R., Thompson, P.J., Shvetsov, Y.B., Dork, T., Park-Simon, T.W., Hillemanns, P., Bogdanova, N., Butzow, R., Nevanlinna, H., Pelttari, L.M., Leminen, A., Modugno, F., Ness, R.B., Edwards, R.P., Kelley, J.L., Heitz, F., Karlan, B.Y., Kjaer, S.K., Hogdall, E., Jensen, A., Goode, E.L., Fridley, B.L., Cunningham, J.M., Winham, S.J., Giles, G.G., Bruinsma, F., Milne, R.L., Southey, M.C., Hildebrandt, M.A.T., Wu, X., Lu, K.H., Liang, D., Levine, D.A., Bisogna, M., Schildkraut, J.M., Berchuck, A., Cramer, D.W, Terry, K.L., Bandera, E.V., Olson, S.H., Salvesen, H.B., Thomsen, L.C., Kopperud, R.K., Bjorge, L., Kiemeney, L.A.L.M., Massuger, L.F.A.G., Pejovic, T., Cook, L.S., Le, N.D., Swenerton, K.D., Brooks-Wilson, A., Kelemen, L.E., Lubinski, J., Huzarski, T., Gronwald, J., Menkiszak, J., Wentzensen, N., Brinton, L., Yang, H., Lissowska, J., Hogdall, C.K., Lundvall, L., Song, H., Tyrer, J.P., Campbell, I., Eccles, D., Paul, J., Glasspool, R., Siddiqui, N., Whittemore, A.S., Sieh, W., McGuire, V., Rothstein, J.H., Narod, S.A., Phelan, C., Risch, H.A., McLaughlin, J.R., and Anton-Culver, H., et al.
Abstract: Contains fulltext : 170949.pdf (publisher's version ) (Closed access), BACKGROUND: Observational studies have reported a positive association between body mass index (BMI) and ovarian cancer risk. However, questions remain as to whether this represents a causal effect, or holds for all histological subtypes. The lack of association observed for serous cancers may, for instance, be due to disease-associated weight loss. Mendelian randomization (MR) uses genetic markers as proxies for risk factors to overcome limitations of observational studies. We used MR to elucidate the relationship between BMI and ovarian cancer, hypothesizing that genetically predicted BMI would be associated with increased risk of non-high grade serous ovarian cancers (non-HGSC) but not HGSC. METHODS: We pooled data from 39 studies (14 047 cases, 23 003 controls) in the Ovarian Cancer Association Consortium. We constructed a weighted genetic risk score (GRS, partial F-statistic = 172), summing alleles at 87 single nucleotide polymorphisms previously associated with BMI, weighting by their published strength of association with BMI. Applying two-stage predictor-substitution MR, we used logistic regression to estimate study-specific odds ratios (OR) and 95% confidence intervals (CI) for the association between genetically predicted BMI and risk, and pooled these using random-effects meta-analysis. RESULTS: Higher genetically predicted BMI was associated with increased risk of non-HGSC (pooled OR = 1.29, 95% CI 1.03-1.61 per 5 units BMI) but not HGSC (pooled OR = 1.06, 95% CI 0.88-1.27). Secondary analyses stratified by behaviour/subtype suggested that, consistent with observational data, the association was strongest for low-grade/borderline serous cancers (OR = 1.93, 95% CI 1.33-2.81). CONCLUSIONS: Our data suggest that higher BMI increases risk of non-HGSC, but not the more common and aggressive HGSC subtype, confirming the observational evidence.
Published: 2016

32. Assessment of variation in immunosuppressive pathway genes reveals TGFBR2 to be associated with risk of clear cell ovarian cancer

Author: Hampras, S.S., Sucheston-Campbell, L.E., Cannioto, R., Chang-Claude, J., Modugno, F., Dork, T., Hillemanns, P., Preus, L., Knutson, K.L., Wallace, P.K., Hong, C.C., Friel, G., Davis, W., Nesline, M., Pearce, C.L., Kelemen, L.E., Goodman, M.T., Bandera, E.V., Terry, K.L., Schoof, N., Eng, K.H., Clay, A., Singh, P.K., Joseph, J.M., Aben, K.K.H., Anton-Culver, H., Antonenkova, N., Baker, H., Bean, Y., Beckmann, M.W., Bisogna, M., Bjorge, L., Bogdanova, N., Brinton, L.A., Brooks-Wilson, A., Bruinsma, F., Butzow, R., Campbell, I.G., Carty, K., Cook, L.S., Cramer, D.W, Cybulski, C., Dansonka-Mieszkowska, A., Dennis, J., Despierre, E., Dicks, E., Doherty, J.A., Bois, A. du, Durst, M., Easton, D., Eccles, D., Edwards, R.P., Ekici, A.B., Fasching, P.A., Fridley, B.L., Gao, Y.T., Gentry-Maharaj, A., Giles, G.G., Glasspool, R., Gronwald, J., Harrington, P., Harter, P., Hasmad, H.N., Hein, A., Heitz, F., Hildebrandt, M.A.T., Hogdall, C., Hogdall, E., Hosono, S., Iversen, E.S., Jakubowska, A., Jensen, A., Ji, B.T., Karlan, B.Y., Kellar, M., Kelley, J.L., Kiemeney, L.A.L.M., Klapdor, R., Kolomeyevskaya, N., Krakstad, C., Kjaer, S.K., Kruszka, B., Kupryjanczyk, J., Lambrechts, D., Lambrechts, S., Le, N.D., Lee, A.W., Lele, S., Leminen, A., Lester, J., Levine, D.A., Liang, D., Lissowska, J., Liu, S., Lu, K., Lubinski, J., Lundvall, L., Massuger, L.F.A.G., Matsuo, K., McGuire, V., et al., Hampras, S.S., Sucheston-Campbell, L.E., Cannioto, R., Chang-Claude, J., Modugno, F., Dork, T., Hillemanns, P., Preus, L., Knutson, K.L., Wallace, P.K., Hong, C.C., Friel, G., Davis, W., Nesline, M., Pearce, C.L., Kelemen, L.E., Goodman, M.T., Bandera, E.V., Terry, K.L., Schoof, N., Eng, K.H., Clay, A., Singh, P.K., Joseph, J.M., Aben, K.K.H., Anton-Culver, H., Antonenkova, N., Baker, H., Bean, Y., Beckmann, M.W., Bisogna, M., Bjorge, L., Bogdanova, N., Brinton, L.A., Brooks-Wilson, A., Bruinsma, F., Butzow, R., Campbell, I.G., Carty, K., Cook, L.S., Cramer, D.W, Cybulski, C., Dansonka-Mieszkowska, A., Dennis, J., Despierre, E., Dicks, E., Doherty, J.A., Bois, A. du, Durst, M., Easton, D., Eccles, D., Edwards, R.P., Ekici, A.B., Fasching, P.A., Fridley, B.L., Gao, Y.T., Gentry-Maharaj, A., Giles, G.G., Glasspool, R., Gronwald, J., Harrington, P., Harter, P., Hasmad, H.N., Hein, A., Heitz, F., Hildebrandt, M.A.T., Hogdall, C., Hogdall, E., Hosono, S., Iversen, E.S., Jakubowska, A., Jensen, A., Ji, B.T., Karlan, B.Y., Kellar, M., Kelley, J.L., Kiemeney, L.A.L.M., Klapdor, R., Kolomeyevskaya, N., Krakstad, C., Kjaer, S.K., Kruszka, B., Kupryjanczyk, J., Lambrechts, D., Lambrechts, S., Le, N.D., Lee, A.W., Lele, S., Leminen, A., Lester, J., Levine, D.A., Liang, D., Lissowska, J., Liu, S., Lu, K., Lubinski, J., Lundvall, L., Massuger, L.F.A.G., Matsuo, K., McGuire, V., and et al.
Abstract: Contains fulltext : 167177.pdf (publisher's version ) (Open Access), BACKGROUND: Regulatory T (Treg) cells, a subset of CD4+ T lymphocytes, are mediators of immunosuppression in cancer, and, thus, variants in genes encoding Treg cell immune molecules could be associated with ovarian cancer. METHODS: In a population of 15,596 epithelial ovarian cancer (EOC) cases and 23,236 controls, we measured genetic associations of 1,351 SNPs in Treg cell pathway genes with odds of ovarian cancer and tested pathway and gene-level associations, overall and by histotype, for the 25 genes, using the admixture likelihood (AML) method. The most significant single SNP associations were tested for correlation with expression levels in 44 ovarian cancer patients. RESULTS: The most significant global associations for all genes in the pathway were seen in endometrioid (p = 0.082) and clear cell (p = 0.083), with the most significant gene level association seen with TGFBR2 (p = 0.001) and clear cell EOC. Gene associations with histotypes at p < 0.05 included: IL12 (p = 0.005 and p = 0.008, serous and high-grade serous, respectively), IL8RA (p = 0.035, endometrioid and mucinous), LGALS1 (p = 0.03, mucinous), STAT5B (p = 0.022, clear cell), TGFBR1 (p = 0.021 endometrioid) and TGFBR2 (p = 0.017 and p = 0.025, endometrioid and mucinous, respectively). CONCLUSIONS: Common inherited gene variation in Treg cell pathways shows some evidence of germline genetic contribution to odds of EOC that varies by histologic subtype and may be associated with mRNA expression of immune-complex receptor in EOC patients.
Published: 2016

33. Genome-Wide Meta-Analyses of Breast, Ovarian, and Prostate Cancer Association Studies Identify Multiple New Susceptibility Loci Shared by at Least Two Cancer Types

Author: Kar, S.P., Beesley, J., Olama, A. Amin Al, Michailidou, K., Tyrer, J., Kote-Jarai, Z., Lawrenson, K., Lindstrom, S., Ramus, S.J., Thompson, D.J., Kibel, A.S., Dansonka-Mieszkowska, A., Michael, A., Dieffenbach, A.K., Gentry-Maharaj, A., Whittemore, A.S., Wolk, A., Monteiro, A., Peixoto, A., Kierzek, A., Cox, A, Rudolph, A., Gonzalez-Neira, A., Wu, A.H., Lindblom, A., Swerdlow, A., Ziogas, A., Ekici, A.B., Burwinkel, B., Karlan, B.Y., Nordestgaard, B.G., Blomqvist, C., Phelan, C., McLean, C., Pearce, C.L., Vachon, C., Cybulski, C., Slavov, C., Stegmaier, C., Maier, C., Ambrosone, C.B., Hogdall, C.K., Teerlink, C.C., Kang, D., Tessier, D.C., Schaid, D.J., Stram, D.O., Cramer, D.W, Neal, D.E., Eccles, D., Flesch-Janys, D., Edwards, D.R., Wokozorczyk, D., Levine, D.A., Yannoukakos, D., Sawyer, E.J., Bandera, E.V., Poole, E.M., Goode, E.L., Khusnutdinova, E., Hogdall, E., Song, F., Bruinsma, F., Heitz, F., Modugno, F., Hamdy, F.C., Wiklund, F., Giles, G.G., Olsson, H., Wildiers, H., Ulmer, H.U., Pandha, H., Risch, H.A., Darabi, H., Salvesen, H.B., Nevanlinna, H., Gronberg, H., Brenner, H., Brauch, H., Anton-Culver, H., Song, H., Lim, H.Y., McNeish, I., Campbell, I., Vergote, I., Gronwald, J., Lubinski, J., Stanford, J.L., Benitez, J., Doherty, J.A., Permuth, J.B., Chang-Claude, J., Donovan, J.L., Dennis, J., Schildkraut, J.M., Schleutker, J., Hopper, J.L., Kupryjanczyk, J., Park, J.Y., Figueroa, J., Kiemeney, L.A., Massuger, L.F.A.G., et al., Kar, S.P., Beesley, J., Olama, A. Amin Al, Michailidou, K., Tyrer, J., Kote-Jarai, Z., Lawrenson, K., Lindstrom, S., Ramus, S.J., Thompson, D.J., Kibel, A.S., Dansonka-Mieszkowska, A., Michael, A., Dieffenbach, A.K., Gentry-Maharaj, A., Whittemore, A.S., Wolk, A., Monteiro, A., Peixoto, A., Kierzek, A., Cox, A, Rudolph, A., Gonzalez-Neira, A., Wu, A.H., Lindblom, A., Swerdlow, A., Ziogas, A., Ekici, A.B., Burwinkel, B., Karlan, B.Y., Nordestgaard, B.G., Blomqvist, C., Phelan, C., McLean, C., Pearce, C.L., Vachon, C., Cybulski, C., Slavov, C., Stegmaier, C., Maier, C., Ambrosone, C.B., Hogdall, C.K., Teerlink, C.C., Kang, D., Tessier, D.C., Schaid, D.J., Stram, D.O., Cramer, D.W, Neal, D.E., Eccles, D., Flesch-Janys, D., Edwards, D.R., Wokozorczyk, D., Levine, D.A., Yannoukakos, D., Sawyer, E.J., Bandera, E.V., Poole, E.M., Goode, E.L., Khusnutdinova, E., Hogdall, E., Song, F., Bruinsma, F., Heitz, F., Modugno, F., Hamdy, F.C., Wiklund, F., Giles, G.G., Olsson, H., Wildiers, H., Ulmer, H.U., Pandha, H., Risch, H.A., Darabi, H., Salvesen, H.B., Nevanlinna, H., Gronberg, H., Brenner, H., Brauch, H., Anton-Culver, H., Song, H., Lim, H.Y., McNeish, I., Campbell, I., Vergote, I., Gronwald, J., Lubinski, J., Stanford, J.L., Benitez, J., Doherty, J.A., Permuth, J.B., Chang-Claude, J., Donovan, J.L., Dennis, J., Schildkraut, J.M., Schleutker, J., Hopper, J.L., Kupryjanczyk, J., Park, J.Y., Figueroa, J., Kiemeney, L.A., Massuger, L.F.A.G., and et al.
Abstract: Contains fulltext : 172624.pdf (publisher's version ) (Closed access), Breast, ovarian, and prostate cancers are hormone-related and may have a shared genetic basis, but this has not been investigated systematically by genome-wide association (GWA) studies. Meta-analyses combining the largest GWA meta-analysis data sets for these cancers totaling 112,349 cases and 116,421 controls of European ancestry, all together and in pairs, identified at P < 10(-8) seven new cross-cancer loci: three associated with susceptibility to all three cancers (rs17041869/2q13/BCL2L11; rs7937840/11q12/INCENP; rs1469713/19p13/GATAD2A), two breast and ovarian cancer risk loci (rs200182588/9q31/SMC2; rs8037137/15q26/RCCD1), and two breast and prostate cancer risk loci (rs5013329/1p34/NSUN4; rs9375701/6q23/L3MBTL3). Index variants in five additional regions previously associated with only one cancer also showed clear association with a second cancer type. Cell-type-specific expression quantitative trait locus and enhancer-gene interaction annotations suggested target genes with potential cross-cancer roles at the new loci. Pathway analysis revealed significant enrichment of death receptor signaling genes near loci with P < 10(-5) in the three-cancer meta-analysis. SIGNIFICANCE: We demonstrate that combining large-scale GWA meta-analysis findings across cancer types can identify completely new risk loci common to breast, ovarian, and prostate cancers. We show that the identification of such cross-cancer risk loci has the potential to shed new light on the shared biology underlying these hormone-related cancers. Cancer Discov; 6(9); 1052-67. (c)2016 AACR.This article is highlighted in the In This Issue feature, p. 932.
Published: 2016

34. Inherited variants affecting RNA editing may contribute to ovarian cancer susceptibility: results from a large-scale collaboration

Author: Permuth, J.B., Reid, B., Earp, M., Chen, Y.A., Monteiro, A.N., Chen, Z., Study, G., Chenevix-Trench, G., Fasching, P.A., Beckmann, M.W., Lambrechts, D., Vanderstichele, A., Niewenhuyse, E. Van, Vergote, I., Rossing, M.A., Doherty, J.A., Chang-Claude, J., Moysich, K., Odunsi, K., Goodman, M.T., Shvetsov, Y.B., Wilkens, L.R., Thompson, P.J., Dork, T., Bogdanova, N., Butzow, R., Nevanlinna, H., Pelttari, L., Leminen, A., Modugno, F., Edwards, R.P., Ness, R.B., Kelley, J., Heitz, F., Karlan, B., Lester, J., Kjaer, S.K., Jensen, A., Giles, G., Hildebrandt, M., Liang, D., Lu, K.H., Wu, X., Levine, D.A., Bisogna, M., Berchuck, A., Cramer, D.W, Terry, K.L., Tworoger, S.S., Poole, E.M., Bandera, E.V., Fridley, B., Cunningham, J., Winham, S.J., Olson, S.H., Orlow, I., Bjorge, L., Kiemeney, L.A.L.M., Massuger, L.F., Pejovic, T., Moffitt, M., Le, N., Cook, L.S., Brooks-Wilson, A., Kelemen, L.E., Gronwald, J., Lubinski, J., Wentzensen, N., Brinton, L.A., Lissowska, J., Yang, H., Hogdall, E., Hogdall, C., Lundvall, L., Pharoah, P.D., Song, H., Campbell, I., Eccles, D., McNeish, I., Whittemore, A., McGuire, V., Sieh, W., Rothstein, J., Phelan, C.M., Risch, H., Narod, S., McLaughlin, J., Anton-Culver, H., Ziogas, A., Menon, U., Gayther, S., Ramus, S.J., Gentry-Maharaj, A., Pearce, C.L., Wu, A.H., Kupryjanczyk, J., Dansonka-Mieszkowska, A., Schildkraut, J.M., Cheng, J.Q., Goode, E.L., Permuth, J.B., Reid, B., Earp, M., Chen, Y.A., Monteiro, A.N., Chen, Z., Study, G., Chenevix-Trench, G., Fasching, P.A., Beckmann, M.W., Lambrechts, D., Vanderstichele, A., Niewenhuyse, E. Van, Vergote, I., Rossing, M.A., Doherty, J.A., Chang-Claude, J., Moysich, K., Odunsi, K., Goodman, M.T., Shvetsov, Y.B., Wilkens, L.R., Thompson, P.J., Dork, T., Bogdanova, N., Butzow, R., Nevanlinna, H., Pelttari, L., Leminen, A., Modugno, F., Edwards, R.P., Ness, R.B., Kelley, J., Heitz, F., Karlan, B., Lester, J., Kjaer, S.K., Jensen, A., Giles, G., Hildebrandt, M., Liang, D., Lu, K.H., Wu, X., Levine, D.A., Bisogna, M., Berchuck, A., Cramer, D.W, Terry, K.L., Tworoger, S.S., Poole, E.M., Bandera, E.V., Fridley, B., Cunningham, J., Winham, S.J., Olson, S.H., Orlow, I., Bjorge, L., Kiemeney, L.A.L.M., Massuger, L.F., Pejovic, T., Moffitt, M., Le, N., Cook, L.S., Brooks-Wilson, A., Kelemen, L.E., Gronwald, J., Lubinski, J., Wentzensen, N., Brinton, L.A., Lissowska, J., Yang, H., Hogdall, E., Hogdall, C., Lundvall, L., Pharoah, P.D., Song, H., Campbell, I., Eccles, D., McNeish, I., Whittemore, A., McGuire, V., Sieh, W., Rothstein, J., Phelan, C.M., Risch, H., Narod, S., McLaughlin, J., Anton-Culver, H., Ziogas, A., Menon, U., Gayther, S., Ramus, S.J., Gentry-Maharaj, A., Pearce, C.L., Wu, A.H., Kupryjanczyk, J., Dansonka-Mieszkowska, A., Schildkraut, J.M., Cheng, J.Q., and Goode, E.L.
Abstract: Contains fulltext : 172820.pdf (publisher's version ) (Open Access), RNA editing in mammals is a form of post-transcriptional modification in which adenosine is converted to inosine by the adenosine deaminases acting on RNA (ADAR) family of enzymes. Based on evidence of altered ADAR expression in epithelial ovarian cancers (EOC), we hypothesized that single nucleotide polymorphisms (SNPs) in ADAR genes modify EOC susceptibility, potentially by altering ovarian tissue gene expression. Using directly genotyped and imputed data from 10,891 invasive EOC cases and 21,693 controls, we evaluated the associations of 5,303 SNPs in ADAD1, ADAR, ADAR2, ADAR3, and SND1. Unconditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI), with adjustment for European ancestry. We conducted gene-level analyses using the Admixture Maximum Likelihood (AML) test and the Sequence-Kernel Association test for common and rare variants (SKAT-CR). Association analysis revealed top risk-associated SNP rs77027562 (OR (95% CI)= 1.39 (1.17-1.64), P=1.0x10-4) in ADAR3 and rs185455523 in SND1 (OR (95% CI)= 0.68 (0.56-0.83), P=2.0x10-4). When restricting to serous histology (n=6,500), the magnitude of association strengthened for rs185455523 (OR=0.60, P=1.0x10-4). Gene-level analyses revealed that variation in ADAR was associated (P<0.05) with EOC susceptibility, with PAML=0.022 and PSKAT-CR=0.020. Expression quantitative trait locus analysis in EOC tissue revealed significant associations (P<0.05) with ADAR expression for several SNPs in ADAR, including rs1127313 (G/A), a SNP in the 3' untranslated region. In summary, germline variation involving RNA editing genes may influence EOC susceptibility, warranting further investigation of inherited and acquired alterations affecting RNA editing.
Published: 2016

35. Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus

Author: Lawrenson, K. (Kate), Kar, S. (Siddhartha), McCue, K. (Karen), Kuchenbaeker, K. (Karoline), Michailidou, K. (Kyriaki), Tyrer, J.P. (Jonathan), Beesley, J. (Jonathan), Ramus, S.J. (Susan), Li, Q. (Qiyuan), Delgado, M.K. (Melissa K.), Lee, J.M. (Janet M.), Aittomäki, K. (Kristiina), Andrulis, I.L. (Irene), Anton-Culver, H. (Hoda), Arndt, V. (Volker), Arun, B.K. (Banu), Arver, B. (Brita Wasteson), Bandera, E.V. (Elisa), Barile, M. (Monica), Barkardottir, R.B. (Rosa B.), Barrowdale, D. (Daniel), Beckmann, M.W. (Matthias), Benítez, J. (Javier), Berchuck, A. (Andrew), Bisogna, M. (Maria), Bjorge, L. (Line), Blomqvist, C. (Carl), Blot, W.J. (William), Bogdanova, N.V. (Natalia), Bojesen, A. (Anders), Bojesen, S.E. (Stig), Bolla, M.K. (Manjeet K.), Bonnani, B. (Bernardo), Borresen-Dale, A.-L. (Anne-Lise), Brauch, H. (Hiltrud), Brennan, P. (Paul), Brenner, H. (Hermann), Bruinsma, F. (Fiona), Brunet, J. (Joan), Buhari, S.A.B.S. (Shaik Ahmad Bin Syed), Burwinkel, B. (Barbara), Butzow, R. (Ralf), Buys, S.S. (Saundra), Cai, Q. (Qiuyin), Caldes, T. (Trinidad), Campbell, I. (Ian), Canniotto, R. (Rikki), Chang-Claude, J. (Jenny), Chiquette, J. (Jocelyne), Choi, J.-Y. (Ji-Yeob), Claes, K.B.M. (Kathleen B.M.), Cook, L.S. (Linda S.), Cox, A. (Angela), Cramer, D.W. (Daniel), Cross, S.S. (Simon), Cybulski, C. (Cezary), Czene, K. (Kamila), Daly, M.B. (Mary B.), Damiola, F. (Francesca), Dansonka-Mieszkowska, A. (Agnieszka), Darabi, H. (Hatef), Dennis, J. (Joe), Devilee, P. (Peter), Díez, O. (Orland), Doherty, J.A. (Jennifer A.), Domchek, S.M. (Susan), Dorfling, C.M. (Cecilia), Dörk, T. (Thilo), Dumont, M. (Martine), Ehrencrona, H. (Hans), Ejlertsen, B. (Bent), Ellis, S.D. (Steve), Engel, C. (Christoph), Lee, E. (Eunjung), Evans, D.G. (D. Gareth), Fasching, P.A. (Peter), Feliubadaló, L. (L.), Figueroa, J.D. (Jonine), Flesch-Janys, D. (Dieter), Fletcher, O. (Olivia), Flyger, H. (Henrik), Foretova, L. (Lenka), Fostira, F. (Florentia), Foulkes, W.D. (William), Fridley, B.L. (Brooke), Friedman, E. (Eitan), Frost, D. (Debra), Gambino, G. (Gaetana), Ganz, P.A. (Patricia A.), Garber, J. (Judy), García-Closas, M. (Montserrat), Gentry-Maharaj, A. (Aleksandra), Ghoussaini, M. (Maya), Giles, G.G. (Graham), Glasspool, R. (Rosalind), Godwin, A.K. (Andrew K.), Goldberg, M.S. (Mark), Goldgar, D. (David), González-Neira, A. (Anna), Goode, E.L. (Ellen), Goodman, M.T. (Marc), Greene, M.H. (Mark H.), Gronwald, J. (Jacek), Guénel, P. (Pascal), Haiman, C.A. (Christopher A.), Hall, P. (Per), Hallberg, E. (Emily), Hamann, U. (Ute), Hansen, T.V.O. (Thomas), harrington, P. (Patricia), Hartman, J.M. (Joost), Hassan, N. (Norhashimah), Healey, S. (Sue), Heitz, P.U., Herzog, J. (Josef), Høgdall, E. (Estrid), Høgdall, C.K. (Claus), Hogervorst, F.B.L. (Frans), Hollestelle, A. (Antoinette), Hopper, J.L. (John), Hulick, P.J. (Peter), Huzarski, T. (Tomasz), Imyanitov, E.N. (Evgeny), Isaacs, C. (Claudine), Ito, H. (Hidemi), Jakubowska, A. (Anna), Janavicius, R. (Ramunas), Jensen, A. (Allan), John, E.M. (Esther), Johnson, N. (Nichola), Kabisch, M. (Maria), Kang, D. (Daehee), Kapuscinski, M.K. (Miroslav K.), Karlan, B.Y. (Beth Y.), Khan, S. (Sofia), Kiemeney, L.A.L.M. (Bart), Kjaer, M. (Michael), Knight, J.A. (Julia), Konstantopoulou, I. (I.), Kosma, V-M. (Veli-Matti), Kristensen, V. (Vessela), Kupryjanczyk, J. (Jolanta), Kwong, A. (Ava), Hoya, M. (Miguel) de La, Laitman, Y. (Yael), Lambrechts, D. (Diether), Le, N.D. (Nhu D.), De Leeneer, K. (Kim), Lester, K.J. (Kathryn), Levine, D.A. (Douglas), Li, J. (Jingmei), Lindblom, A. (Annika), Long, J. (Jirong), Lophatananon, A. (Artitaya), Loud, J.T. (Jennifer), Lu, K.H. (Karen), Lubinski, J. (Jan), Mannermaa, A. (Arto), Manoukian, S. (Siranoush), Le Marchand, L. (Loic), Margolin, S. (Sara), Marme, F. (Frederick), Massuger, L.F. (Leon), Matsuo, K. (Keitaro), Mazoyer, S. (Sylvie), McGuffog, L. (Lesley), McLean, C.A. (Catriona Ann), McNeish, I. (Iain), Meindl, A. (Alfons), Menon, U. (Usha), Mensenkamp, A.R. (Arjen R.), Milne, R.L. (Roger), Montagna, M. (Marco), Moysich, K.B. (Kirsten), Muir, K.R. (K.), Mulligan, A.-M. (Anna-Marie), Nathanson, K.L. (Katherine), Ness, R.B. (Roberta), Neuhausen, S.L. (Susan), Nevanlinna, H. (Heli), Nord, S. (Silje), Nussbaum, R.L. (Robert L.), Odunsi, K. (Kunle), Offit, K. (Kenneth), Olah, E., Olopade, O.I. (Olufunmilayo I.), Olson, J.E. (Janet), Olswold, C. (Curtis), O'Malley, D.M. (David M.), Orlow, I. (Irene), Orr, N. (Nick), Osorio, A. (Ana), Park, S.K. (Sue Kyung), Pearce, C.L. (Celeste), Pejovic, T. (Tanja), Peterlongo, P. (Paolo), Pfeiler, G. (Georg), Phelan, C. (Catherine), Poole, E.M. (Elizabeth), Pykäs, K. (Katri), Radice, P. (Paolo), Rantala, J. (Johanna), Rashid, M.U. (Muhammad), Rennert, G. (Gad), Rhenius, V. (Valerie), Rhiem, K. (Kerstin), Risch, H. (Harvey), Rodriguez, G.C. (Gustavo), Rossing, M.A. (Mary Anne), Rudolph, A. (Anja), Salvesen, H.B. (Helga), Sangrajrang, S. (Suleeporn), Sawyer, E.J. (Elinor J.), Schildkraut, J.M. (Joellen), Schmidt, M.K. (Marjanka), Schmutzler, R.K. (Rita), Sellers, T.A. (Thomas A.), Seynaeve, C.M. (Caroline), Shah, M. (Mitul), Shen, C.-Y. (Chen-Yang), Shu, X.-O. (Xiao-Ou), Sieh, W. (Weiva), Singer, C.F. (Christian), Sinilnikova, O. (Olga), Slager, S. (Susan), Song, H. (Honglin), Soucy, P. (Penny), Southey, M.C. (Melissa), Stenmark-Askmalm, M. (Marie), Stoppa-Lyonnet, D. (Dominique), Sutter, C. (Christian), Swerdlow, A.J. (Anthony ), Tchatchou, S. (Sandrine), Teixeira, P.J., Teo, S.-H. (Soo-Hwang), Terry, K.L. (Kathryn), Terry, M.B. (Mary Beth), Thomassen, M. (Mads), Tibiletti, M.G. (Maria Grazia), Tihomirova, L. (Laima), Tognazzo, S. (Silvia), Toland, A.E. (Amanda), Tomlinson, I.P. (Ian), Torres, D. (Diana), Truong, T. (Thérèse), Tseng, C.-C. (Chiu-Chen), Tung, N. (Nadine), Tworoger, S.S. (Shelley S.), Vachon, C. (Celine), Van Den Ouweland, A.M.W. (Ans M.W.), Van Doorn, H.C. (Helena C.), Rensburg, E.J. (Elizabeth) van, Veer, L.J. (Laura) van 't, Vanderstichele, A. (Adriaan), Vergote, I. (Ignace), Vijai, J. (Joseph), Wang, Q. (Qin), Wang-Gohrke, S. (Shan), Weitzel, J.N. (Jeffrey), Wentzensen, N. (N.), Whittemore, A.S. (Alice), Wildiers, H. (Hans), Winqvist, R. (Robert), Wu, A.H. (Anna), Yannoukakos, D. (Drakoulis), Yoon, S.-Y. (Sook-Yee), Yu, J-C. (Jyh-Cherng), Zheng, W. (Wei), Zheng, Y. (Ying), Khanna, K.K. (Kum Kum), Simard, J. (Jacques), Monteiro, A.N.A. (Alvaro N.), French, J.D. (Juliet), Couch, F.J. (Fergus), Freedman, M. (Matthew), Easton, D.F. (Douglas F.), Dunning, A.M. (Alison), Pharoah, P.D.P. (Paul), Edwards, S.L. (Stacey), Chenevix-Trench, G. (Georgia), Antoniou, A.C. (Antonis), Gayther, S.A. (Simon), Bowtell, D. (David), DeFazio, A. (Anna), Webb, P. (Penny), Collonge-Rame, M.-A., Damette, A. (Alexandre), Barouk-Simonet, E. (Emmanuelle), Bonnet, F. (Françoise), Bubien, V. (Virginie), Sevenet, N. (Nicolas), Longy, M. (Michel), Berthet, P. (Pascaline), Vaur, D. (Dominique), Castera, L. (Laurent), Ferrer, S.F., Bignon, Y.-J. (Yves-Jean), Uhrhammer, N. (Nancy), Coron, F. (Fanny), Faivre, L. (Laurence), Baurand, A. (Amandine), Jacquot, C. (Caroline), Bertolone, G. (Geoffrey), Lizard, S. (Sarab), Leroux, D. (Dominique), Dreyfus, H. (Hélène), Rebischung, C. (Christine), Peysselon, M. (Magalie), Peyrat, J.-P., Fournier, J. (Joëlle), Révillion, F. (Françoise), Adenis, C. (Claude), Vénat-Bouvet, L. (Laurence), Léone, M. (Mélanie), Boutry-Kryza, N. (N.), Calender, A. (Alain), Giraud, S. (Sophie), Verny-Pierre, C. (Carole), Lasset, C. (Christine), Bonadona, V. (Valérie), Barjhoux, L. (Laure), Sobol, H. (Hagay), Bourdon, V. (Violaine), Noguchi, T. (Tetsuro), Remenieras, A. (Audrey), Coupier, I. (Isabelle), Pujol, P. (Pascal), Sokolowska, J. (Johanna), Bronner, M. (Myriam), Delnatte, C.D. (Capucine), Bézieau, S. (Stéphane), Mari, V. (Véronique), Gauthier-Villars, M. (Marion), Buecher, B. (Bruno), Rouleau, E. (Etienne), Golmard, L. (Lisa), Moncoutier, V. (Virginie), Belotti, M. (Muriel), Pauw, A. (Antoine) de, Elan, C. (Camille), Fourme, E. (Emmanuelle), Birot, A.-M. (Anne-Marie), Saule, C. (Claire), Laurent, M. (Maïté), Houdayer, C. (Claude), Lesueur, F. (Fabienne), Mebirouk, N. (Noura), Coulet, F. (Florence), Colas, C. (Chrystelle), Soubrier, F., Warcoin, M. (Mathilde), Prieur, F. (Fabienne), Lebrun, M. (Marine), Kientz, C. (Caroline), Muller, D.W. (Danièle), Fricker, J.P. (Jean Pierre), Toulas, C. (Christine), Guimbaud, R. (Rosine), Gladieff, L. (Laurence), Feillel, V. (Viviane), Mortemousque, I. (Isabelle), Bressac-de Paillerets, B. (Brigitte), Caron, O. (Olivier), Guillaud-Bataille, M. (Marine), Gregory, H. (Helen), Miedzybrodzka, Z. (Zosia), Morrison, P.J. (Patrick), Donaldson, A. (Alan), Rogers, M.T. (Mark), Kennedy, M.J. (John), Porteous, M.E. (Mary), Brady, A. (A.), Barwell, J. (Julian), Foo, C. (Claire), Lalloo, F. (Fiona), Side, L. (Lucy), Eason, J. (Jacqueline), Henderson, A. (Alex), Walker, L.J. (Lisa), Cook, J. (Jackie), Snape, K. (Katie), Murray, A. (Alexandra), McCann, E. (Emma), Rookus, M.A. (Matti), Leeuwen, F.E. (Flora) van, Kolk, L.E. (Lizet) van der, Russell, N.S. (Nicola), Lange, J.L. (J.) de, Wijnands, R., Collée, J.M. (Margriet), Hooning, M.J. (Maartje), Seynaeve, C., Deurzen, C.H.M. (Carolien) van, Obdeijn, A.I.M. (Inge-Marie), Asperen, C.J. (Christi) van, Tollenaar, R.A.E.M. (Rob), Cronenburg, T.C.T.E.F. van, Kets, C.M. (Marleen), Ausems, M.G.E.M. (Margreet), Pol, C. (Carmen) van der, Os, T.A.M. (Theo) van, Waisfisz, Q. (Quinten), Meijers-Heijboer, E.J. (Hanne), Gómez García, E.B. (Encarna), Oosterwijk, J.C. (Jan), Mourits, M.J. (Marjan), Bock, G.H. (Geertruida) de, Vasen, H. (Hans), Siesling, S., Verloop, J., Overbeek, L.I.H. (Lucy), Fox, S.B. (Stephen), Kirk, J. (Judy), Lindeman, G.J. (Geoffrey), Price, M. (Melanie), Lawrenson, K. (Kate), Kar, S. (Siddhartha), McCue, K. (Karen), Kuchenbaeker, K. (Karoline), Michailidou, K. (Kyriaki), Tyrer, J.P. (Jonathan), Beesley, J. (Jonathan), Ramus, S.J. (Susan), Li, Q. (Qiyuan), Delgado, M.K. (Melissa K.), Lee, J.M. (Janet M.), Aittomäki, K. (Kristiina), Andrulis, I.L. (Irene), Anton-Culver, H. (Hoda), Arndt, V. (Volker), Arun, B.K. (Banu), Arver, B. (Brita Wasteson), Bandera, E.V. (Elisa), Barile, M. (Monica), Barkardottir, R.B. (Rosa B.), Barrowdale, D. (Daniel), Beckmann, M.W. (Matthias), Benítez, J. (Javier), Berchuck, A. (Andrew), Bisogna, M. (Maria), Bjorge, L. (Line), Blomqvist, C. (Carl), Blot, W.J. (William), Bogdanova, N.V. (Natalia), Bojesen, A. (Anders), Bojesen, S.E. (Stig), Bolla, M.K. (Manjeet K.), Bonnani, B. (Bernardo), Borresen-Dale, A.-L. (Anne-Lise), Brauch, H. (Hiltrud), Brennan, P. (Paul), Brenner, H. (Hermann), Bruinsma, F. (Fiona), Brunet, J. (Joan), Buhari, S.A.B.S. (Shaik Ahmad Bin Syed), Burwinkel, B. (Barbara), Butzow, R. (Ralf), Buys, S.S. (Saundra), Cai, Q. (Qiuyin), Caldes, T. (Trinidad), Campbell, I. (Ian), Canniotto, R. (Rikki), Chang-Claude, J. (Jenny), Chiquette, J. (Jocelyne), Choi, J.-Y. (Ji-Yeob), Claes, K.B.M. (Kathleen B.M.), Cook, L.S. (Linda S.), Cox, A. (Angela), Cramer, D.W. (Daniel), Cross, S.S. (Simon), Cybulski, C. (Cezary), Czene, K. (Kamila), Daly, M.B. (Mary B.), Damiola, F. (Francesca), Dansonka-Mieszkowska, A. (Agnieszka), Darabi, H. (Hatef), Dennis, J. (Joe), Devilee, P. (Peter), Díez, O. (Orland), Doherty, J.A. (Jennifer A.), Domchek, S.M. (Susan), Dorfling, C.M. (Cecilia), Dörk, T. (Thilo), Dumont, M. (Martine), Ehrencrona, H. (Hans), Ejlertsen, B. (Bent), Ellis, S.D. (Steve), Engel, C. (Christoph), Lee, E. (Eunjung), Evans, D.G. (D. Gareth), Fasching, P.A. (Peter), Feliubadaló, L. (L.), Figueroa, J.D. (Jonine), Flesch-Janys, D. (Dieter), Fletcher, O. (Olivia), Flyger, H. (Henrik), Foretova, L. (Lenka), Fostira, F. (Florentia), Foulkes, W.D. (William), Fridley, B.L. (Brooke), Friedman, E. (Eitan), Frost, D. (Debra), Gambino, G. (Gaetana), Ganz, P.A. (Patricia A.), Garber, J. (Judy), García-Closas, M. (Montserrat), Gentry-Maharaj, A. (Aleksandra), Ghoussaini, M. (Maya), Giles, G.G. (Graham), Glasspool, R. (Rosalind), Godwin, A.K. (Andrew K.), Goldberg, M.S. (Mark), Goldgar, D. (David), González-Neira, A. (Anna), Goode, E.L. (Ellen), Goodman, M.T. (Marc), Greene, M.H. (Mark H.), Gronwald, J. (Jacek), Guénel, P. (Pascal), Haiman, C.A. (Christopher A.), Hall, P. (Per), Hallberg, E. (Emily), Hamann, U. (Ute), Hansen, T.V.O. (Thomas), harrington, P. (Patricia), Hartman, J.M. (Joost), Hassan, N. (Norhashimah), Healey, S. (Sue), Heitz, P.U., Herzog, J. (Josef), Høgdall, E. (Estrid), Høgdall, C.K. (Claus), Hogervorst, F.B.L. (Frans), Hollestelle, A. (Antoinette), Hopper, J.L. (John), Hulick, P.J. (Peter), Huzarski, T. (Tomasz), Imyanitov, E.N. (Evgeny), Isaacs, C. (Claudine), Ito, H. (Hidemi), Jakubowska, A. (Anna), Janavicius, R. (Ramunas), Jensen, A. (Allan), John, E.M. (Esther), Johnson, N. (Nichola), Kabisch, M. (Maria), Kang, D. (Daehee), Kapuscinski, M.K. (Miroslav K.), Karlan, B.Y. (Beth Y.), Khan, S. (Sofia), Kiemeney, L.A.L.M. (Bart), Kjaer, M. (Michael), Knight, J.A. (Julia), Konstantopoulou, I. (I.), Kosma, V-M. (Veli-Matti), Kristensen, V. (Vessela), Kupryjanczyk, J. (Jolanta), Kwong, A. (Ava), Hoya, M. (Miguel) de La, Laitman, Y. (Yael), Lambrechts, D. (Diether), Le, N.D. (Nhu D.), De Leeneer, K. (Kim), Lester, K.J. (Kathryn), Levine, D.A. (Douglas), Li, J. (Jingmei), Lindblom, A. (Annika), Long, J. (Jirong), Lophatananon, A. (Artitaya), Loud, J.T. (Jennifer), Lu, K.H. (Karen), Lubinski, J. (Jan), Mannermaa, A. (Arto), Manoukian, S. (Siranoush), Le Marchand, L. (Loic), Margolin, S. (Sara), Marme, F. (Frederick), Massuger, L.F. (Leon), Matsuo, K. (Keitaro), Mazoyer, S. (Sylvie), McGuffog, L. (Lesley), McLean, C.A. (Catriona Ann), McNeish, I. (Iain), Meindl, A. (Alfons), Menon, U. (Usha), Mensenkamp, A.R. (Arjen R.), Milne, R.L. (Roger), Montagna, M. (Marco), Moysich, K.B. (Kirsten), Muir, K.R. (K.), Mulligan, A.-M. (Anna-Marie), Nathanson, K.L. (Katherine), Ness, R.B. (Roberta), Neuhausen, S.L. (Susan), Nevanlinna, H. (Heli), Nord, S. (Silje), Nussbaum, R.L. (Robert L.), Odunsi, K. (Kunle), Offit, K. (Kenneth), Olah, E., Olopade, O.I. (Olufunmilayo I.), Olson, J.E. (Janet), Olswold, C. (Curtis), O'Malley, D.M. (David M.), Orlow, I. (Irene), Orr, N. (Nick), Osorio, A. (Ana), Park, S.K. (Sue Kyung), Pearce, C.L. (Celeste), Pejovic, T. (Tanja), Peterlongo, P. (Paolo), Pfeiler, G. (Georg), Phelan, C. (Catherine), Poole, E.M. (Elizabeth), Pykäs, K. (Katri), Radice, P. (Paolo), Rantala, J. (Johanna), Rashid, M.U. (Muhammad), Rennert, G. (Gad), Rhenius, V. (Valerie), Rhiem, K. (Kerstin), Risch, H. (Harvey), Rodriguez, G.C. (Gustavo), Rossing, M.A. (Mary Anne), Rudolph, A. (Anja), Salvesen, H.B. (Helga), Sangrajrang, S. (Suleeporn), Sawyer, E.J. (Elinor J.), Schildkraut, J.M. (Joellen), Schmidt, M.K. (Marjanka), Schmutzler, R.K. (Rita), Sellers, T.A. (Thomas A.), Seynaeve, C.M. (Caroline), Shah, M. (Mitul), Shen, C.-Y. (Chen-Yang), Shu, X.-O. (Xiao-Ou), Sieh, W. (Weiva), Singer, C.F. (Christian), Sinilnikova, O. (Olga), Slager, S. (Susan), Song, H. (Honglin), Soucy, P. (Penny), Southey, M.C. (Melissa), Stenmark-Askmalm, M. (Marie), Stoppa-Lyonnet, D. (Dominique), Sutter, C. (Christian), Swerdlow, A.J. (Anthony ), Tchatchou, S. (Sandrine), Teixeira, P.J., Teo, S.-H. (Soo-Hwang), Terry, K.L. (Kathryn), Terry, M.B. (Mary Beth), Thomassen, M. (Mads), Tibiletti, M.G. (Maria Grazia), Tihomirova, L. (Laima), Tognazzo, S. (Silvia), Toland, A.E. (Amanda), Tomlinson, I.P. (Ian), Torres, D. (Diana), Truong, T. (Thérèse), Tseng, C.-C. (Chiu-Chen), Tung, N. (Nadine), Tworoger, S.S. (Shelley S.), Vachon, C. (Celine), Van Den Ouweland, A.M.W. (Ans M.W.), Van Doorn, H.C. (Helena C.), Rensburg, E.J. (Elizabeth) van, Veer, L.J. (Laura) van 't, Vanderstichele, A. (Adriaan), Vergote, I. (Ignace), Vijai, J. (Joseph), Wang, Q. (Qin), Wang-Gohrke, S. (Shan), Weitzel, J.N. (Jeffrey), Wentzensen, N. (N.), Whittemore, A.S. (Alice), Wildiers, H. (Hans), Winqvist, R. (Robert), Wu, A.H. (Anna), Yannoukakos, D. (Drakoulis), Yoon, S.-Y. (Sook-Yee), Yu, J-C. (Jyh-Cherng), Zheng, W. (Wei), Zheng, Y. (Ying), Khanna, K.K. (Kum Kum), Simard, J. (Jacques), Monteiro, A.N.A. (Alvaro N.), French, J.D. (Juliet), Couch, F.J. (Fergus), Freedman, M. (Matthew), Easton, D.F. (Douglas F.), Dunning, A.M. (Alison), Pharoah, P.D.P. (Paul), Edwards, S.L. (Stacey), Chenevix-Trench, G. (Georgia), Antoniou, A.C. (Antonis), Gayther, S.A. (Simon), Bowtell, D. (David), DeFazio, A. (Anna), Webb, P. (Penny), Collonge-Rame, M.-A., Damette, A. (Alexandre), Barouk-Simonet, E. (Emmanuelle), Bonnet, F. (Françoise), Bubien, V. (Virginie), Sevenet, N. (Nicolas), Longy, M. (Michel), Berthet, P. (Pascaline), Vaur, D. (Dominique), Castera, L. (Laurent), Ferrer, S.F., Bignon, Y.-J. (Yves-Jean), Uhrhammer, N. (Nancy), Coron, F. (Fanny), Faivre, L. (Laurence), Baurand, A. (Amandine), Jacquot, C. (Caroline), Bertolone, G. (Geoffrey), Lizard, S. (Sarab), Leroux, D. (Dominique), Dreyfus, H. (Hélène), Rebischung, C. (Christine), Peysselon, M. (Magalie), Peyrat, J.-P., Fournier, J. (Joëlle), Révillion, F. (Françoise), Adenis, C. (Claude), Vénat-Bouvet, L. (Laurence), Léone, M. (Mélanie), Boutry-Kryza, N. (N.), Calender, A. (Alain), Giraud, S. (Sophie), Verny-Pierre, C. (Carole), Lasset, C. (Christine), Bonadona, V. (Valérie), Barjhoux, L. (Laure), Sobol, H. (Hagay), Bourdon, V. (Violaine), Noguchi, T. (Tetsuro), Remenieras, A. (Audrey), Coupier, I. (Isabelle), Pujol, P. (Pascal), Sokolowska, J. (Johanna), Bronner, M. (Myriam), Delnatte, C.D. (Capucine), Bézieau, S. (Stéphane), Mari, V. (Véronique), Gauthier-Villars, M. (Marion), Buecher, B. (Bruno), Rouleau, E. (Etienne), Golmard, L. (Lisa), Moncoutier, V. (Virginie), Belotti, M. (Muriel), Pauw, A. (Antoine) de, Elan, C. (Camille), Fourme, E. (Emmanuelle), Birot, A.-M. (Anne-Marie), Saule, C. (Claire), Laurent, M. (Maïté), Houdayer, C. (Claude), Lesueur, F. (Fabienne), Mebirouk, N. (Noura), Coulet, F. (Florence), Colas, C. (Chrystelle), Soubrier, F., Warcoin, M. (Mathilde), Prieur, F. (Fabienne), Lebrun, M. (Marine), Kientz, C. (Caroline), Muller, D.W. (Danièle), Fricker, J.P. (Jean Pierre), Toulas, C. (Christine), Guimbaud, R. (Rosine), Gladieff, L. (Laurence), Feillel, V. (Viviane), Mortemousque, I. (Isabelle), Bressac-de Paillerets, B. (Brigitte), Caron, O. (Olivier), Guillaud-Bataille, M. (Marine), Gregory, H. (Helen), Miedzybrodzka, Z. (Zosia), Morrison, P.J. (Patrick), Donaldson, A. (Alan), Rogers, M.T. (Mark), Kennedy, M.J. (John), Porteous, M.E. (Mary), Brady, A. (A.), Barwell, J. (Julian), Foo, C. (Claire), Lalloo, F. (Fiona), Side, L. (Lucy), Eason, J. (Jacqueline), Henderson, A. (Alex), Walker, L.J. (Lisa), Cook, J. (Jackie), Snape, K. (Katie), Murray, A. (Alexandra), McCann, E. (Emma), Rookus, M.A. (Matti), Leeuwen, F.E. (Flora) van, Kolk, L.E. (Lizet) van der, Russell, N.S. (Nicola), Lange, J.L. (J.) de, Wijnands, R., Collée, J.M. (Margriet), Hooning, M.J. (Maartje), Seynaeve, C., Deurzen, C.H.M. (Carolien) van, Obdeijn, A.I.M. (Inge-Marie), Asperen, C.J. (Christi) van, Tollenaar, R.A.E.M. (Rob), Cronenburg, T.C.T.E.F. van, Kets, C.M. (Marleen), Ausems, M.G.E.M. (Margreet), Pol, C. (Carmen) van der, Os, T.A.M. (Theo) van, Waisfisz, Q. (Quinten), Meijers-Heijboer, E.J. (Hanne), Gómez García, E.B. (Encarna), Oosterwijk, J.C. (Jan), Mourits, M.J. (Marjan), Bock, G.H. (Geertruida) de, Vasen, H. (Hans), Siesling, S., Verloop, J., Overbeek, L.I.H. (Lucy), Fox, S.B. (Stephen), Kirk, J. (Judy), Lindeman, G.J. (Geoffrey), and Price, M. (Melanie)
Abstract: A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10-20), ER-negative BC (P=1.1 × 10-13), BRCA1-associated BC (P=7.7 × 10-16) and triple negative BC (P-diff=2 × 10-5). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10-3) and ABHD8 (P<2 × 10-3). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3′-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk.
Published: 2016
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36. BRCA2 Polymorphic Stop Codon K3326X and the Risk of Breast, Prostate, and Ovarian Cancers

Author: Meeks, H.D. (Huong D.), Song, H. (Honglin), Michailidou, K. (Kyriaki), Bolla, M.K. (Manjeet), Dennis, J. (Joe), Wang, Q. (Qing), Barrowdale, D. (Daniel), Frost, D. (Debra), McGuffog, L. (Lesley), Ellis, S.D. (Steve), Feng, B. (Bingjian), Buys, S.S. (Saundra), Hopper, J.L. (John), Southey, M.C. (Melissa), Tesoriero, A. (Andrea), James, M. (Margaret), Bruinsma, F. (Fiona), Campbell, I. (Ian), Broeks, A. (Annegien), Schmidt, M.K. (Marjanka), Hogervorst, F.B.L. (Frans), Beckmann, M.W. (Matthias), Fasching, P.A. (Peter), Fletcher, O. (Olivia), Johnson, N. (Nichola), Sawyer, E.J. (Elinor), Riboli, E. (Elio), Banerjee, S. (Susana), Menon, U. (Usha), Tomlinson, I. (Ian), Burwinkel, B. (Barbara), Hamann, U. (Ute), Marme, F. (Federick), Rudolph, A. (Anja), Janavicius, R. (Ramunas), Tihomirova, L. (Laima), Tung, N. (Nadine), Garber, J. (Judy), Cramer, D. (Daniel), Terry, K.L. (Kathryn), Poole, E.M. (Elizabeth), Tworoger, S. (Shelley), Dorfling, C.M. (Cecilia), Rensburg, E.J. (Elizabeth) van, Godwin, A.K. (Andrew K.), Guénel, P. (Pascal), Truong, T. (Thérèse), Stoppa-Lyonnet, D. (Dominique), Damiola, F. (Francesca), Mazoyer, S. (Sylvie), Sinilnikova, O. (Olga), Isaacs, C. (Claudine), Maugard, C., Bojesen, S.E. (Stig), Flyger, H. (Henrik), Gerdes, A-M. (Anne-Marie), Hansen, T.V.O. (Thomas), Jensen, A. (Allen), Kjaer, M. (Michael), Høgdall, C.K. (Claus), Høgdall, E. (Estrid), Pedersen, I.S. (Inge Sokilde), Thomassen, M. (Mads), Benítez, J. (Javier), González-Neira, A. (Anna), Osorio, A. (Ana), Hoya, M.D.L. (Miguel De La), Segura, P.P. (Pedro Perez), Díez, O. (Orland), Lázaro, C. (Conxi), Brunet, J. (Joan), Anton-Culver, H. (Hoda), Eunjung, L. (Lee), John, E.M. (Esther), Neuhausen, S.L. (Susan), Ding, Y.C. (Yuan), Castillo, D. (Danielle), Weitzel, J.N. (Jeffrey), Ganz, P.A. (Patricia A.), Nussbaum, R. (Robert), Chan, S. (Salina), Karlan, B.Y. (Beth Y.), Lester, K.J. (Kathryn), Wu, A. (Anna), Gayther, S.A. (Simon), Ramus, S.J. (Susan), Sieh, W. (Weiva), Whittermore, A.S. (Alice S.), Monteiro, A.N.A. (Alvaro N.A.), Phelan, C. (Catherine), Terry, M.B. (Mary Beth), Piedmonte, M. (Marion), Offit, K. (Kenneth), Robson, M. (Mark), Levine, D.A. (Douglas), Moysich, K.B. (Kirsten B.), Cannioto, R. (Rikki), Olson, S.H. (Sara), Daly, M.B. (Mary B.), Nathanson, K.L. (Katherine), Domchek, S.M. (Susan), Lu, K.H. (Karen), Liang, D. (Dong), Hildebrant, M.A.T. (Michelle A.T.), Ness, R.B. (Roberta), Modugno, F. (Francesmary), Pearce, L. (Leigh), Goodman, M.T. (Marc T.), Thompson, P.J. (Pamela J.), Brenner, H. (Hermann), Butterbach, K. (Katja), Meindl, A. (Alfons), Hahnen, E. (Eric), Wapenschmidt, B. (Barbara), Brauch, H. (Hiltrud), Brüning, T. (Thomas), Blomqvist, C. (Carl), Khan, S. (Sofia), Nevanlinna, H. (Heli), Pelttari, L.M. (Liisa), Aittomäki, K. (Kristiina), Butzow, R. (Ralf), Bogdanova, N.V. (Natalia), Dörk, T. (Thilo), Lindblom, A. (Annika), Margolin, S. (Sara), Rantala, J. (Johanna), Kosma, V-M. (Veli-Matti), Mannermaa, A. (Arto), Lambrechts, D. (Diether), Neven, P. (Patrick), Claes, K.B.M. (Kathleen B.M.), Van Maerken, T. (Tom), Chang-Claude, J. (Jenny), Flesch-Janys, D. (Dieter), Heitz, P.U., Varon-Mateeva, R. (Raymonda), Peterlongo, P. (Paolo), Radice, P. (Paolo), Viel, A. (Alessandra), Barile, M. (Monica), Peissel, B. (Bernard), Manoukian, S. (Siranoush), Montagna, M. (Marco), Oliani, C. (Cristina), Peixoto, A. (Ana), Teixeira, P.J., Collavoli, A. (Anita), Hallberg, B. (Boubou), Olson, J.E. (Janet), Goode, E.L. (Ellen L.), Hart, S.N. (Steven N.), Shimelis, H. (Hermela), Cunningham, J.M. (Julie), Giles, G.G. (Graham), Milne, R.L. (Roger), Healey, S. (Sue), Tucker, K. (Kathy), Haiman, C.A. (Christopher A.), Henderson, B.E. (Brian), Goldberg, M.S. (Mark), Tischkowitz, M. (Marc), Simard, J. (Jacques), Soucy, P. (Penny), Eccles, D. (Diana), Le, N. (Nhu), Borresen-Dale, A.-L. (Anne-Lise), Kristensen, V. (Vessela), Salvesen, H.B. (Helga), Bjorge, L. (Line), Bandera, E.V. (Elisa), Risch, H. (Harvey), Zheng, W. (Wei), Beeghly-Fadiel, A. (Alicia), Cai, H. (Hui), Pykäs, K. (Katri), Tollenaar, R.A.E.M. (Rob), Ouweland, A.M.W. (Ans) van den, Andrulis, I.L. (Irene), Knight, J.A. (Julia A.), Narod, S. (Steven), Devilee, P. (Peter), Winqvist, R. (Robert), Figueroa, J.D. (Jonine), Greene, M.H. (Mark H.), Mai, P.L. (Phuong), Loud, J.T. (Jennifer), García-Closas, M. (Montserrat), Schoemaker, M. (Minouk), Czene, K. (Kamila), Darabi, H. (Hatef), McNeish, I. (Iain), Siddiquil, N. (Nadeem), Glasspool, R. (Rosalind), Kwong, A. (Ava), Park, S.K. (Sue K.), Teo, S.-H. (Soo-Hwang), Yoon, S.-Y. (Sook-Yee), Matsuo, K. (Keitaro), Hosono, N. (Naoya), Woo, Y.L. (Yin Ling), Gao, Y. (Ying), Foretova, L. (Lenka), Singer, C.F. (Christian), Rappaport-Feurhauser, C. (Christine), Friedman, E. (Eitan), Laitman, Y. (Yael), Rennert, G. (Gad), Imyanitov, E.N. (Evgeny), Hulick, P.J. (Peter), Olopade, O.I. (Olufunmilayo I.), Senter, L. (Leigha), Olah, E. (Edith), Doherty, J.A. (Jennifer A.), Schildkraut, J.M. (Joellen), Koppert, L.B. (Linetta), Kiemeney, L.A.L.M. (Bart), Massuger, L.F. (Leon), Cook, L.S. (Linda S.), Pejovic, T. (Tanja), Li, J. (Jingmei), Borg, Å. (Åke), Öfverholm, A. (Anna), Rossing, M.A. (Mary Anne), Wentzensen, N. (N.), Henriksson, K. (Karin), Cox, A. (Angela), Cross, S.S. (Simon), Pasini, B. (Barbara), Shah, M. (Mitul), Kabisch, M. (Maria), Torres, D. (Diana), Jakubowska, A. (Anna), Lubinski, J. (Jan), Gronwald, J. (Jacek), Agnarsson, B.A. (Bjarni), Kupryjanczyk, J. (Jolanta), Moes-Sosnowska, J. (Joanna), Fostira, F. (Florentia), Konstantopoulou, I. (I.), Slager, S. (Susan), Jones, M. (Michael), Antoniou, A.C. (Antonis), Berchuck, A. (Andrew), Swerdlow, A.J. (Anthony ), Chenevix-Trench, G. (Georgia), Dunning, A.M. (Alison), Pharoah, P.D.P. (Paul), Hall, P. (Per), Easton, D.F. (Douglas F.), Couch, F.J. (Fergus), Spurdle, A.B. (Amanda), Goldgar, D. (David), Meeks, H.D. (Huong D.), Song, H. (Honglin), Michailidou, K. (Kyriaki), Bolla, M.K. (Manjeet), Dennis, J. (Joe), Wang, Q. (Qing), Barrowdale, D. (Daniel), Frost, D. (Debra), McGuffog, L. (Lesley), Ellis, S.D. (Steve), Feng, B. (Bingjian), Buys, S.S. (Saundra), Hopper, J.L. (John), Southey, M.C. (Melissa), Tesoriero, A. (Andrea), James, M. (Margaret), Bruinsma, F. (Fiona), Campbell, I. (Ian), Broeks, A. (Annegien), Schmidt, M.K. (Marjanka), Hogervorst, F.B.L. (Frans), Beckmann, M.W. (Matthias), Fasching, P.A. (Peter), Fletcher, O. (Olivia), Johnson, N. (Nichola), Sawyer, E.J. (Elinor), Riboli, E. (Elio), Banerjee, S. (Susana), Menon, U. (Usha), Tomlinson, I. (Ian), Burwinkel, B. (Barbara), Hamann, U. (Ute), Marme, F. (Federick), Rudolph, A. (Anja), Janavicius, R. (Ramunas), Tihomirova, L. (Laima), Tung, N. (Nadine), Garber, J. (Judy), Cramer, D. (Daniel), Terry, K.L. (Kathryn), Poole, E.M. (Elizabeth), Tworoger, S. (Shelley), Dorfling, C.M. (Cecilia), Rensburg, E.J. (Elizabeth) van, Godwin, A.K. (Andrew K.), Guénel, P. (Pascal), Truong, T. (Thérèse), Stoppa-Lyonnet, D. (Dominique), Damiola, F. (Francesca), Mazoyer, S. (Sylvie), Sinilnikova, O. (Olga), Isaacs, C. (Claudine), Maugard, C., Bojesen, S.E. (Stig), Flyger, H. (Henrik), Gerdes, A-M. (Anne-Marie), Hansen, T.V.O. (Thomas), Jensen, A. (Allen), Kjaer, M. (Michael), Høgdall, C.K. (Claus), Høgdall, E. (Estrid), Pedersen, I.S. (Inge Sokilde), Thomassen, M. (Mads), Benítez, J. (Javier), González-Neira, A. (Anna), Osorio, A. (Ana), Hoya, M.D.L. (Miguel De La), Segura, P.P. (Pedro Perez), Díez, O. (Orland), Lázaro, C. (Conxi), Brunet, J. (Joan), Anton-Culver, H. (Hoda), Eunjung, L. (Lee), John, E.M. (Esther), Neuhausen, S.L. (Susan), Ding, Y.C. (Yuan), Castillo, D. (Danielle), Weitzel, J.N. (Jeffrey), Ganz, P.A. (Patricia A.), Nussbaum, R. (Robert), Chan, S. (Salina), Karlan, B.Y. (Beth Y.), Lester, K.J. (Kathryn), Wu, A. (Anna), Gayther, S.A. (Simon), Ramus, S.J. (Susan), Sieh, W. (Weiva), Whittermore, A.S. (Alice S.), Monteiro, A.N.A. (Alvaro N.A.), Phelan, C. (Catherine), Terry, M.B. (Mary Beth), Piedmonte, M. (Marion), Offit, K. (Kenneth), Robson, M. (Mark), Levine, D.A. (Douglas), Moysich, K.B. (Kirsten B.), Cannioto, R. (Rikki), Olson, S.H. (Sara), Daly, M.B. (Mary B.), Nathanson, K.L. (Katherine), Domchek, S.M. (Susan), Lu, K.H. (Karen), Liang, D. (Dong), Hildebrant, M.A.T. (Michelle A.T.), Ness, R.B. (Roberta), Modugno, F. (Francesmary), Pearce, L. (Leigh), Goodman, M.T. (Marc T.), Thompson, P.J. (Pamela J.), Brenner, H. (Hermann), Butterbach, K. (Katja), Meindl, A. (Alfons), Hahnen, E. (Eric), Wapenschmidt, B. (Barbara), Brauch, H. (Hiltrud), Brüning, T. (Thomas), Blomqvist, C. (Carl), Khan, S. (Sofia), Nevanlinna, H. (Heli), Pelttari, L.M. (Liisa), Aittomäki, K. (Kristiina), Butzow, R. (Ralf), Bogdanova, N.V. (Natalia), Dörk, T. (Thilo), Lindblom, A. (Annika), Margolin, S. (Sara), Rantala, J. (Johanna), Kosma, V-M. (Veli-Matti), Mannermaa, A. (Arto), Lambrechts, D. (Diether), Neven, P. (Patrick), Claes, K.B.M. (Kathleen B.M.), Van Maerken, T. (Tom), Chang-Claude, J. (Jenny), Flesch-Janys, D. (Dieter), Heitz, P.U., Varon-Mateeva, R. (Raymonda), Peterlongo, P. (Paolo), Radice, P. (Paolo), Viel, A. (Alessandra), Barile, M. (Monica), Peissel, B. (Bernard), Manoukian, S. (Siranoush), Montagna, M. (Marco), Oliani, C. (Cristina), Peixoto, A. (Ana), Teixeira, P.J., Collavoli, A. (Anita), Hallberg, B. (Boubou), Olson, J.E. (Janet), Goode, E.L. (Ellen L.), Hart, S.N. (Steven N.), Shimelis, H. (Hermela), Cunningham, J.M. (Julie), Giles, G.G. (Graham), Milne, R.L. (Roger), Healey, S. (Sue), Tucker, K. (Kathy), Haiman, C.A. (Christopher A.), Henderson, B.E. (Brian), Goldberg, M.S. (Mark), Tischkowitz, M. (Marc), Simard, J. (Jacques), Soucy, P. (Penny), Eccles, D. (Diana), Le, N. (Nhu), Borresen-Dale, A.-L. (Anne-Lise), Kristensen, V. (Vessela), Salvesen, H.B. (Helga), Bjorge, L. (Line), Bandera, E.V. (Elisa), Risch, H. (Harvey), Zheng, W. (Wei), Beeghly-Fadiel, A. (Alicia), Cai, H. (Hui), Pykäs, K. (Katri), Tollenaar, R.A.E.M. (Rob), Ouweland, A.M.W. (Ans) van den, Andrulis, I.L. (Irene), Knight, J.A. (Julia A.), Narod, S. (Steven), Devilee, P. (Peter), Winqvist, R. (Robert), Figueroa, J.D. (Jonine), Greene, M.H. (Mark H.), Mai, P.L. (Phuong), Loud, J.T. (Jennifer), García-Closas, M. (Montserrat), Schoemaker, M. (Minouk), Czene, K. (Kamila), Darabi, H. (Hatef), McNeish, I. (Iain), Siddiquil, N. (Nadeem), Glasspool, R. (Rosalind), Kwong, A. (Ava), Park, S.K. (Sue K.), Teo, S.-H. (Soo-Hwang), Yoon, S.-Y. (Sook-Yee), Matsuo, K. (Keitaro), Hosono, N. (Naoya), Woo, Y.L. (Yin Ling), Gao, Y. (Ying), Foretova, L. (Lenka), Singer, C.F. (Christian), Rappaport-Feurhauser, C. (Christine), Friedman, E. (Eitan), Laitman, Y. (Yael), Rennert, G. (Gad), Imyanitov, E.N. (Evgeny), Hulick, P.J. (Peter), Olopade, O.I. (Olufunmilayo I.), Senter, L. (Leigha), Olah, E. (Edith), Doherty, J.A. (Jennifer A.), Schildkraut, J.M. (Joellen), Koppert, L.B. (Linetta), Kiemeney, L.A.L.M. (Bart), Massuger, L.F. (Leon), Cook, L.S. (Linda S.), Pejovic, T. (Tanja), Li, J. (Jingmei), Borg, Å. (Åke), Öfverholm, A. (Anna), Rossing, M.A. (Mary Anne), Wentzensen, N. (N.), Henriksson, K. (Karin), Cox, A. (Angela), Cross, S.S. (Simon), Pasini, B. (Barbara), Shah, M. (Mitul), Kabisch, M. (Maria), Torres, D. (Diana), Jakubowska, A. (Anna), Lubinski, J. (Jan), Gronwald, J. (Jacek), Agnarsson, B.A. (Bjarni), Kupryjanczyk, J. (Jolanta), Moes-Sosnowska, J. (Joanna), Fostira, F. (Florentia), Konstantopoulou, I. (I.), Slager, S. (Susan), Jones, M. (Michael), Antoniou, A.C. (Antonis), Berchuck, A. (Andrew), Swerdlow, A.J. (Anthony ), Chenevix-Trench, G. (Georgia), Dunning, A.M. (Alison), Pharoah, P.D.P. (Paul), Hall, P. (Per), Easton, D.F. (Douglas F.), Couch, F.J. (Fergus), Spurdle, A.B. (Amanda), and Goldgar, D. (David)
Abstract: Background: The K3326X variant in BRCA2 (BRCA2∗c.9976A>T p.Lys3326∗rs11571833) has been found to be associated with small increased risks of breast cancer. However, it is not clear to what extent linkage disequilibrium with fully pathogenic mutations might account for this association. There is scant information about the effect of K3326X in other hormonerelated cancers. Methods: Using weighted logistic regression, we analyzed data from the large iCOGS study including 76637 cancer case patients and 83796 control patients to estimate odds ratios (ORw) and 95% confidence intervals (CIs) for K3326X variant carriers in relation to breast, ovarian, and prostate cancer risks, with weights defined as probability of not having a pathogenic BRCA2 variant. Using Cox proportional hazards modeling, we also examined the associations of K3326X with breast and ovarian cancer risks among 7183 BRCA1 variant carriers. All statistical tests were two-sided. Results: The K3326X variant was associated with breast (ORw = 1.28, 95% CI = 1.17 to 1.40, P = 5.9×10-6) and invasive ovarian cancer (ORw = 1.26, 95% CI = 1.10 to 1.43, P = 3.8×10-3). These associations were stronger for serous ovarian cancer and for estrogen receptor-negative breast cancer (ORw = 1.46, 95% CI = 1.2 to 1.70, P = 3.4×10-5 and ORw = 1.50, 95% CI = 1.28 to
Published: 2016
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37. No clinical utility of KRAS variant rs61764370 for ovarian or breast cancer

Author: Hollestelle, A. (Antoinette), Baan, F.H. (Frederieke) van der, Berchuck, A. (Andrew), Johnatty, S.E. (Sharon), Aben, K.K.H. (Katja), Agnarsson, B.A. (Bjarni), Aittomäki, K. (Kristiina), Alducci, E. (Elisa), Andrulis, I.L. (Irene), Anton-Culver, H. (Hoda), Antonenkova, N.N. (Natalia), Antoniou, A.C. (Antonis), Apicella, C. (Carmel), Arndt, V. (Volker), Arnold, N. (Norbert), Arun, B.K. (Banu), Arver, B. (Brita Wasteson), Ashworth, A. (Alan), Baglietto, L. (Laura), Balleine, R. (Rosemary), Bandera, E.V. (Elisa), Barrowdale, D. (Daniel), Bean, Y.T. (Yukie), Beckmann, L. (Lars), Beckmann, M.W. (Matthias), Benítez, J. (Javier), Berger, A. (Andreas), Berger, R. (Raanan), Beuselinck, B. (B.), Bisogna, M. (Maria), Bjorge, L. (Line), Blomqvist, C. (Carl), Bogdanova, N.V. (Natalia), Bojesen, A. (Anders), Bojesen, S.E. (Stig), Bolla, M.K. (Manjeet), Bonnani, B. (Bernardo), Brand, J.S. (Judith S.), Brauch, H. (Hiltrud), Brenner, H. (Hermann), Brinton, L.A. (Louise), Brooks-Wilson, A. (Angela), Bruinsma, F. (Fiona), Brunet, J. (Joan), Brüning, T. (Thomas), Budzilowska, A. (Agnieszka), Bunker, C.H. (Clareann H.), Burwinkel, B. (Barbara), Butzow, R. (Ralf), Buys, S.S. (Saundra S.), Caligo, M.A. (Maria), Campbell, I. (Ian), Carter, J. (Jonathan), Chang-Claude, J. (Jenny), Chanock, S.J. (Stephen J.), Claes, K.B.M. (Kathleen B.M.), Collée, J.M. (Margriet), Cook, L.S. (Linda S.), Couch, F.J. (Fergus), Cox, A. (Angela), Cramer, D.W. (Daniel), Cross, S.S. (Simon), Cunningham, J.M. (Julie), Cybulski, C. (Cezary), Czene, K. (Kamila), Damiola, F. (Francesca), Dansonka-Mieszkowska, A. (Agnieszka), Darabi, H. (Hatef), Hoya, M. (Miguel) de La, DeFazio, A. (Anna), Dennis, J. (Joe), Devilee, P. (Peter), Dicks, E. (Ed), Díez, O. (Orland), Doherty, J.A. (Jennifer A.), Domchek, S.M. (Susan), Dorfling, C.M. (Cecilia), Dörk, T. (Thilo), Santos Silva, I. (Isabel) dos, Du Bois, A. (Andreas), Dumont, M. (Martine), Dunning, A.M. (Alison), Duran, M. (Mercedes), Easton, D.F. (Douglas F.), Eccles, D. (Diana), Edwards, R. (Robert), Ehrencrona, H. (Hans), Ejlertsen, B. (Bent), Ekici, A.B. (Arif), Ellis, S.D. (Steve), Engel, C. (Christoph), Eriksson, M. (Mikael), Fasching, P.A. (Peter), Feliubadaló, L. (L.), Figueroa, J.D. (Jonine), Flesch-Janys, D. (Dieter), Fletcher, O. (Olivia), Fontaine, A. (Annette), Fortuzzi, S. (S.), Fostira, F. (Florentia), Fridley, B.L. (Brooke), Friebel, M.O.W. (Mark ), Friedman, E. (Eitan), Friel, G. (Grace), Frost, D. (Debra), Garber, J. (Judy), García-Closas, M. (Montserrat), Gayther, S.A. (Simon), Gentry-Maharaj, A. (Aleksandra), Gerdes, A-M. (Anne-Marie), Giles, G.G. (Graham), Glasspool, R. (Rosalind), Glendon, G. (Gord), Godwin, A.K. (Andrew K.), Goodman, M.T. (Marc T.), Gore, M. (Martin), Greene, M.H. (Mark H.), Grip, M. (Mervi), Gronwald, J. (Jacek), Gschwantler-Kaulich, D. (Daphne), Guénel, P. (Pascal), Guzman, S.R. (Starr R.), Haeberle, L. (Lothar), Haiman, C.A. (Christopher A.), Hall, P. (Per), Halverson, S.L. (Sandra L.), Hamann, U. (Ute), Hansen, T.V.O. (Thomas), Harter, P. (Philipp), Hartikainen, J.M. (J.), Healey, S. (Sue), Hein, R. (Rebecca), Heitz, P.U., Henderson, B.E. (Brian), Herzog, J. (Josef), Hildebrandt, M.A.T. (Michelle), Høgdall, C.K. (Claus), Høgdall, E. (Estrid), Hogervorst, F.B.L. (Frans), Hopper, J.L. (John), Humphreys, K. (Keith), Huzarski, T. (Tomasz), Imyanitov, E.N. (Evgeny N.), Isaacs, C. (Claudine), Jakubowska, A. (Anna), Janavicius, R. (Ramunas), Jaworska, K. (Katarzyna), Jensen, A. (Allan), Jensen, U.B., Johnson, N. (Nichola), Jukkola-Vuorinen, A. (Arja), Kabisch, M. (Maria), Karlan, B.Y. (Beth Y.), Kataja, V. (Vesa), Kauff, N. (Noah), Kelemen, L.E. (Linda), Kerin, M. (Michael), Kiemeney, L.A.L.M. (Bart), Kjaer, M. (Michael), Knight, J.A. (Julia), Knol-Bout, J.P. (Jacoba P.), Konstantopoulou, I. (I.), Kosma, V-M. (Veli-Matti), Krakstad, C. (Camilla), Kristensen, V. (Vessela), Kuchenbaecker, K.B. (Karoline), Kupryjanczyk, J. (Jolanta), Laitman, Y. (Yael), Lambrechts, D. (Diether), Lambrechts, S. (Sandrina), Larson, M.C. (Melissa), Lasa, A. (Adriana), Laurent-Puig, P. (Pierre), Lázaro, C. (Conxi), Le, N. (Nhu), Le Marchand, L. (Loic), Leminen, A. (Arto), Lester, K.J. (Kathryn), Levine, D.A. (Douglas), Li, J. (Jingmei), Liang, D. (Dong), Lindblom, A. (Annika), Lindor, N.M. (Noralane), Lissowska, J. (Jolanta), Long, J. (Jirong), Lu, K.H. (Karen), Lubinski, J. (Jan), Lundvall, L. (Lene), Lurie, G. (Galina), Mai, P.L. (Phuong), Mannermaa, A. (Arto), Margolin, S. (Sara), Mariette, F. (F.), Marme, F. (Federick), Martens, J.W.M. (John), Massuger, L.F. (Leon), Maugard, C., Mazoyer, S. (Sylvie), McGuffog, L. (Lesley), McGuire, W.P., McLean, C.A. (Catriona Ann), McNeish, I. (Iain), Meindl, A. (Alfons), Menegaux, F. (Florence), Menéndez, P. (Primitiva), Menkiszak, J. (Janusz), Menon, U. (Usha), Mensenkamp, A.R. (Arjen), Miller, N. (Nicola), Milne, R.L. (Roger), Modugno, F. (Francesmary), Montagna, M. (Marco), Moysich, K.B. (Kirsten B.), Müller, H. (Heiko), Mulligan, A.-M. (Anna-Marie), Muranen, T.A. (Taru), Narod, S.A. (Steven A.), Nathanson, K.L. (Katherine), Ness, R.B. (Roberta B.), Neuhausen, S.L. (Susan), Nevanlinna, H. (Heli), Neven, P. (Patrick), Nielsen, F. (Finn), Nielsen, S.F. (Sune), Nordestgaard, B.G. (Børge), Nussbaum, R. (Robert), Odunsi, K. (Kunle), Offit, K. (Kenneth), Olah, E., Olopade, O.I. (Olufunmilayo I.), Olson, J.E. (Janet), Olson, S.H. (Sara), Oosterwijk, J.C. (Jan), Orlow, I. (Irene), Orr, N. (Nick), Orsulic, S. (Sandra), Osorio, A. (Ana), Ottini, L. (Laura), Paul, J. (James), Pearce, C.L. (Celeste), Pedersen, I.S. (Inge Sokilde), Peissel, B. (Bernard), Pejovic, T. (Tanja), Pelttari, L.M. (Liisa), Perkins, J. (Jo), Permuth-Wey, J. (Jenny), Peterlongo, P. (Paolo), Peto, J. (Julian), Phelan, C. (Catherine), Phillips, K.-A. (Kelly-Anne), Piedmonte, M. (Marion), Pike, M.C. (Malcolm C.), Platte, R. (Radka), Plisiecka-Halasa, J. (Joanna), Poole, E.M. (Elizabeth), Poppe, B. (Bruce), Pykäs, K. (Katri), Radice, P. (Paolo), Ramus, S.J. (Susan), Rebbeck, R. (Timothy), Reed, M.W.R. (Malcolm W.R.), Rennert, G. (Gad), Risch, H. (Harvey), Robson, M. (Mark), Rodriguez, G. (Gustavo), Romero, A. (Atocha), Rossing, M.A. (Mary Anne), Rothstein, J.H. (Joseph H.), Rudolph, A. (Anja), Runnebaum, I.B. (Ingo), Salani, R. (Ritu), Salvesen, H.B. (Helga), Sawyer, E.J. (Elinor), Schildkraut, J.M. (Joellen), Schmidt, M.K. (Marjanka), Schmutzler, R.K. (Rita), Schneeweiss, A. (Andreas), Schoemaker, M. (Minouk), Schrauder, A. (André), Schumacher, F.R. (Fredrick), Schwaab, I. (Ira), Scuvera, G. (Giulietta), Sellers, T.A. (Thomas A.), Severi, G. (Gianluca), Seynaeve, C.M. (Caroline), Shah, M. (Mitul), Shrubsole, M. (Martha), Siddiqui, N. (Nadeem), Sieh, W. (Weiva), Simard, J. (Jacques), Singer, C.F. (Christian), Sinilnikova, O. (Olga), Smeets, D. (Dominiek), Sohn, C. (Christof), Soller, M. (Maria), Song, H. (Honglin), Soucy, P. (Penny), Southey, M.C. (Melissa), Stegmaier, C. (Christa), Stoppa-Lyonnet, D. (Dominique), Sucheston, L. (Lara), Swerdlow, A.J. (Anthony ), Tangen, I.L. (Ingvild L.), Tea, M.-K., Teixeira, P.J., Terry, K.L. (Kathryn), Terry, M.B. (Mary Beth), Thomassen, M. (Mads), Thompson, P.J. (Pamela J.), Tihomirova, L. (Laima), Tischkowitz, M. (Marc), Toland, A.E. (Amanda), Tollenaar, R.A.E.M. (Rob), Tomlinson, I. (Ian), Torres, D. (Diana), Truong, T. (Thérèse), Tsimiklis, H. (Helen), Tung, N. (Nadine), Tworoger, S. (Shelley), Tyrer, J.P. (Jonathan), Vachon, C. (Celine), Veer, L.J. (Laura) van 't, Altena, A.M. (Anne) van, Asperen, C.J. (Christi) van, Van Den Berg, D. (David), Ouweland, A.M.W. (Ans) van den, Doorn, H.C. (Lena) van, Van Nieuwenhuysen, E. (Els), Rensburg, E.J. (Elizabeth) van, Vergote, I. (Ignace), Verhoef, S., Vierkant, R.A. (Robert), Vijai, J. (Joseph), Vitonis, A.F. (Allison), Wachenfeldt, A. (Anna) von, Walsh, C.S. (Christine), Wang, Q. (Qing), Wang-Gohrke, S. (Shan), Wapenschmidt, B. (Barbara), Weischer, M. (Maren), Weitzel, J.N. (Jeffrey), Weltens, C. (Caroline), Wentzensen, N. (N.), Whittemore, A.S. (Alice S.), Wilkens, L.R. (Lynne R.), Winqvist, R. (Robert), Wu, A.H. (Anna), Wu, X. (Xifeng), Yang, H.P. (Hannah P.), Zaffaroni, D. (Daniela), Zamora, M.P. (Pilar), Zheng, W. (Wei), Ziogas, A. (Argyrios), Chenevix-Trench, G. (Georgia), Pharoah, P.D.P. (Paul), Rookus, M.A. (Matti), Hooning, M.J. (Maartje), Goode, E.L. (Ellen L.), Breast Cancer Family Register, EMBRACE, GENICA Network, HEBON, SWE-BRCA, Hollestelle, A. (Antoinette), Baan, F.H. (Frederieke) van der, Berchuck, A. (Andrew), Johnatty, S.E. (Sharon), Aben, K.K.H. (Katja), Agnarsson, B.A. (Bjarni), Aittomäki, K. (Kristiina), Alducci, E. (Elisa), Andrulis, I.L. (Irene), Anton-Culver, H. (Hoda), Antonenkova, N.N. (Natalia), Antoniou, A.C. (Antonis), Apicella, C. (Carmel), Arndt, V. (Volker), Arnold, N. (Norbert), Arun, B.K. (Banu), Arver, B. (Brita Wasteson), Ashworth, A. (Alan), Baglietto, L. (Laura), Balleine, R. (Rosemary), Bandera, E.V. (Elisa), Barrowdale, D. (Daniel), Bean, Y.T. (Yukie), Beckmann, L. (Lars), Beckmann, M.W. (Matthias), Benítez, J. (Javier), Berger, A. (Andreas), Berger, R. (Raanan), Beuselinck, B. (B.), Bisogna, M. (Maria), Bjorge, L. (Line), Blomqvist, C. (Carl), Bogdanova, N.V. (Natalia), Bojesen, A. (Anders), Bojesen, S.E. (Stig), Bolla, M.K. (Manjeet), Bonnani, B. (Bernardo), Brand, J.S. (Judith S.), Brauch, H. (Hiltrud), Brenner, H. (Hermann), Brinton, L.A. (Louise), Brooks-Wilson, A. (Angela), Bruinsma, F. (Fiona), Brunet, J. (Joan), Brüning, T. (Thomas), Budzilowska, A. (Agnieszka), Bunker, C.H. (Clareann H.), Burwinkel, B. (Barbara), Butzow, R. (Ralf), Buys, S.S. (Saundra S.), Caligo, M.A. (Maria), Campbell, I. (Ian), Carter, J. (Jonathan), Chang-Claude, J. (Jenny), Chanock, S.J. (Stephen J.), Claes, K.B.M. (Kathleen B.M.), Collée, J.M. (Margriet), Cook, L.S. (Linda S.), Couch, F.J. (Fergus), Cox, A. (Angela), Cramer, D.W. (Daniel), Cross, S.S. (Simon), Cunningham, J.M. (Julie), Cybulski, C. (Cezary), Czene, K. (Kamila), Damiola, F. (Francesca), Dansonka-Mieszkowska, A. (Agnieszka), Darabi, H. (Hatef), Hoya, M. (Miguel) de La, DeFazio, A. (Anna), Dennis, J. (Joe), Devilee, P. (Peter), Dicks, E. (Ed), Díez, O. (Orland), Doherty, J.A. (Jennifer A.), Domchek, S.M. (Susan), Dorfling, C.M. (Cecilia), Dörk, T. (Thilo), Santos Silva, I. (Isabel) dos, Du Bois, A. (Andreas), Dumont, M. (Martine), Dunning, A.M. (Alison), Duran, M. (Mercedes), Easton, D.F. (Douglas F.), Eccles, D. (Diana), Edwards, R. (Robert), Ehrencrona, H. (Hans), Ejlertsen, B. (Bent), Ekici, A.B. (Arif), Ellis, S.D. (Steve), Engel, C. (Christoph), Eriksson, M. (Mikael), Fasching, P.A. (Peter), Feliubadaló, L. (L.), Figueroa, J.D. (Jonine), Flesch-Janys, D. (Dieter), Fletcher, O. (Olivia), Fontaine, A. (Annette), Fortuzzi, S. (S.), Fostira, F. (Florentia), Fridley, B.L. (Brooke), Friebel, M.O.W. (Mark ), Friedman, E. (Eitan), Friel, G. (Grace), Frost, D. (Debra), Garber, J. (Judy), García-Closas, M. (Montserrat), Gayther, S.A. (Simon), Gentry-Maharaj, A. (Aleksandra), Gerdes, A-M. (Anne-Marie), Giles, G.G. (Graham), Glasspool, R. (Rosalind), Glendon, G. (Gord), Godwin, A.K. (Andrew K.), Goodman, M.T. (Marc T.), Gore, M. (Martin), Greene, M.H. (Mark H.), Grip, M. (Mervi), Gronwald, J. (Jacek), Gschwantler-Kaulich, D. (Daphne), Guénel, P. (Pascal), Guzman, S.R. (Starr R.), Haeberle, L. (Lothar), Haiman, C.A. (Christopher A.), Hall, P. (Per), Halverson, S.L. (Sandra L.), Hamann, U. (Ute), Hansen, T.V.O. (Thomas), Harter, P. (Philipp), Hartikainen, J.M. (J.), Healey, S. (Sue), Hein, R. (Rebecca), Heitz, P.U., Henderson, B.E. (Brian), Herzog, J. (Josef), Hildebrandt, M.A.T. (Michelle), Høgdall, C.K. (Claus), Høgdall, E. (Estrid), Hogervorst, F.B.L. (Frans), Hopper, J.L. (John), Humphreys, K. (Keith), Huzarski, T. (Tomasz), Imyanitov, E.N. (Evgeny N.), Isaacs, C. (Claudine), Jakubowska, A. (Anna), Janavicius, R. (Ramunas), Jaworska, K. (Katarzyna), Jensen, A. (Allan), Jensen, U.B., Johnson, N. (Nichola), Jukkola-Vuorinen, A. (Arja), Kabisch, M. (Maria), Karlan, B.Y. (Beth Y.), Kataja, V. (Vesa), Kauff, N. (Noah), Kelemen, L.E. (Linda), Kerin, M. (Michael), Kiemeney, L.A.L.M. (Bart), Kjaer, M. (Michael), Knight, J.A. (Julia), Knol-Bout, J.P. (Jacoba P.), Konstantopoulou, I. (I.), Kosma, V-M. (Veli-Matti), Krakstad, C. (Camilla), Kristensen, V. (Vessela), Kuchenbaecker, K.B. (Karoline), Kupryjanczyk, J. (Jolanta), Laitman, Y. (Yael), Lambrechts, D. (Diether), Lambrechts, S. (Sandrina), Larson, M.C. (Melissa), Lasa, A. (Adriana), Laurent-Puig, P. (Pierre), Lázaro, C. (Conxi), Le, N. (Nhu), Le Marchand, L. (Loic), Leminen, A. (Arto), Lester, K.J. (Kathryn), Levine, D.A. (Douglas), Li, J. (Jingmei), Liang, D. (Dong), Lindblom, A. (Annika), Lindor, N.M. (Noralane), Lissowska, J. (Jolanta), Long, J. (Jirong), Lu, K.H. (Karen), Lubinski, J. (Jan), Lundvall, L. (Lene), Lurie, G. (Galina), Mai, P.L. (Phuong), Mannermaa, A. (Arto), Margolin, S. (Sara), Mariette, F. (F.), Marme, F. (Federick), Martens, J.W.M. (John), Massuger, L.F. (Leon), Maugard, C., Mazoyer, S. (Sylvie), McGuffog, L. (Lesley), McGuire, W.P., McLean, C.A. (Catriona Ann), McNeish, I. (Iain), Meindl, A. (Alfons), Menegaux, F. (Florence), Menéndez, P. (Primitiva), Menkiszak, J. (Janusz), Menon, U. (Usha), Mensenkamp, A.R. (Arjen), Miller, N. (Nicola), Milne, R.L. (Roger), Modugno, F. (Francesmary), Montagna, M. (Marco), Moysich, K.B. (Kirsten B.), Müller, H. (Heiko), Mulligan, A.-M. (Anna-Marie), Muranen, T.A. (Taru), Narod, S.A. (Steven A.), Nathanson, K.L. (Katherine), Ness, R.B. (Roberta B.), Neuhausen, S.L. (Susan), Nevanlinna, H. (Heli), Neven, P. (Patrick), Nielsen, F. (Finn), Nielsen, S.F. (Sune), Nordestgaard, B.G. (Børge), Nussbaum, R. (Robert), Odunsi, K. (Kunle), Offit, K. (Kenneth), Olah, E., Olopade, O.I. (Olufunmilayo I.), Olson, J.E. (Janet), Olson, S.H. (Sara), Oosterwijk, J.C. (Jan), Orlow, I. (Irene), Orr, N. (Nick), Orsulic, S. (Sandra), Osorio, A. (Ana), Ottini, L. (Laura), Paul, J. (James), Pearce, C.L. (Celeste), Pedersen, I.S. (Inge Sokilde), Peissel, B. (Bernard), Pejovic, T. (Tanja), Pelttari, L.M. (Liisa), Perkins, J. (Jo), Permuth-Wey, J. (Jenny), Peterlongo, P. (Paolo), Peto, J. (Julian), Phelan, C. (Catherine), Phillips, K.-A. (Kelly-Anne), Piedmonte, M. (Marion), Pike, M.C. (Malcolm C.), Platte, R. (Radka), Plisiecka-Halasa, J. (Joanna), Poole, E.M. (Elizabeth), Poppe, B. (Bruce), Pykäs, K. (Katri), Radice, P. (Paolo), Ramus, S.J. (Susan), Rebbeck, R. (Timothy), Reed, M.W.R. (Malcolm W.R.), Rennert, G. (Gad), Risch, H. (Harvey), Robson, M. (Mark), Rodriguez, G. (Gustavo), Romero, A. (Atocha), Rossing, M.A. (Mary Anne), Rothstein, J.H. (Joseph H.), Rudolph, A. (Anja), Runnebaum, I.B. (Ingo), Salani, R. (Ritu), Salvesen, H.B. (Helga), Sawyer, E.J. (Elinor), Schildkraut, J.M. (Joellen), Schmidt, M.K. (Marjanka), Schmutzler, R.K. (Rita), Schneeweiss, A. (Andreas), Schoemaker, M. (Minouk), Schrauder, A. (André), Schumacher, F.R. (Fredrick), Schwaab, I. (Ira), Scuvera, G. (Giulietta), Sellers, T.A. (Thomas A.), Severi, G. (Gianluca), Seynaeve, C.M. (Caroline), Shah, M. (Mitul), Shrubsole, M. (Martha), Siddiqui, N. (Nadeem), Sieh, W. (Weiva), Simard, J. (Jacques), Singer, C.F. (Christian), Sinilnikova, O. (Olga), Smeets, D. (Dominiek), Sohn, C. (Christof), Soller, M. (Maria), Song, H. (Honglin), Soucy, P. (Penny), Southey, M.C. (Melissa), Stegmaier, C. (Christa), Stoppa-Lyonnet, D. (Dominique), Sucheston, L. (Lara), Swerdlow, A.J. (Anthony ), Tangen, I.L. (Ingvild L.), Tea, M.-K., Teixeira, P.J., Terry, K.L. (Kathryn), Terry, M.B. (Mary Beth), Thomassen, M. (Mads), Thompson, P.J. (Pamela J.), Tihomirova, L. (Laima), Tischkowitz, M. (Marc), Toland, A.E. (Amanda), Tollenaar, R.A.E.M. (Rob), Tomlinson, I. (Ian), Torres, D. (Diana), Truong, T. (Thérèse), Tsimiklis, H. (Helen), Tung, N. (Nadine), Tworoger, S. (Shelley), Tyrer, J.P. (Jonathan), Vachon, C. (Celine), Veer, L.J. (Laura) van 't, Altena, A.M. (Anne) van, Asperen, C.J. (Christi) van, Van Den Berg, D. (David), Ouweland, A.M.W. (Ans) van den, Doorn, H.C. (Lena) van, Van Nieuwenhuysen, E. (Els), Rensburg, E.J. (Elizabeth) van, Vergote, I. (Ignace), Verhoef, S., Vierkant, R.A. (Robert), Vijai, J. (Joseph), Vitonis, A.F. (Allison), Wachenfeldt, A. (Anna) von, Walsh, C.S. (Christine), Wang, Q. (Qing), Wang-Gohrke, S. (Shan), Wapenschmidt, B. (Barbara), Weischer, M. (Maren), Weitzel, J.N. (Jeffrey), Weltens, C. (Caroline), Wentzensen, N. (N.), Whittemore, A.S. (Alice S.), Wilkens, L.R. (Lynne R.), Winqvist, R. (Robert), Wu, A.H. (Anna), Wu, X. (Xifeng), Yang, H.P. (Hannah P.), Zaffaroni, D. (Daniela), Zamora, M.P. (Pilar), Zheng, W. (Wei), Ziogas, A. (Argyrios), Chenevix-Trench, G. (Georgia), Pharoah, P.D.P. (Paul), Rookus, M.A. (Matti), Hooning, M.J. (Maartje), Goode, E.L. (Ellen L.), Breast Cancer Family Register, EMBRACE, GENICA Network, HEBON, and SWE-BRCA
Abstract: Objective Clinical genetic testing is commercially available for rs61764370, an inherited variant residing in a KRAS 3′ UTR microRNA binding site, based on suggested associations with increased ovarian and br
Published: 2016
Full Text: View/download PDF

38. Assessment of Multifactor Gene-Environment Interactions and Ovarian Cancer Risk: Candidate Genes, Obesity, and Hormone-Related Risk Factors

Author: Usset, J.L., Raghavan, R., Tyrer, J.P., McGuire, V., Sieh, W., Webb, P., Chang-Claude, J., Rudolph, A., Anton-Culver, H., Berchuck, A., Brinton, L., Cunningham, J.M., Defazio, A., Doherty, J.A., Edwards, R.P., Gayther, S.A., Gentry-Maharaj, A., Goodman, M.T., Hogdall, E., Jensen, A., Johnatty, S.E., Kiemeney, L.A.L.M., Kjaer, S.K., Larson, M.C., Lurie, G., Massuger, L.F., Menon, U., Modugno, F., Moysich, K.B., Ness, R.B., Pike, M.C., Ramus, S.J., Rossing, M.A., Rothstein, J., Song, H., Thompson, P.J., Berg, D.J. Van Den, Vierkant, R.A., Wang-Gohrke, S., Wentzensen, N., Whittemore, A.S., Wilkens, L.R., Wu, A.H., Yang, H., Pearce, C.L., Schildkraut, J.M., Pharoah, P., Goode, E.L., Fridley, B.L., Usset, J.L., Raghavan, R., Tyrer, J.P., McGuire, V., Sieh, W., Webb, P., Chang-Claude, J., Rudolph, A., Anton-Culver, H., Berchuck, A., Brinton, L., Cunningham, J.M., Defazio, A., Doherty, J.A., Edwards, R.P., Gayther, S.A., Gentry-Maharaj, A., Goodman, M.T., Hogdall, E., Jensen, A., Johnatty, S.E., Kiemeney, L.A.L.M., Kjaer, S.K., Larson, M.C., Lurie, G., Massuger, L.F., Menon, U., Modugno, F., Moysich, K.B., Ness, R.B., Pike, M.C., Ramus, S.J., Rossing, M.A., Rothstein, J., Song, H., Thompson, P.J., Berg, D.J. Van Den, Vierkant, R.A., Wang-Gohrke, S., Wentzensen, N., Whittemore, A.S., Wilkens, L.R., Wu, A.H., Yang, H., Pearce, C.L., Schildkraut, J.M., Pharoah, P., Goode, E.L., and Fridley, B.L.
Abstract: Contains fulltext : 171815.pdf (publisher's version ) (Closed access), BACKGROUND: Many epithelial ovarian cancer (EOC) risk factors relate to hormone exposure and elevated estrogen levels are associated with obesity in postmenopausal women. Therefore, we hypothesized that gene-environment interactions related to hormone-related risk factors could differ between obese and non-obese women. METHODS: We considered interactions between 11,441 SNPs within 80 candidate genes related to hormone biosynthesis and metabolism and insulin-like growth factors with six hormone-related factors (oral contraceptive use, parity, endometriosis, tubal ligation, hormone replacement therapy, and estrogen use) and assessed whether these interactions differed between obese and non-obese women. Interactions were assessed using logistic regression models and data from 14 case-control studies (6,247 cases; 10,379 controls). Histotype-specific analyses were also completed. RESULTS: SNPs in the following candidate genes showed notable interaction: IGF1R (rs41497346, estrogen plus progesterone hormone therapy, histology = all, P = 4.9 x 10(-6)) and ESR1 (rs12661437, endometriosis, histology = all, P = 1.5 x 10(-5)). The most notable obesity-gene-hormone risk factor interaction was within INSR (rs113759408, parity, histology = endometrioid, P = 8.8 x 10(-6)). CONCLUSIONS: We have demonstrated the feasibility of assessing multifactor interactions in large genetic epidemiology studies. Follow-up studies are necessary to assess the robustness of our findings for ESR1, CYP11A1, IGF1R, CYP11B1, INSR, and IGFBP2 Future work is needed to develop powerful statistical methods able to detect these complex interactions. IMPACT: Assessment of multifactor interaction is feasible, and, here, suggests that the relationship between genetic variants within candidate genes and hormone-related risk factors may vary EOC susceptibility. Cancer Epidemiol Biomarkers Prev; 25(5); 780-90. (c)2016 AACR.
Published: 2016

39. Genome-wide significant risk associations for mucinous ovarian carcinoma

Author: Kelemen, L.E., Lawrenson, K., Tyrer, J., Li, Q., Lee, J.M., Seo, J.H., Phelan, C.M., Beesley, J., Chen, X., Spindler, T.J., Aben, K.K.H., Anton-Culver, H., Antonenkova, N., Baker, H., Bandera, E.V., Bean, Y., Beckmann, M.W., Bisogna, M., Bjorge, T., Bogdanova, N., Brinton, L.A., Brooks-Wilson, A., Bruinsma, F., Butzow, R., Campbell, I., Carty, K., Chang-Claude, J., Chen, Y.A., Chen, Z.H., Cook, L.S., Cramer, D.W, Cunningham, J.M., Cybulski, C., Dansonka-Mieszkowska, A., Dennis, J., Dicks, E., Doherty, J.A., Kiemeney, L.A., Altena, A.M. van, et al., Kelemen, L.E., Lawrenson, K., Tyrer, J., Li, Q., Lee, J.M., Seo, J.H., Phelan, C.M., Beesley, J., Chen, X., Spindler, T.J., Aben, K.K.H., Anton-Culver, H., Antonenkova, N., Baker, H., Bandera, E.V., Bean, Y., Beckmann, M.W., Bisogna, M., Bjorge, T., Bogdanova, N., Brinton, L.A., Brooks-Wilson, A., Bruinsma, F., Butzow, R., Campbell, I., Carty, K., Chang-Claude, J., Chen, Y.A., Chen, Z.H., Cook, L.S., Cramer, D.W, Cunningham, J.M., Cybulski, C., Dansonka-Mieszkowska, A., Dennis, J., Dicks, E., Doherty, J.A., Kiemeney, L.A., Altena, A.M. van, and et al.
Abstract: Item does not contain fulltext
Published: 2015

40. Evaluating the ovarian cancer gonadotropin hypothesis: A candidate gene study

Author: Lee, A.W., Tyrer, J.P., Doherty, J.A., Stram, D.A., Kupryjanczyk, J., Dansonka-Mieszkowska, A., Plisiecka-Halasa, J., Spiewankiewicz, B., Myers, E.J., Study, G., Chenevix-Trench, G., Fasching, P.A., Beckmann, M.W., Ekici, A.B., Hein, A., Vergote, I., Nieuwenhuysen, E. Van, Lambrechts, D., Wicklund, K.G., Eilber, U., Wang-Gohrke, S., Chang-Claude, J., Rudolph, A., Sucheston-Campbell, L., Odunsi, K., Moysich, K.B., Shvetsov, Y.B., Thompson, P.J., Goodman, M.T., Wilkens, L.R., Dork, T., Hillemanns, P., Durst, M., Runnebaum, I.B., Bogdanova, N., Pelttari, L.M., Nevanlinna, H., Leminen, A., Edwards, R.P., Kelley, J.L., Harter, P., Schwaab, I., Heitz, F., Bois, A. du, Orsulic, S., Lester, J., Walsh, C., Karlan, B.Y., Hogdall, E., Kjaer, S.K., Jensen, A., Vierkant, R.A., Cunningham, J.M., Goode, E.L., Fridley, B.L., Southey, M.C., Giles, G.G., Bruinsma, F., Wu, X., Hildebrandt, M.A.T., Lu, K., Liang, D., Bisogna, M., Levine, D.A., Weber, R.P., Schildkraut, J.M., Iversen, E.S., Berchuck, A., Terry, K.L., Cramer, D.W, Tworoger, S.S., Poole, E.M., Olson, S.H., Orlow, I., Bandera, E.V., Bjorge, L., Tangen, I.L., Salvesen, H.B., Krakstad, C., Massuger, L.F.A.G., Kiemeney, L.A.L.M., Aben, K.K.H., Altena, A.M. van, Bean, Y., Pejovic, T., Kellar, M., Le, N.D., Cook, L.S., Kelemen, L.E., Brooks-Wilson, A., Lubinski, J., Gronwald, J., Cybulski, C., Jakubowska, A., Wentzensen, N., Brinton, L.A., Lissowska, J., Yang, H., Nedergaard, L., et al., Lee, A.W., Tyrer, J.P., Doherty, J.A., Stram, D.A., Kupryjanczyk, J., Dansonka-Mieszkowska, A., Plisiecka-Halasa, J., Spiewankiewicz, B., Myers, E.J., Study, G., Chenevix-Trench, G., Fasching, P.A., Beckmann, M.W., Ekici, A.B., Hein, A., Vergote, I., Nieuwenhuysen, E. Van, Lambrechts, D., Wicklund, K.G., Eilber, U., Wang-Gohrke, S., Chang-Claude, J., Rudolph, A., Sucheston-Campbell, L., Odunsi, K., Moysich, K.B., Shvetsov, Y.B., Thompson, P.J., Goodman, M.T., Wilkens, L.R., Dork, T., Hillemanns, P., Durst, M., Runnebaum, I.B., Bogdanova, N., Pelttari, L.M., Nevanlinna, H., Leminen, A., Edwards, R.P., Kelley, J.L., Harter, P., Schwaab, I., Heitz, F., Bois, A. du, Orsulic, S., Lester, J., Walsh, C., Karlan, B.Y., Hogdall, E., Kjaer, S.K., Jensen, A., Vierkant, R.A., Cunningham, J.M., Goode, E.L., Fridley, B.L., Southey, M.C., Giles, G.G., Bruinsma, F., Wu, X., Hildebrandt, M.A.T., Lu, K., Liang, D., Bisogna, M., Levine, D.A., Weber, R.P., Schildkraut, J.M., Iversen, E.S., Berchuck, A., Terry, K.L., Cramer, D.W, Tworoger, S.S., Poole, E.M., Olson, S.H., Orlow, I., Bandera, E.V., Bjorge, L., Tangen, I.L., Salvesen, H.B., Krakstad, C., Massuger, L.F.A.G., Kiemeney, L.A.L.M., Aben, K.K.H., Altena, A.M. van, Bean, Y., Pejovic, T., Kellar, M., Le, N.D., Cook, L.S., Kelemen, L.E., Brooks-Wilson, A., Lubinski, J., Gronwald, J., Cybulski, C., Jakubowska, A., Wentzensen, N., Brinton, L.A., Lissowska, J., Yang, H., Nedergaard, L., and et al.
Abstract: Contains fulltext : 155211.pdf (publisher's version ) (Closed access), OBJECTIVE: Ovarian cancer is a hormone-related disease with a strong genetic basis. However, none of its high-penetrance susceptibility genes and GWAS-identified variants to date are known to be involved in hormonal pathways. Given the hypothesized etiologic role of gonadotropins, an assessment of how variability in genes involved in the gonadotropin signaling pathway impacts disease risk is warranted. METHODS: Genetic data from 41 ovarian cancer study sites were pooled and unconditional logistic regression was used to evaluate whether any of the 2185 SNPs from 11 gonadotropin signaling pathway genes was associated with ovarian cancer risk. A burden test using the admixture likelihood (AML) method was also used to evaluate gene-level associations. RESULTS: We did not find any genome-wide significant associations between individual SNPs and ovarian cancer risk. However, there was some suggestion of gene-level associations for four gonadotropin signaling pathway genes: INHBB (p=0.045, mucinous), LHCGR (p=0.046, high-grade serous), GNRH (p=0.041, high-grade serous), and FSHB (p=0.036, overall invasive). There was also suggestive evidence for INHA (p=0.060, overall invasive). CONCLUSIONS: Ovarian cancer studies have limited sample numbers, thus fewer genome-wide susceptibility alleles, with only modest associations, have been identified relative to breast and prostate cancers. We have evaluated the majority of ovarian cancer studies with biological samples, to our knowledge, leaving no opportunity for replication. Using both our understanding of biology and powerful gene-level tests, we have identified four putative ovarian cancer loci near INHBB, LHCGR, GNRH, and FSHB that warrant a second look if larger sample sizes and denser genotype chips become available.
Published: 2015

41. Shared genetics underlying epidemiological association between endometriosis and ovarian cancer

Author: Lu, Y., Cuellar-Partida, G., Painter, J.N., Nyholt, D.R., Morris, A.P., Fasching, P.A., Hein, A., Burghaus, S., Beckmann, M.W., Lambrechts, D., Nieuwenhuysen, E. Van, Vergote, I., Vanderstichele, A., Doherty, J.A., Rossing, M.A., Wicklund, K.G., Chang-Claude, J., Eilber, U., Rudolph, A., Wang-Gohrke, S., Goodman, M.T., Bogdanova, N., Dork, T., Durst, M., Hillemanns, P., Runnebaum, I.B., Antonenkova, N., Butzow, R., Leminen, A., Nevanlinna, H., Pelttari, L.M., Edwards, R.P., Kelley, J.L., Modugno, F., Moysich, K.B., Ness, R.B., Cannioto, R., Hogdall, E., Jensen, A., Giles, G.G., Bruinsma, F., Kjaer, S.K., Hildebrandt, M.A., Liang, D., Lu, K.H., Wu, X., Bisogna, M., Dao, F., Levine, D.A., Cramer, D.W, Terry, K.L., Tworoger, S.S., Missmer, S., Bjorge, L., Salvesen, H.B., Kopperud, R.K., Bischof, K., Aben, K.K.H., Kiemeney, L.A.L.M., Massuger, L.F.A.G., Brooks-Wilson, A., Olson, S.H., McGuire, V., Rothstein, J.H., Sieh, W., Whittemore, A.S., Cook, L.S., Le, N.D., Gilks, C.B., Gronwald, J., Jakubowska, A., Lubinski, J., Gawelko, J., Song, H., Tyrer, J.P., Wentzensen, N., Brinton, L., Trabert, B., Lissowska, J., McLaughlin, J.R., Narod, S.A., Phelan, C., Anton-Culver, H., Ziogas, A., Eccles, D., Gayther, S.A., Gentry-Maharaj, A., Menon, U., Ramus, S.J., Wu, A.H., Dansonka-Mieszkowska, A., Kupryjanczyk, J., Timorek, A., Szafron, L., Cunningham, J.M., Fridley, B.L., Winham, S.J., Bandera, E.V., Poole, E.M., Morgan, T.K., et al., Lu, Y., Cuellar-Partida, G., Painter, J.N., Nyholt, D.R., Morris, A.P., Fasching, P.A., Hein, A., Burghaus, S., Beckmann, M.W., Lambrechts, D., Nieuwenhuysen, E. Van, Vergote, I., Vanderstichele, A., Doherty, J.A., Rossing, M.A., Wicklund, K.G., Chang-Claude, J., Eilber, U., Rudolph, A., Wang-Gohrke, S., Goodman, M.T., Bogdanova, N., Dork, T., Durst, M., Hillemanns, P., Runnebaum, I.B., Antonenkova, N., Butzow, R., Leminen, A., Nevanlinna, H., Pelttari, L.M., Edwards, R.P., Kelley, J.L., Modugno, F., Moysich, K.B., Ness, R.B., Cannioto, R., Hogdall, E., Jensen, A., Giles, G.G., Bruinsma, F., Kjaer, S.K., Hildebrandt, M.A., Liang, D., Lu, K.H., Wu, X., Bisogna, M., Dao, F., Levine, D.A., Cramer, D.W, Terry, K.L., Tworoger, S.S., Missmer, S., Bjorge, L., Salvesen, H.B., Kopperud, R.K., Bischof, K., Aben, K.K.H., Kiemeney, L.A.L.M., Massuger, L.F.A.G., Brooks-Wilson, A., Olson, S.H., McGuire, V., Rothstein, J.H., Sieh, W., Whittemore, A.S., Cook, L.S., Le, N.D., Gilks, C.B., Gronwald, J., Jakubowska, A., Lubinski, J., Gawelko, J., Song, H., Tyrer, J.P., Wentzensen, N., Brinton, L., Trabert, B., Lissowska, J., McLaughlin, J.R., Narod, S.A., Phelan, C., Anton-Culver, H., Ziogas, A., Eccles, D., Gayther, S.A., Gentry-Maharaj, A., Menon, U., Ramus, S.J., Wu, A.H., Dansonka-Mieszkowska, A., Kupryjanczyk, J., Timorek, A., Szafron, L., Cunningham, J.M., Fridley, B.L., Winham, S.J., Bandera, E.V., Poole, E.M., Morgan, T.K., and et al.
Abstract: Contains fulltext : 153959.pdf (publisher's version ) (Closed access), Epidemiological studies have demonstrated associations between endometriosis and certain histotypes of ovarian cancer, including clear cell, low-grade serous and endometrioid carcinomas. We aimed to determine whether the observed associations might be due to shared genetic aetiology. To address this, we used two endometriosis datasets genotyped on common arrays with full-genome coverage (3194 cases and 7060 controls) and a large ovarian cancer dataset genotyped on the customized Illumina Infinium iSelect (iCOGS) arrays (10 065 cases and 21 663 controls). Previous work has suggested that a large number of genetic variants contribute to endometriosis and ovarian cancer (all histotypes combined) susceptibility. Here, using the iCOGS data, we confirmed polygenic architecture for most histotypes of ovarian cancer. This led us to evaluate if the polygenic effects are shared across diseases. We found evidence for shared genetic risks between endometriosis and all histotypes of ovarian cancer, except for the intestinal mucinous type. Clear cell carcinoma showed the strongest genetic correlation with endometriosis (0.51, 95% CI = 0.18-0.84). Endometrioid and low-grade serous carcinomas had similar correlation coefficients (0.48, 95% CI = 0.07-0.89 and 0.40, 95% CI = 0.05-0.75, respectively). High-grade serous carcinoma, which often arises from the fallopian tubes, showed a weaker genetic correlation with endometriosis (0.25, 95% CI = 0.11-0.39), despite the absence of a known epidemiological association. These results suggest that the epidemiological association between endometriosis and ovarian adenocarcinoma may be attributable to shared genetic susceptibility loci.
Published: 2015

42. Cis-eQTL analysis and functional validation of candidate susceptibility genes for high-grade serous ovarian cancer

Author: Lawrenson, K., Li, Q., Kar, S., Seo, J.H., Tyrer, J., Spindler, T.J., Lee, J. van der, Chen, Y, Karst, A., Drapkin, R., Aben, K.K.H., Anton-Culver, H., Antonenkova, N., Baker, H., Bandera, E.V., Bean, Y., Beckmann, M.W., Berchuck, A., Bisogna, M., Bjorge, L., Bogdanova, N., Brinton, L.A., Brooks-Wilson, A., Bruinsma, F., Butzow, R., Campbell, I.G., Carty, K., Chang-Claude, J., Chenevix-Trench, G., Chen, A, Chen, Z., Cook, L.S., Cramer, D.W, Cunningham, J.M., Cybulski, C., Dansonka-Mieszkowska, A., Dennis, J., Dicks, E., Doherty, J.A., Dork, T., Bois, A. du, Durst, M., Eccles, D., Easton, D.T., Edwards, R.P., Eilber, U., Ekici, A.B., Fasching, P.A., Fridley, B.L., Gao, Y.T., Gentry-Maharaj, A., Giles, G.G., Glasspool, R., Goode, E.L., Goodman, M.T., Grownwald, J., Harrington, P., Harter, P., Hasmad, H.N., Hein, A., Heitz, F., Hildebrandt, M.A., Hillemanns, P., Hogdall, E., Hogdall, C., Hosono, S., Iversen, E.S., Jakubowska, A., James, P., Jensen, A., Ji, B.T., Karlan, B.Y., Kjaer, S. Kruger, Kelemen, L.E., Kellar, M., Kelley, J.L., Kiemeney, L.A., Krakstad, C., Kupryjanczyk, J., Lambrechts, D., Lambrechts, S., Le, N.D., Lee, A.W., Lele, S., Leminen, A., Lester, J., Levine, D.A., Liang, D., Lissowska, J., Lu, K., Lubinski, J., Lundvall, L., Massuger, L.F., Matsuo, K., McGuire, V., McLaughlin, J.R., Nevanlinna, H., McNeish, I., Menon, U., Modugno, F., et al., Lawrenson, K., Li, Q., Kar, S., Seo, J.H., Tyrer, J., Spindler, T.J., Lee, J. van der, Chen, Y, Karst, A., Drapkin, R., Aben, K.K.H., Anton-Culver, H., Antonenkova, N., Baker, H., Bandera, E.V., Bean, Y., Beckmann, M.W., Berchuck, A., Bisogna, M., Bjorge, L., Bogdanova, N., Brinton, L.A., Brooks-Wilson, A., Bruinsma, F., Butzow, R., Campbell, I.G., Carty, K., Chang-Claude, J., Chenevix-Trench, G., Chen, A, Chen, Z., Cook, L.S., Cramer, D.W, Cunningham, J.M., Cybulski, C., Dansonka-Mieszkowska, A., Dennis, J., Dicks, E., Doherty, J.A., Dork, T., Bois, A. du, Durst, M., Eccles, D., Easton, D.T., Edwards, R.P., Eilber, U., Ekici, A.B., Fasching, P.A., Fridley, B.L., Gao, Y.T., Gentry-Maharaj, A., Giles, G.G., Glasspool, R., Goode, E.L., Goodman, M.T., Grownwald, J., Harrington, P., Harter, P., Hasmad, H.N., Hein, A., Heitz, F., Hildebrandt, M.A., Hillemanns, P., Hogdall, E., Hogdall, C., Hosono, S., Iversen, E.S., Jakubowska, A., James, P., Jensen, A., Ji, B.T., Karlan, B.Y., Kjaer, S. Kruger, Kelemen, L.E., Kellar, M., Kelley, J.L., Kiemeney, L.A., Krakstad, C., Kupryjanczyk, J., Lambrechts, D., Lambrechts, S., Le, N.D., Lee, A.W., Lele, S., Leminen, A., Lester, J., Levine, D.A., Liang, D., Lissowska, J., Lu, K., Lubinski, J., Lundvall, L., Massuger, L.F., Matsuo, K., McGuire, V., McLaughlin, J.R., Nevanlinna, H., McNeish, I., Menon, U., Modugno, F., and et al.
Abstract: Contains fulltext : 154767.pdf (publisher's version ) (Open Access), Genome-wide association studies have reported 11 regions conferring risk of high-grade serous epithelial ovarian cancer (HGSOC). Expression quantitative trait locus (eQTL) analyses can identify candidate susceptibility genes at risk loci. Here we evaluate cis-eQTL associations at 47 regions associated with HGSOC risk (P
Published: 2015

43. Common Genetic Variation In Cellular Transport Genes and Epithelial Ovarian Cancer (EOC) Risk

Author: Chornokur, G., Lin, H.Y., Tyrer, J.P., Lawrenson, K., Dennis, J., Amankwah, E.K., Qu, X., Tsai, Y.Y., Jim, H.S., Chen, Z., Chen, A.Y., Permuth-Wey, J., Aben, K.K.H., Anton-Culver, H., Antonenkova, N., Bruinsma, F., Bandera, E.V., Bean, Y.T., Beckmann, M.W., Bisogna, M., Bjorge, L., Bogdanova, N., Brinton, L.A., Brooks-Wilson, A., Bunker, C.H., Butzow, R., Campbell, I.G., Carty, K., Chang-Claude, J., Cook, L.S., Cramer, D.W, Cunningham, J.M., Cybulski, C., Dansonka-Mieszkowska, A., Bois, A. du, Despierre, E., Dicks, E., Doherty, J.A., Dork, T., Durst, M., Easton, D.F., Eccles, D.M., Edwards, R.P., Ekici, A.B., Fasching, P.A., Fridley, B.L., Gao, Y.T., Gentry-Maharaj, A., Giles, G.G., Glasspool, R., Goodman, M.T., Gronwald, J., Harrington, P., Harter, P., Hein, A., Heitz, F., Hildebrandt, M.A.T., Hillemanns, P., Hogdall, C.K., Hogdall, E., Hosono, S., Jakubowska, A., Jensen, A., Ji, B.T., Karlan, B.Y., Kelemen, L.E., Kellar, M., Kiemeney, L.A.L.M., Krakstad, C., Kjaer, S.K., Kupryjanczyk, J., Lambrechts, D., Lambrechts, S., Le, N.D., Lee, A.W., Lele, S., Leminen, A., Lester, J., Levine, D.A., Liang, D., Lim, B.K., Lissowska, J., Lu, K., Lubinski, J., Lundvall, L., Massuger, L.F.A.G., Matsuo, K., McGuire, V., McLaughlin, J.R., McNeish, I., Menon, U., Milne, R.L., Modugno, F., Moysich, K.B., Ness, R.B., Nevanlinna, H., Eilber, U., Odunsi, K., Olson, S.H., Orlow, I., et al., Chornokur, G., Lin, H.Y., Tyrer, J.P., Lawrenson, K., Dennis, J., Amankwah, E.K., Qu, X., Tsai, Y.Y., Jim, H.S., Chen, Z., Chen, A.Y., Permuth-Wey, J., Aben, K.K.H., Anton-Culver, H., Antonenkova, N., Bruinsma, F., Bandera, E.V., Bean, Y.T., Beckmann, M.W., Bisogna, M., Bjorge, L., Bogdanova, N., Brinton, L.A., Brooks-Wilson, A., Bunker, C.H., Butzow, R., Campbell, I.G., Carty, K., Chang-Claude, J., Cook, L.S., Cramer, D.W, Cunningham, J.M., Cybulski, C., Dansonka-Mieszkowska, A., Bois, A. du, Despierre, E., Dicks, E., Doherty, J.A., Dork, T., Durst, M., Easton, D.F., Eccles, D.M., Edwards, R.P., Ekici, A.B., Fasching, P.A., Fridley, B.L., Gao, Y.T., Gentry-Maharaj, A., Giles, G.G., Glasspool, R., Goodman, M.T., Gronwald, J., Harrington, P., Harter, P., Hein, A., Heitz, F., Hildebrandt, M.A.T., Hillemanns, P., Hogdall, C.K., Hogdall, E., Hosono, S., Jakubowska, A., Jensen, A., Ji, B.T., Karlan, B.Y., Kelemen, L.E., Kellar, M., Kiemeney, L.A.L.M., Krakstad, C., Kjaer, S.K., Kupryjanczyk, J., Lambrechts, D., Lambrechts, S., Le, N.D., Lee, A.W., Lele, S., Leminen, A., Lester, J., Levine, D.A., Liang, D., Lim, B.K., Lissowska, J., Lu, K., Lubinski, J., Lundvall, L., Massuger, L.F.A.G., Matsuo, K., McGuire, V., McLaughlin, J.R., McNeish, I., Menon, U., Milne, R.L., Modugno, F., Moysich, K.B., Ness, R.B., Nevanlinna, H., Eilber, U., Odunsi, K., Olson, S.H., and Orlow, I., et al.
Abstract: Contains fulltext : 154822.PDF (publisher's version ) (Open Access), BACKGROUND: Defective cellular transport processes can lead to aberrant accumulation of trace elements, iron, small molecules and hormones in the cell, which in turn may promote the formation of reactive oxygen species, promoting DNA damage and aberrant expression of key regulatory cancer genes. As DNA damage and uncontrolled proliferation are hallmarks of cancer, including epithelial ovarian cancer (EOC), we hypothesized that inherited variation in the cellular transport genes contributes to EOC risk. METHODS: In total, DNA samples were obtained from 14,525 case subjects with invasive EOC and from 23,447 controls from 43 sites in the Ovarian Cancer Association Consortium (OCAC). Two hundred seventy nine SNPs, representing 131 genes, were genotyped using an Illumina Infinium iSelect BeadChip as part of the Collaborative Oncological Gene-environment Study (COGS). SNP analyses were conducted using unconditional logistic regression under a log-additive model, and the FDR q<0.2 was applied to adjust for multiple comparisons. RESULTS: The most significant evidence of an association for all invasive cancers combined and for the serous subtype was observed for SNP rs17216603 in the iron transporter gene HEPH (invasive: OR = 0.85, P = 0.00026; serous: OR = 0.81, P = 0.00020); this SNP was also associated with the borderline/low malignant potential (LMP) tumors (P = 0.021). Other genes significantly associated with EOC histological subtypes (p<0.05) included the UGT1A (endometrioid), SLC25A45 (mucinous), SLC39A11 (low malignant potential), and SERPINA7 (clear cell carcinoma). In addition, 1785 SNPs in six genes (HEPH, MGST1, SERPINA, SLC25A45, SLC39A11 and UGT1A) were imputed from the 1000 Genomes Project and examined for association with INV EOC in white-European subjects. The most significant imputed SNP was rs117729793 in SLC39A11 (per allele, OR = 2.55, 95% CI = 1.5-4.35, p = 5.66x10-4). CONCLUSION: These results, generated on a large cohort of women, revealed associatio
Published: 2015

44. Genome-wide Analysis Identifies Novel Loci Associated with Ovarian Cancer Outcomes: Findings from the Ovarian Cancer Association Consortium

Author: Johnatty, S.E., Tyrer, J.P., Kar, S., Beesley, J., Lu, Y., Gao, B., Fasching, P.A., Hein, A., Ekici, A.B., Beckmann, M.W., Lambrechts, D., Nieuwenhuysen, E. Van, Vergote, I., Lambrechts, S., Rossing, M.A., Doherty, J.A., Chang-Claude, J., Modugno, F., Ness, R.B., Moysich, K.B., Levine, D.A., Kiemeney, L.A.L.M., Massuger, L.F.A.G., Gronwald, J., Lubinski, J., Jakubowska, A., Cybulski, C., Brinton, L., Lissowska, J., Wentzensen, N., Song, H., Rhenius, V., Campbell, I., Eccles, D., Sieh, W., Whittemore, A.S., McGuire, V., Rothstein, J.H., Sutphen, R., Anton-Culver, H., Ziogas, A., Gayther, S.A., Gentry-Maharaj, A., Menon, U., Ramus, S.J., Pearce, C.L., Pike, M.C., Stram, D.O., Wu, A.H., Kupryjanczyk, J., Dansonka-Mieszkowska, A., Rzepecka, I.K., Spiewankiewicz, B., Goodman, M.T., Wilkens, L.R., Carney, M.E., Thompson, P.J., Heitz, F., Bois, A. du, Schwaab, I., Harter, P., Pisterer, J., Hillemanns, P., Karlan, B.Y., Walsh, C., Lester, J., Orsulic, S., Winham, S.J., Earp, M., Larson, M.C., Fogarty, Z.C., Hogdall, E., Jensen, A., Kjaer, S.K., Fridley, B.L., Cunningham, J.M., Vierkant, R.A., Schildkraut, J.M., Iversen, E.S., Terry, K.L., Cramer, D.W, Bandera, E.V., Orlow, I., Pejovic, T., Bean, Y., Hogdall, C., Lundvall, L., McNeish, I., Paul, J., Carty, K., Siddiqui, N., Glasspool, R., Sellers, T., Kennedy, C., Chiew, Y.E., Berchuck, A., MacGregor, S., Pharoah, P.D., Goode, E.L., Defazio, A., et al., Johnatty, S.E., Tyrer, J.P., Kar, S., Beesley, J., Lu, Y., Gao, B., Fasching, P.A., Hein, A., Ekici, A.B., Beckmann, M.W., Lambrechts, D., Nieuwenhuysen, E. Van, Vergote, I., Lambrechts, S., Rossing, M.A., Doherty, J.A., Chang-Claude, J., Modugno, F., Ness, R.B., Moysich, K.B., Levine, D.A., Kiemeney, L.A.L.M., Massuger, L.F.A.G., Gronwald, J., Lubinski, J., Jakubowska, A., Cybulski, C., Brinton, L., Lissowska, J., Wentzensen, N., Song, H., Rhenius, V., Campbell, I., Eccles, D., Sieh, W., Whittemore, A.S., McGuire, V., Rothstein, J.H., Sutphen, R., Anton-Culver, H., Ziogas, A., Gayther, S.A., Gentry-Maharaj, A., Menon, U., Ramus, S.J., Pearce, C.L., Pike, M.C., Stram, D.O., Wu, A.H., Kupryjanczyk, J., Dansonka-Mieszkowska, A., Rzepecka, I.K., Spiewankiewicz, B., Goodman, M.T., Wilkens, L.R., Carney, M.E., Thompson, P.J., Heitz, F., Bois, A. du, Schwaab, I., Harter, P., Pisterer, J., Hillemanns, P., Karlan, B.Y., Walsh, C., Lester, J., Orsulic, S., Winham, S.J., Earp, M., Larson, M.C., Fogarty, Z.C., Hogdall, E., Jensen, A., Kjaer, S.K., Fridley, B.L., Cunningham, J.M., Vierkant, R.A., Schildkraut, J.M., Iversen, E.S., Terry, K.L., Cramer, D.W, Bandera, E.V., Orlow, I., Pejovic, T., Bean, Y., Hogdall, C., Lundvall, L., McNeish, I., Paul, J., Carty, K., Siddiqui, N., Glasspool, R., Sellers, T., Kennedy, C., Chiew, Y.E., Berchuck, A., MacGregor, S., Pharoah, P.D., Goode, E.L., Defazio, A., and et al.
Abstract: Contains fulltext : 152262.pdf (publisher's version ) (Closed access), PURPOSE: Chemotherapy resistance remains a major challenge in the treatment of ovarian cancer. We hypothesize that germline polymorphisms might be associated with clinical outcome. EXPERIMENTAL DESIGN: We analyzed approximately 2.8 million genotyped and imputed SNPs from the iCOGS experiment for progression-free survival (PFS) and overall survival (OS) in 2,901 European epithelial ovarian cancer (EOC) patients who underwent first-line treatment of cytoreductive surgery and chemotherapy regardless of regimen, and in a subset of 1,098 patients treated with >/=4 cycles of paclitaxel and carboplatin at standard doses. We evaluated the top SNPs in 4,434 EOC patients, including patients from The Cancer Genome Atlas. In addition, we conducted pathway analysis of all intragenic SNPs and tested their association with PFS and OS using gene set enrichment analysis. RESULTS: Five SNPs were significantly associated (P
Published: 2015

45. Common variants at the CHEK2 gene locus and risk of epithelial ovarian cancer

Author: Lawrenson, K., Iversen, E.S., Tyrer, J., Weber, R.P., Concannon, P., Hazelett, D.J., Li, Q., Marks, J.R., Berchuck, A., Lee, J.M., Aben, K.K.H., Anton-Culver, H., Antonenkova, N., Bandera, E.V., Bean, Y., Beckmann, M.W., Bisogna, M., Bjorge, L., Bogdanova, N., Brinton, L.A., Brooks-Wilson, A., Bruinsma, F., Butzow, R., Campbell, I.G., Carty, K., Chang-Claude, J., Chenevix-Trench, G., Chen, A, Chen, Z., Cook, L.S., Cramer, D.W, Cunningham, J.M., Cybulski, C., Plisiecka-Halasa, J., Dennis, J., Dicks, E., Doherty, J.A., Dork, T., Bois, A. du, Eccles, D., Easton, D.T., Edwards, R.P., Eilber, U., Ekici, A.B., Fasching, P.A., Fridley, B.L., Gao, Y.T., Gentry-Maharaj, A., Giles, G.G., Glasspool, R., Goode, E.L., Goodman, M.T., Gronwald, J., Harter, P., Hasmad, H.N., Hein, A., Heitz, F., Hildebrandt, M.A.T., Hillemanns, P., Hogdall, E., Hogdall, C., Hosono, S., Jakubowska, A., Paul, J., Jensen, A., Karlan, B.Y., Kjaer, S.K., Kelemen, L.E., Kellar, M., Kelley, J.L., Kiemeney, L.A., Krakstad, C., Lambrechts, D., Lambrechts, S., Le, N.D., Lee, A.W., Cannioto, R., Leminen, A., Lester, J., Levine, D.A., Liang, D., Lissowska, J., Lu, K., Lubinski, J., Lundvall, L., Massuger, L.F., Matsuo, K., McGuire, V., McLaughlin, J.R., Nevanlinna, H., McNeish, I., Menon, U., Modugno, F., Moysich, K.B., Narod, S.A., Nedergaard, L., Ness, R.B., Azmi, M.A. Noor, Odunsi, K., Olson, S.H., Lawrenson, K., Iversen, E.S., Tyrer, J., Weber, R.P., Concannon, P., Hazelett, D.J., Li, Q., Marks, J.R., Berchuck, A., Lee, J.M., Aben, K.K.H., Anton-Culver, H., Antonenkova, N., Bandera, E.V., Bean, Y., Beckmann, M.W., Bisogna, M., Bjorge, L., Bogdanova, N., Brinton, L.A., Brooks-Wilson, A., Bruinsma, F., Butzow, R., Campbell, I.G., Carty, K., Chang-Claude, J., Chenevix-Trench, G., Chen, A, Chen, Z., Cook, L.S., Cramer, D.W, Cunningham, J.M., Cybulski, C., Plisiecka-Halasa, J., Dennis, J., Dicks, E., Doherty, J.A., Dork, T., Bois, A. du, Eccles, D., Easton, D.T., Edwards, R.P., Eilber, U., Ekici, A.B., Fasching, P.A., Fridley, B.L., Gao, Y.T., Gentry-Maharaj, A., Giles, G.G., Glasspool, R., Goode, E.L., Goodman, M.T., Gronwald, J., Harter, P., Hasmad, H.N., Hein, A., Heitz, F., Hildebrandt, M.A.T., Hillemanns, P., Hogdall, E., Hogdall, C., Hosono, S., Jakubowska, A., Paul, J., Jensen, A., Karlan, B.Y., Kjaer, S.K., Kelemen, L.E., Kellar, M., Kelley, J.L., Kiemeney, L.A., Krakstad, C., Lambrechts, D., Lambrechts, S., Le, N.D., Lee, A.W., Cannioto, R., Leminen, A., Lester, J., Levine, D.A., Liang, D., Lissowska, J., Lu, K., Lubinski, J., Lundvall, L., Massuger, L.F., Matsuo, K., McGuire, V., McLaughlin, J.R., Nevanlinna, H., McNeish, I., Menon, U., Modugno, F., Moysich, K.B., Narod, S.A., Nedergaard, L., Ness, R.B., Azmi, M.A. Noor, Odunsi, K., and Olson, S.H.
Abstract: Contains fulltext : 152042.pdf (publisher's version ) (Closed access), Genome-wide association studies have identified 20 genomic regions associated with risk of epithelial ovarian cancer (EOC), but many additional risk variants may exist. Here, we evaluated associations between common genetic variants [single nucleotide polymorphisms (SNPs) and indels] in DNA repair genes and EOC risk. We genotyped 2896 common variants at 143 gene loci in DNA samples from 15 397 patients with invasive EOC and controls. We found evidence of associations with EOC risk for variants at FANCA, EXO1, E2F4, E2F2, CREB5 and CHEK2 genes (P
Published: 2015

46. Network-Based Integration of GWAS and Gene Expression Identifies a HOX-Centric Network Associated with Serous Ovarian Cancer Risk

Author: Kar, S.P., Tyrer, J.P., Li, Q., Lawrenson, K., Aben, K.K.H., Anton-Culver, H., Antonenkova, N., Chenevix-Trench, G., Baker, H., Bandera, E.V., Bean, Y.T., Beckmann, M.W., Berchuck, A., Bisogna, M., Bjorge, L., Bogdanova, N., Brinton, L., Brooks-Wilson, A., Butzow, R., Campbell, I., Carty, K., Chang-Claude, J., Chen, Y.A., Chen, Z., Cook, L.S., Cramer, D., Cunningham, J.M., Cybulski, C., Dansonka-Mieszkowska, A., Dennis, J., Dicks, E., Doherty, J.A., Dork, T., Bois, A. du, Durst, M., Eccles, D., Easton, D.F., Edwards, R.P., Ekici, A.B., Fasching, P.A., Fridley, B.L., Gao, Y.T., Gentry-Maharaj, A., Giles, G.G., Glasspool, R., Goode, E.L., Goodman, M.T., Grownwald, J., Harrington, P., Harter, P., Hein, A., Heitz, F., Hildebrandt, M.A.T., Hillemanns, P., Hogdall, E., Hogdall, C.K., Hosono, S., Iversen, E.S., Jakubowska, A., Paul, J., Jensen, A., Ji, B.T., Karlan, B.Y., Kjaer, S.K., Kelemen, L.E., Kellar, M., Kelley, J., Kiemeney, L.A.L.M., Krakstad, C., Kupryjanczyk, J., Lambrechts, D., Lambrechts, S., Le, N.D., Lee, A.W., Lele, S., Leminen, A., Lester, J., Levine, D.A., Liang, D., Lissowska, J., Lu, K., Lubinski, J., Lundvall, L., Massuger, L.F., Matsuo, K., McGuire, V., McLaughlin, J.R., McNeish, I.A., Menon, U., Modugno, F., Moysich, K.B., Narod, S.A., Nedergaard, L., Ness, R.B., Nevanlinna, H., Odunsi, K., Olson, S.H., Orlow, I., Orsulic, S., Weber, R.P., Kar, S.P., Tyrer, J.P., Li, Q., Lawrenson, K., Aben, K.K.H., Anton-Culver, H., Antonenkova, N., Chenevix-Trench, G., Baker, H., Bandera, E.V., Bean, Y.T., Beckmann, M.W., Berchuck, A., Bisogna, M., Bjorge, L., Bogdanova, N., Brinton, L., Brooks-Wilson, A., Butzow, R., Campbell, I., Carty, K., Chang-Claude, J., Chen, Y.A., Chen, Z., Cook, L.S., Cramer, D., Cunningham, J.M., Cybulski, C., Dansonka-Mieszkowska, A., Dennis, J., Dicks, E., Doherty, J.A., Dork, T., Bois, A. du, Durst, M., Eccles, D., Easton, D.F., Edwards, R.P., Ekici, A.B., Fasching, P.A., Fridley, B.L., Gao, Y.T., Gentry-Maharaj, A., Giles, G.G., Glasspool, R., Goode, E.L., Goodman, M.T., Grownwald, J., Harrington, P., Harter, P., Hein, A., Heitz, F., Hildebrandt, M.A.T., Hillemanns, P., Hogdall, E., Hogdall, C.K., Hosono, S., Iversen, E.S., Jakubowska, A., Paul, J., Jensen, A., Ji, B.T., Karlan, B.Y., Kjaer, S.K., Kelemen, L.E., Kellar, M., Kelley, J., Kiemeney, L.A.L.M., Krakstad, C., Kupryjanczyk, J., Lambrechts, D., Lambrechts, S., Le, N.D., Lee, A.W., Lele, S., Leminen, A., Lester, J., Levine, D.A., Liang, D., Lissowska, J., Lu, K., Lubinski, J., Lundvall, L., Massuger, L.F., Matsuo, K., McGuire, V., McLaughlin, J.R., McNeish, I.A., Menon, U., Modugno, F., Moysich, K.B., Narod, S.A., Nedergaard, L., Ness, R.B., Nevanlinna, H., Odunsi, K., Olson, S.H., Orlow, I., Orsulic, S., and Weber, R.P.
Abstract: Contains fulltext : 153484.pdf (publisher's version ) (Closed access), BACKGROUND: Genome-wide association studies (GWAS) have so far reported 12 loci associated with serous epithelial ovarian cancer (EOC) risk. We hypothesized that some of these loci function through nearby transcription factor (TF) genes and that putative target genes of these TFs as identified by coexpression may also be enriched for additional EOC risk associations. METHODS: We selected TF genes within 1 Mb of the top signal at the 12 genome-wide significant risk loci. Mutual information, a form of correlation, was used to build networks of genes strongly coexpressed with each selected TF gene in the unified microarray dataset of 489 serous EOC tumors from The Cancer Genome Atlas. Genes represented in this dataset were subsequently ranked using a gene-level test based on results for germline SNPs from a serous EOC GWAS meta-analysis (2,196 cases/4,396 controls). RESULTS: Gene set enrichment analysis identified six networks centered on TF genes (HOXB2, HOXB5, HOXB6, HOXB7 at 17q21.32 and HOXD1, HOXD3 at 2q31) that were significantly enriched for genes from the risk-associated end of the ranked list (P < 0.05 and FDR < 0.05). These results were replicated (P < 0.05) using an independent association study (7,035 cases/21,693 controls). Genes underlying enrichment in the six networks were pooled into a combined network. CONCLUSION: We identified a HOX-centric network associated with serous EOC risk containing several genes with known or emerging roles in serous EOC development. IMPACT: Network analysis integrating large, context-specific datasets has the potential to offer mechanistic insights into cancer susceptibility and prioritize genes for experimental characterization. Cancer Epidemiol Biomarkers Prev; 24(10); 1574-84. (c)2015 AACR.
Published: 2015

47. Consortium analysis of gene and gene-folate interactions in purine and pyrimidine metabolism pathways with ovarian carcinoma risk

Author: Kelemen, L.E., Terry, K.L., Goodman, M.T., Webb, P.M., Bandera, E.V., McGuire, V., Rossing, M.A., Wang, Q., Dicks, E., Tyrer, J.P., Song, H., Kupryjanczyk, J., Dansonka-Mieszkowska, A., Plisiecka-Halasa, J., Timorek, A., Menon, U., Gentry-Maharaj, A., Gayther, S.A., Ramus, S.J., Narod, S.A., Risch, H.A., McLaughlin, J.R., Siddiqui, N., Glasspool, R., Paul, J., Carty, K., Gronwald, J., Lubinski, J., Jakubowska, A., Cybulski, C., Kiemeney, L.A.L.M., Massuger, L.F.A.G., Altena, A.M. van, Aben, K.K.H., Olson, S.H., Orlow, I., Cramer, D.W, Levine, D.A., Bisogna, M., Giles, G.G., Southey, M.C., Bruinsma, F., Kjaer, S.K., Hogdall, E., Jensen, A., Hogdall, C.K., Lundvall, L., Engelholm, S.A., Heitz, F., Bois, A. du, Harter, P., Schwaab, I., Butzow, R., Nevanlinna, H., Pelttari, L.M., Leminen, A., Thompson, P.J., Lurie, G., Wilkens, L.R., Lambrechts, D., Nieuwenhuysen, E. Van, Lambrechts, S., Vergote, I., Beesley, J., Investigators, A.S.G.A., Fasching, P.A., Beckmann, M.W., Hein, A., Ekici, A.B., Doherty, J.A., Wu, A.H., Pearce, C.L., Pike, M.C., Stram, D., Chang-Claude, J., Rudolph, A., Dork, T., Durst, M., Hillemanns, P., Runnebaum, I.B., Bogdanova, N., Antonenkova, N., Odunsi, K., Edwards, R.P., Kelley, J.L., Modugno, F., Ness, R.B., Karlan, B.Y., Walsh, C., Lester, J., Orsulic, S., Fridley, B.L., Vierkant, R.A., Cunningham, J.M., Wu, X., Lu, K., Liang, D., Hildebrandt, M.A.T., Weber, R.P., Iversen, E.S., Kelemen, L.E., Terry, K.L., Goodman, M.T., Webb, P.M., Bandera, E.V., McGuire, V., Rossing, M.A., Wang, Q., Dicks, E., Tyrer, J.P., Song, H., Kupryjanczyk, J., Dansonka-Mieszkowska, A., Plisiecka-Halasa, J., Timorek, A., Menon, U., Gentry-Maharaj, A., Gayther, S.A., Ramus, S.J., Narod, S.A., Risch, H.A., McLaughlin, J.R., Siddiqui, N., Glasspool, R., Paul, J., Carty, K., Gronwald, J., Lubinski, J., Jakubowska, A., Cybulski, C., Kiemeney, L.A.L.M., Massuger, L.F.A.G., Altena, A.M. van, Aben, K.K.H., Olson, S.H., Orlow, I., Cramer, D.W, Levine, D.A., Bisogna, M., Giles, G.G., Southey, M.C., Bruinsma, F., Kjaer, S.K., Hogdall, E., Jensen, A., Hogdall, C.K., Lundvall, L., Engelholm, S.A., Heitz, F., Bois, A. du, Harter, P., Schwaab, I., Butzow, R., Nevanlinna, H., Pelttari, L.M., Leminen, A., Thompson, P.J., Lurie, G., Wilkens, L.R., Lambrechts, D., Nieuwenhuysen, E. Van, Lambrechts, S., Vergote, I., Beesley, J., Investigators, A.S.G.A., Fasching, P.A., Beckmann, M.W., Hein, A., Ekici, A.B., Doherty, J.A., Wu, A.H., Pearce, C.L., Pike, M.C., Stram, D., Chang-Claude, J., Rudolph, A., Dork, T., Durst, M., Hillemanns, P., Runnebaum, I.B., Bogdanova, N., Antonenkova, N., Odunsi, K., Edwards, R.P., Kelley, J.L., Modugno, F., Ness, R.B., Karlan, B.Y., Walsh, C., Lester, J., Orsulic, S., Fridley, B.L., Vierkant, R.A., Cunningham, J.M., Wu, X., Lu, K., Liang, D., Hildebrandt, M.A.T., Weber, R.P., and Iversen, E.S.
Abstract: Contains fulltext : 137688.pdf (publisher's version ) (Closed access), SCOPE: We reevaluated previously reported associations between variants in pathways of one-carbon (1-C) (folate) transfer genes and ovarian carcinoma (OC) risk, and in related pathways of purine and pyrimidine metabolism, and assessed interactions with folate intake. METHODS AND RESULTS: Odds ratios (OR) for 446 genetic variants were estimated among 13,410 OC cases and 22,635 controls, and among 2281 cases and 3444 controls with folate information. Following multiple testing correction, the most significant main effect associations were for dihydropyrimidine dehydrogenase (DPYD) variants rs11587873 (OR = 0.92; p = 6 x 10(-5)) and rs828054 (OR = 1.06; p = 1 x 10(-4)). Thirteen variants in the pyrimidine metabolism genes, DPYD, DPYS, PPAT, and TYMS, also interacted significantly with folate in a multivariant analysis (corrected p = 9.9 x 10(-6)) but collectively explained only 0.2% of OC risk. Although no other associations were significant after multiple testing correction, variants in SHMT1 in 1-C transfer, previously reported with OC, suggested lower risk at higher folate (p(interaction) = 0.03-0.006). CONCLUSION: Variation in pyrimidine metabolism genes, particularly DPYD, which was previously reported to be associated with OC, may influence risk; however, stratification by folate intake is unlikely to modify disease risk appreciably in these women. SHMT1 SNP-by-folate interactions are plausible but require further validation. Polymorphisms in selected genes in purine metabolism were not associated with OC.
Published: 2014

48. Risk of ovarian cancer and the NF-kappaB pathway: genetic association with IL1A and TNFSF10

Author: Charbonneau, B., Block, M.S., Bamlet, W.R., Vierkant, R.A., Kalli, K.R., Fogarty, Z., Rider, D.N., Sellers, T.A., Tworoger, S.S., Poole, E., Risch, H.A., Salvesen, H.B., Kiemeney, B., Baglietto, L., Giles, G.G., Severi, G., Trabert, B., Wentzensen, N., Chenevix-Trench, G., Whittemore, A.S., Sieh, W., Chang-Claude, J., Bandera, E.V., Orlow, I., Terry, K., Goodman, M.T., Thompson, P.J., Cook, L.S., Rossing, M.A., Ness, R.B., Narod, S.A., Kupryjanczyk, J., Lu, K., Butzow, R., Dork, T., Pejovic, T., Campbell, I., Le, N.D., Bunker, C.H., Bogdanova, N., Runnebaum, I.B., Eccles, D., Paul, J., Wu, A.H., Gayther, S.A., Hogdall, E., Heitz, F., Kaye, S.B., Karlan, B.Y., Anton-Culver, H., Gronwald, J., Hogdall, C.K., Lambrechts, D., Fasching, P.A., Menon, U., Schildkraut, J., Pearce, C.L., Levine, D.A., Kjaer, S.K., Cramer, D., Flanagan, J.M., Phelan, C.M., Brown, R., Massuger, L.F.A.G., Song, H., Doherty, J.A., Krakstad, C., Liang, D., Odunsi, K., Berchuck, A., Jensen, A., Lubinski, J., Nevanlinna, H., Bean, Y.T., Lurie, G., Ziogas, A., Walsh, C., Despierre, E., Brinton, L., Hein, A., Rudolph, A., Dansonka-Mieszkowska, A., Olson, S.H., Harter, P., Tyrer, J., Vitonis, A.F., Brooks-Wilson, A., Aben, K.K.H., Pike, M.C., Ramus, S.J., Wik, E., Cybulski, C., Lin, J., Sucheston, L., Edwards, R., McGuire, V., Lester, J., Bois, A. du, Lundvall, L., et al., Charbonneau, B., Block, M.S., Bamlet, W.R., Vierkant, R.A., Kalli, K.R., Fogarty, Z., Rider, D.N., Sellers, T.A., Tworoger, S.S., Poole, E., Risch, H.A., Salvesen, H.B., Kiemeney, B., Baglietto, L., Giles, G.G., Severi, G., Trabert, B., Wentzensen, N., Chenevix-Trench, G., Whittemore, A.S., Sieh, W., Chang-Claude, J., Bandera, E.V., Orlow, I., Terry, K., Goodman, M.T., Thompson, P.J., Cook, L.S., Rossing, M.A., Ness, R.B., Narod, S.A., Kupryjanczyk, J., Lu, K., Butzow, R., Dork, T., Pejovic, T., Campbell, I., Le, N.D., Bunker, C.H., Bogdanova, N., Runnebaum, I.B., Eccles, D., Paul, J., Wu, A.H., Gayther, S.A., Hogdall, E., Heitz, F., Kaye, S.B., Karlan, B.Y., Anton-Culver, H., Gronwald, J., Hogdall, C.K., Lambrechts, D., Fasching, P.A., Menon, U., Schildkraut, J., Pearce, C.L., Levine, D.A., Kjaer, S.K., Cramer, D., Flanagan, J.M., Phelan, C.M., Brown, R., Massuger, L.F.A.G., Song, H., Doherty, J.A., Krakstad, C., Liang, D., Odunsi, K., Berchuck, A., Jensen, A., Lubinski, J., Nevanlinna, H., Bean, Y.T., Lurie, G., Ziogas, A., Walsh, C., Despierre, E., Brinton, L., Hein, A., Rudolph, A., Dansonka-Mieszkowska, A., Olson, S.H., Harter, P., Tyrer, J., Vitonis, A.F., Brooks-Wilson, A., Aben, K.K.H., Pike, M.C., Ramus, S.J., Wik, E., Cybulski, C., Lin, J., Sucheston, L., Edwards, R., McGuire, V., Lester, J., Bois, A. du, Lundvall, L., and et al.
Abstract: Contains fulltext : 136742.pdf (publisher's version ) (Closed access), A missense single-nucleotide polymorphism (SNP) in the immune modulatory gene IL1A has been associated with ovarian cancer risk (rs17561). Although the exact mechanism through which this SNP alters risk of ovarian cancer is not clearly understood, rs17561 has also been associated with risk of endometriosis, an epidemiologic risk factor for ovarian cancer. Interleukin-1alpha (IL1A) is both regulated by and able to activate NF-kappaB, a transcription factor family that induces transcription of many proinflammatory genes and may be an important mediator in carcinogenesis. We therefore tagged SNPs in more than 200 genes in the NF-kappaB pathway for a total of 2,282 SNPs (including rs17561) for genotype analysis of 15,604 cases of ovarian cancer in patients of European descent, including 6,179 of high-grade serous (HGS), 2,100 endometrioid, 1,591 mucinous, 1,034 clear cell, and 1,016 low-grade serous, including 23,235 control cases spanning 40 studies in the Ovarian Cancer Association Consortium. In this large population, we confirmed the association between rs17561 and clear cell ovarian cancer [OR, 0.84; 95% confidence interval (CI), 0.76-0.93; P = 0.00075], which remained intact even after excluding participants in the prior study (OR, 0.85; 95% CI, 0.75-0.95; P = 0.006). Considering a multiple-testing-corrected significance threshold of P < 2.5 x 10(-5), only one other variant, the TNFSF10 SNP rs6785617, was associated significantly with a risk of ovarian cancer (low malignant potential tumors OR, 0.85; 95% CI, 0.79-0.91; P = 0.00002). Our results extend the evidence that borderline tumors may have a distinct genetic etiology. Further investigation of how these SNPs might modify ovarian cancer associations with other inflammation-related risk factors is warranted.
Published: 2014

49. Genome-wide association study of subtype-specific epithelial ovarian cancer risk alleles using pooled DNA

Author: Earp, M.A., Kelemen, L.E., Magliocco, A.M., Swenerton, K.D., Chenevix-Trench, G., Lu, Y., Hein, A., Ekici, A.B., Beckmann, M.W., Fasching, P.A., Lambrechts, D., Despierre, E., Vergote, I., Lambrechts, S., Doherty, J.A., Rossing, M.A., Chang-Claude, J., Rudolph, A., Friel, G., Moysich, K.B., Odunsi, K., Sucheston-Campbell, L., Lurie, G., Goodman, M.T., Carney, M.E., Thompson, P.J., Runnebaum, I.B., Durst, M., Hillemanns, P., Dork, T., Antonenkova, N., Bogdanova, N., Leminen, A., Nevanlinna, H., Pelttari, L.M., Butzow, R., Bunker, C.H., Modugno, F., Edwards, R.P., Ness, R.B., Bois, A. du, Heitz, F., Schwaab, I., Harter, P., Karlan, B.Y., Walsh, C., Lester, J., Jensen, A., Kjaer, S.K., Hogdall, C.K., Hogdall, E., Lundvall, L., Sellers, T.A., Fridley, B.L., Goode, E.L., Cunningham, J.M., Vierkant, R.A., Giles, G.G., Baglietto, L., Severi, G., Southey, M.C., Liang, D., Wu, X., Lu, K., Hildebrandt, M.A.T., Levine, D.A., Bisogna, M., Schildkraut, J.M., Iversen, E.S., Weber, R.P., Berchuck, A., Cramer, D.W, Terry, K.L., Poole, E.M., Tworoger, S.S., Bandera, E.V., Chandran, U., Orlow, I., Olson, S.H., Wik, E., Salvesen, H.B., Bjorge, L., Halle, M.K., Altena, A.M. van, Aben, K.K.H., Kiemeney, B., Massuger, L.F.A.G., Pejovic, T., Bean, Y.T., Cybulski, C., Gronwald, J., Lubinski, J., Wentzensen, N., Brinton, L.A., Lissowska, J., Garcia-Closas, M., Dicks, E., et al., Earp, M.A., Kelemen, L.E., Magliocco, A.M., Swenerton, K.D., Chenevix-Trench, G., Lu, Y., Hein, A., Ekici, A.B., Beckmann, M.W., Fasching, P.A., Lambrechts, D., Despierre, E., Vergote, I., Lambrechts, S., Doherty, J.A., Rossing, M.A., Chang-Claude, J., Rudolph, A., Friel, G., Moysich, K.B., Odunsi, K., Sucheston-Campbell, L., Lurie, G., Goodman, M.T., Carney, M.E., Thompson, P.J., Runnebaum, I.B., Durst, M., Hillemanns, P., Dork, T., Antonenkova, N., Bogdanova, N., Leminen, A., Nevanlinna, H., Pelttari, L.M., Butzow, R., Bunker, C.H., Modugno, F., Edwards, R.P., Ness, R.B., Bois, A. du, Heitz, F., Schwaab, I., Harter, P., Karlan, B.Y., Walsh, C., Lester, J., Jensen, A., Kjaer, S.K., Hogdall, C.K., Hogdall, E., Lundvall, L., Sellers, T.A., Fridley, B.L., Goode, E.L., Cunningham, J.M., Vierkant, R.A., Giles, G.G., Baglietto, L., Severi, G., Southey, M.C., Liang, D., Wu, X., Lu, K., Hildebrandt, M.A.T., Levine, D.A., Bisogna, M., Schildkraut, J.M., Iversen, E.S., Weber, R.P., Berchuck, A., Cramer, D.W, Terry, K.L., Poole, E.M., Tworoger, S.S., Bandera, E.V., Chandran, U., Orlow, I., Olson, S.H., Wik, E., Salvesen, H.B., Bjorge, L., Halle, M.K., Altena, A.M. van, Aben, K.K.H., Kiemeney, B., Massuger, L.F.A.G., Pejovic, T., Bean, Y.T., Cybulski, C., Gronwald, J., Lubinski, J., Wentzensen, N., Brinton, L.A., Lissowska, J., Garcia-Closas, M., Dicks, E., and et al.
Abstract: Contains fulltext : 138102.pdf (publisher's version ) (Closed access), Epithelial ovarian cancer (EOC) is a heterogeneous cancer with both genetic and environmental risk factors. Variants influencing the risk of developing the less-common EOC subtypes have not been fully investigated. We performed a genome-wide association study (GWAS) of EOC according to subtype by pooling genomic DNA from 545 cases and 398 controls of European descent, and testing for allelic associations. We evaluated for replication 188 variants from the GWAS [56 variants for mucinous, 55 for endometrioid and clear cell, 53 for low-malignant potential (LMP) serous, and 24 for invasive serous EOC], selected using pre-defined criteria. Genotypes from 13,188 cases and 23,164 controls of European descent were used to perform unconditional logistic regression under the log-additive genetic model; odds ratios (OR) and 95 % confidence intervals are reported. Nine variants tagging six loci were associated with subtype-specific EOC risk at P < 0.05, and had an OR that agreed in direction of effect with the GWAS results. Several of these variants are in or near genes with a biological rationale for conferring EOC risk, including ZFP36L1 and RAD51B for mucinous EOC (rs17106154, OR = 1.17, P = 0.029, n = 1,483 cases), GRB10 for endometrioid and clear cell EOC (rs2190503, P = 0.014, n = 2,903 cases), and C22orf26/BPIL2 for LMP serous EOC (rs9609538, OR = 0.86, P = 0.0043, n = 892 cases). In analyses that included the 75 GWAS samples, the association between rs9609538 (OR = 0.84, P = 0.0007) and LMP serous EOC risk remained statistically significant at P < 0.0012 adjusted for multiple testing. Replication in additional samples will be important to verify these results for the less-common EOC subtypes.
Published: 2014

50. Cigarette smoking and risk of ovarian cancer: a pooled analysis of 21 case-control studies

Author: Faber, M.T., Kjaer, S.K., Dehlendorff, C., Chang-Claude, J., Andersen, K.K., Hogdall, E., Webb, P.M., Jordan, S.J., Rossing, M.A., Doherty, J.A., Lurie, G., Thompson, P.J., Carney, M.E., Goodman, M.T., Ness, R.B., Modugno, F., Edwards, R.P., Bunker, C.H., Goode, E.L., Fridley, B.L., Vierkant, R.A., Larson, M.C., Schildkraut, J., Cramer, D.W, Terry, K.L., Vitonis, A.F., Bandera, E.V., Olson, S.H., King, M., Chandran, U., Kiemeney, L.A.L.M., Massuger, L.F.A.G., Altena, A.M. van, Vermeulen, S., Brinton, L., Wentzensen, N., Lissowska, J., Yang, H.P., Moysich, K.B., Odunsi, K., Kasza, K., Odunsi-Akanji, O., Song, H., Pharaoh, P., Shah, M., Whittemore, A.S., McGuire, V., Sieh, W., Sutphen, R., Menon, U., Gayther, S.A., Ramus, S.J., Gentry-Maharaj, A., Pearce, C.L., Wu, A.H., Pike, M.C., Risch, H.A., Jensen, A., et al., Faber, M.T., Kjaer, S.K., Dehlendorff, C., Chang-Claude, J., Andersen, K.K., Hogdall, E., Webb, P.M., Jordan, S.J., Rossing, M.A., Doherty, J.A., Lurie, G., Thompson, P.J., Carney, M.E., Goodman, M.T., Ness, R.B., Modugno, F., Edwards, R.P., Bunker, C.H., Goode, E.L., Fridley, B.L., Vierkant, R.A., Larson, M.C., Schildkraut, J., Cramer, D.W, Terry, K.L., Vitonis, A.F., Bandera, E.V., Olson, S.H., King, M., Chandran, U., Kiemeney, L.A.L.M., Massuger, L.F.A.G., Altena, A.M. van, Vermeulen, S., Brinton, L., Wentzensen, N., Lissowska, J., Yang, H.P., Moysich, K.B., Odunsi, K., Kasza, K., Odunsi-Akanji, O., Song, H., Pharaoh, P., Shah, M., Whittemore, A.S., McGuire, V., Sieh, W., Sutphen, R., Menon, U., Gayther, S.A., Ramus, S.J., Gentry-Maharaj, A., Pearce, C.L., Wu, A.H., Pike, M.C., Risch, H.A., Jensen, A., and et al.
Abstract: Contains fulltext : 118139.pdf (publisher's version ) (Closed access), PURPOSE: The majority of previous studies have observed an increased risk of mucinous ovarian tumors associated with cigarette smoking, but the association with other histological types is unclear. In a large pooled analysis, we examined the risk of epithelial ovarian cancer associated with multiple measures of cigarette smoking with a focus on characterizing risks according to tumor behavior and histology. METHODS: We used data from 21 case-control studies of ovarian cancer (19,066 controls, 11,972 invasive and 2,752 borderline cases). Study-specific odds ratios (OR) and 95 % confidence intervals (CI) were obtained from logistic regression models and combined into a pooled odds ratio using a random effects model. RESULTS: Current cigarette smoking increased the risk of invasive mucinous (OR = 1.31; 95 % CI: 1.03-1.65) and borderline mucinous ovarian tumors (OR = 1.83; 95 % CI: 1.39-2.41), while former smoking increased the risk of borderline serous ovarian tumors (OR = 1.30; 95 % CI: 1.12-1.50). For these histological types, consistent dose-response associations were observed. No convincing associations between smoking and risk of invasive serous and endometrioid ovarian cancer were observed, while our results provided some evidence of a decreased risk of invasive clear cell ovarian cancer. CONCLUSIONS: Our results revealed marked differences in the risk profiles of histological types of ovarian cancer with regard to cigarette smoking, although the magnitude of the observed associations was modest. Our findings, which may reflect different etiologies of the histological types, add to the fact that ovarian cancer is a heterogeneous disease.
Published: 2013

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