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345 results on '"Köbel, M"'

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

Author

Millstein, J, Budden, T, Goode, EL, Anglesio, MS, Talhouk, A, Intermaggio, MP, Leong, HS, Chen, S, Elatre, W, Gilks, B, Nazeran, T, Volchek, M, Bentley, RC, Wang, C, Chiu, DS, Kommoss, S, Leung, SCY, Senz, J, Lum, A, Chow, V, Sudderuddin, H, Mackenzie, R, George, J, AOCS Group, Fereday, S, Hendley, J, Traficante, N, Steed, H, Koziak, JM, Köbel, M, McNeish, IA, Goranova, T, Ennis, D, Macintyre, G, Silva De Silva, D, Ramón Y Cajal, T, García-Donas, J, Hernando Polo, S, Rodriguez, GC, Cushing-Haugen, KL, Harris, HR, Greene, CS, Zelaya, RA, Behrens, S, Fortner, RT, Sinn, P, Herpel, E, Lester, J, Lubiński, J, Oszurek, O, Tołoczko, A, Cybulski, C, Menkiszak, J, Pearce, CL, Pike, MC, Tseng, C, Alsop, J, Rhenius, V, Song, H, Jimenez-Linan, M, Piskorz, AM, Gentry-Maharaj, A, Karpinskyj, C, Widschwendter, M, Singh, N, Kennedy, CJ, Sharma, R, Harnett, PR, Gao, B, Johnatty, SE, Sayer, R, Boros, J, Winham, SJ, Keeney, GL, Kaufmann, SH, Larson, MC, Luk, H, Hernandez, BY, Thompson, PJ, Wilkens, LR, Carney, ME, Trabert, B, Lissowska, J, Brinton, L, Sherman, ME, Bodelon, C, Hinsley, S, Lewsley, LA, Glasspool, R, Banerjee, SN, Stronach, EA, Haluska, P, Ray-Coquard, I, Mahner, S, Winterhoff, B, Slamon, D, Levine, DA, Kelemen, LE, Benitez, J, and Chang-Claude, J

Subjects
AOCS Group, Humans, Cystadenocarcinoma, Serous, Ovarian Neoplasms, Prognosis, Proportional Hazards Models, Survival Analysis, Female, Transcriptome, formalin-fixed paraffin-embedded, gene expression, high-grade serous ovarian cancer, overall survival, prognosis, Rare Diseases, Genetic Testing, Cancer, Ovarian Cancer, Genetics, 4.4 Population screening, 4.2 Evaluation of markers and technologies, Oncology & Carcinogenesis, Oncology and Carcinogenesis
Abstract

BackgroundMedian overall survival (OS) for women with high-grade serous ovarian cancer (HGSOC) is ∼4 years, yet survival varies widely between patients. There are no well-established, gene expression signatures associated with prognosis. The aim of this study was to develop a robust prognostic signature for OS in patients with HGSOC.Patients and methodsExpression of 513 genes, selected from a meta-analysis of 1455 tumours and other candidates, was measured using NanoString technology from formalin-fixed paraffin-embedded tumour tissue collected from 3769 women with HGSOC from multiple studies. Elastic net regularization for survival analysis was applied to develop a prognostic model for 5-year OS, trained on 2702 tumours from 15 studies and evaluated on an independent set of 1067 tumours from six studies.ResultsExpression levels of 276 genes were associated with OS (false discovery rate < 0.05) in covariate-adjusted single-gene analyses. The top five genes were TAP1, ZFHX4, CXCL9, FBN1 and PTGER3 (P < 0.001). The best performing prognostic signature included 101 genes enriched in pathways with treatment implications. Each gain of one standard deviation in the gene expression score conferred a greater than twofold increase in risk of death [hazard ratio (HR) 2.35, 95% confidence interval (CI) 2.02-2.71; P < 0.001]. Median survival [HR (95% CI)] by gene expression score quintile was 9.5 (8.3 to -), 5.4 (4.6-7.0), 3.8 (3.3-4.6), 3.2 (2.9-3.7) and 2.3 (2.1-2.6) years.ConclusionThe OTTA-SPOT (Ovarian Tumor Tissue Analysis consortium - Stratified Prognosis of Ovarian Tumours) gene expression signature may improve risk stratification in clinical trials by identifying patients who are least likely to achieve 5-year survival. The identified novel genes associated with the outcome may also yield opportunities for the development of targeted therapeutic approaches.

Published
2020

2. 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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3. Response of soil carbon and plant diversity to grazing and precipitation in High Nature Value farmlands

Author

Deosaran, R., Carvalho, F., Nunes, A., Köbel, M., Serafim, J., Hooda, P.S., Waller, M., Branquinho, C., Brown, Kerry A., Deosaran, R., Carvalho, F., Nunes, A., Köbel, M., Serafim, J., Hooda, P.S., Waller, M., Branquinho, C., and Brown, Kerry A.

Abstract

Mediterranean oak-dominated agro-silvo-pastoral systems of southwestern Europe (called montado in Portugal and dehesa in Spain) are semi-natural, savannah-style High Nature Value farmlands (HNVfs) shaped by centuries of anthropogenic (e.g., cultivation, grazing) and natural (e.g., drought) disturbances. Therefore, changes in grazing and precipitation may alter their vegetation composition and ecosystem properties and impact upon their long-term viability. We quantified the responses of soil organic carbon (SOC) and plant taxonomic and functional trait diversities to cattle grazing and inter-annual changes in precipitation across three open-woodland sites within the montado landscape in Alentejo, southern Portugal. The sites are characterised by the presence or absence of cattle grazing and different amounts of mean annual precipitation (ranging from semiarid to dry subhumid). Three different precipitation periods were used: a shorter autumn-to-spring period and longer 12- and 18-month periods before sampling. Specific leaf area, plant height and seed mass were used to estimate single-trait community weighted means and a multi-trait measure of community functional diversity (Rao’s Q). SOC and plant species richness responded negatively to the presence of cattle grazing but positively to increase in precipitation (and its interaction with cattle grazing), while trait-based measures were largely unresponsive to cattle grazing and precipitation (though RLQ analysis revealed strong controls of the environmental variables on plant life cycle, growth form, leaf phenology and dispersal strategies). SOC was most responsive to longer-term (18-month) changes in precipitation, whereas plant species richness was most responsive to shorter-term (autumn-to-spring) changes in precipitation. These results suggest that different components of plant diversity respond differently to external drivers in montado HNVfs, while the response time of soil properties may be longer than that of

Published
2024

6. Concurrent RB1 loss and BRCA-deficiency predicts enhanced immunological response and long-term survival in tubo-ovarian high-grade serous carcinoma.

Author

Saner, FAM, Takahashi, K, Budden, T, Pandey, A, Ariyaratne, D, Zwimpfer, TA, Meagher, NS, Fereday, S, Twomey, L, Pishas, KI, Hoang, T, Bolithon, A, Traficante, N, Alsop, K, Christie, EL, Kang, E-Y, Nelson, GS, Ghatage, P, Lee, C-H, Riggan, MJ, Alsop, J, Beckmann, MW, Boros, J, Brand, AH, Brooks-Wilson, A, Carney, ME, Coulson, P, Courtney-Brooks, M, Cushing-Haugen, KL, Cybulski, C, El-Bahrawy, MA, Elishaev, E, Erber, R, Gayther, SA, Gentry-Maharaj, A, Blake Gilks, C, Harnett, PR, Harris, HR, Hartmann, A, Hein, A, Hendley, J, AOCS Group, Hernandez, BY, Jakubowska, A, Jimenez-Linan, M, Jones, ME, Kaufmann, SH, Kennedy, CJ, Kluz, T, Koziak, JM, Kristjansdottir, B, Le, ND, Lener, M, Lester, J, Lubiński, J, Mateoiu, C, Orsulic, S, Ruebner, M, Schoemaker, MJ, Shah, M, Sharma, R, Sherman, ME, Shvetsov, YB, Singh, N, Rinda Soong, T, Steed, H, Sukumvanich, P, Talhouk, A, Taylor, SE, Vierkant, RA, Wang, C, Widschwendter, M, Wilkens, LR, Winham, SJ, Anglesio, MS, Berchuck, A, Brenton, JD, Campbell, I, Cook, LS, Doherty, JA, Fasching, PA, Fortner, RT, Goodman, MT, Gronwald, J, Huntsman, DG, Karlan, BY, Kelemen, LE, Menon, U, Modugno, F, Pharoah, PDP, Schildkraut, JM, Sundfeldt, K, Swerdlow, AJ, Goode, EL, DeFazio, A, Köbel, M, Ramus, SJ, Bowtell, DDL, Garsed, DW, Saner, FAM, Takahashi, K, Budden, T, Pandey, A, Ariyaratne, D, Zwimpfer, TA, Meagher, NS, Fereday, S, Twomey, L, Pishas, KI, Hoang, T, Bolithon, A, Traficante, N, Alsop, K, Christie, EL, Kang, E-Y, Nelson, GS, Ghatage, P, Lee, C-H, Riggan, MJ, Alsop, J, Beckmann, MW, Boros, J, Brand, AH, Brooks-Wilson, A, Carney, ME, Coulson, P, Courtney-Brooks, M, Cushing-Haugen, KL, Cybulski, C, El-Bahrawy, MA, Elishaev, E, Erber, R, Gayther, SA, Gentry-Maharaj, A, Blake Gilks, C, Harnett, PR, Harris, HR, Hartmann, A, Hein, A, Hendley, J, AOCS Group, Hernandez, BY, Jakubowska, A, Jimenez-Linan, M, Jones, ME, Kaufmann, SH, Kennedy, CJ, Kluz, T, Koziak, JM, Kristjansdottir, B, Le, ND, Lener, M, Lester, J, Lubiński, J, Mateoiu, C, Orsulic, S, Ruebner, M, Schoemaker, MJ, Shah, M, Sharma, R, Sherman, ME, Shvetsov, YB, Singh, N, Rinda Soong, T, Steed, H, Sukumvanich, P, Talhouk, A, Taylor, SE, Vierkant, RA, Wang, C, Widschwendter, M, Wilkens, LR, Winham, SJ, Anglesio, MS, Berchuck, A, Brenton, JD, Campbell, I, Cook, LS, Doherty, JA, Fasching, PA, Fortner, RT, Goodman, MT, Gronwald, J, Huntsman, DG, Karlan, BY, Kelemen, LE, Menon, U, Modugno, F, Pharoah, PDP, Schildkraut, JM, Sundfeldt, K, Swerdlow, AJ, Goode, EL, DeFazio, A, Köbel, M, Ramus, SJ, Bowtell, DDL, and Garsed, DW

Abstract

BACKGROUND: Somatic loss of the tumour suppressor RB1 is a common event in tubo-ovarian high-grade serous carcinoma (HGSC), which frequently co-occurs with alterations in homologous recombination DNA repair genes including BRCA1 and BRCA2 (BRCA). We examined whether tumour expression of RB1 was associated with survival across ovarian cancer histotypes (HGSC, endometrioid (ENOC), clear cell (CCOC), mucinous (MOC), low-grade serous carcinoma (LGSC)), and how co-occurrence of germline BRCA pathogenic variants and RB1 loss influences long-term survival in a large series of HGSC. PATIENTS AND METHODS: RB1 protein expression patterns were classified by immunohistochemistry in epithelial ovarian carcinomas of 7436 patients from 20 studies participating in the Ovarian Tumor Tissue Analysis consortium and assessed for associations with overall survival (OS), accounting for patient age at diagnosis and FIGO stage. We examined RB1 expression and germline BRCA status in a subset of 1134 HGSC, and related genotype to survival, tumour infiltrating CD8+ lymphocyte counts and transcriptomic subtypes. Using CRISPR-Cas9, we deleted RB1 in HGSC cell lines with and without BRCA1 mutations to model co-loss with treatment response. We also performed genomic analyses on 126 primary HGSC to explore the molecular characteristics of concurrent homologous recombination deficiency and RB1 loss. RESULTS: RB1 protein loss was most frequent in HGSC (16.4%) and was highly correlated with RB1 mRNA expression. RB1 loss was associated with longer OS in HGSC (hazard ratio [HR] 0.74, 95% confidence interval [CI] 0.66-0.83, P = 6.8 ×10-7), but with poorer prognosis in ENOC (HR 2.17, 95% CI 1.17-4.03, P = 0.0140). Germline BRCA mutations and RB1 loss co-occurred in HGSC (P < 0.0001). Patients with both RB1 loss and germline BRCA mutations had a superior OS (HR 0.38, 95% CI 0.25-0.58, P = 5.2 ×10-6) compared to patients with either alteration alone, and their median OS was three times longer than non-carr

Published
2023

7. 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

13. OP015/#492 Further stratification of no specific molecular profile (NSMP/P53WT) endometrial carcinomas to refine prognosis and identify therapeutic opportunities

Author

Thompson, E, primary, Huvila, J, additional, Chiu, D, additional, Leung, S, additional, Lum, A, additional, Jamieson, A, additional, Köbel, M, additional, Plante, M, additional, Scott, S, additional, Salvador, S, additional, Vicus, D, additional, Helpman, L, additional, Kinloch, M, additional, Grondin, K, additional, Irving, J, additional, Talhouk, A, additional, Huntsman, D, additional, Kommoss, S, additional, Gilks, C, additional, and Mcalpine, J, additional

Published
2021
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17. 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

19. 454 Study in progress: international retrospective study on lymphadenectomy in endometrioid ovarian carcinoma patients with early stage disease (LEOPARD)

Author

Krämer, P, primary, Grube, M, additional, Renno, T, additional, Brar, H, additional, McAlpine, JN, additional, de Kroon, CD, additional, Heitz, F, additional, Heublein, S, additional, Manchanda, R, additional, Plante, M, additional, Bachvarov, D, additional, Zeimet, AG, additional, Schmalfeldt, B, additional, Wimberger, P, additional, Lampe, B, additional, Trillsch, F, additional, Grimm, C, additional, Staebler, A, additional, Kommoss, F, additional, Talhouk, A, additional, Köbel, M, additional, Anglesio, MS, additional, and Kommoss, S, additional

Published
2020
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20. Molecular stratification of clear cell ovarian carcinomas

Author

Feil, L, additional, Senz, J, additional, Ta, M, additional, Huvila, J, additional, Greif, K, additional, Krämer, B, additional, Brucker, S, additional, Grimm, C, additional, Bartl, T, additional, Zeder-Gösz, C, additional, Schmöckel, E, additional, Trillsch, F, additional, Mahner, S, additional, Kommoss, F, additional, Lehr, H.-A, additional, Wiedemeyer, K, additional, Köbel, M, additional, Staebler, A, additional, Anglesio, M, additional, and Kommoss, S, additional

Published
2020
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21. Anwendung der molekularen Risikostratifikation des Endometriums auf das endometrioide Ovarialkarzinom- eine retrospektive, internationale Multizenterstudie

Author

Heitz, F, additional, Krämer, P, additional, Talhouk, A, additional, MA, Brett, additional, DS, Chiu, additional, ES, Cairns, additional, Scheunhage, D, additional, RF, Hammond, additional, Senz, J, additional, Leung, S, additional, Hartkopf, A, additional, Krämer, B, additional, Brucker, S, additional, du Bois, A, additional, Harter, P, additional, FK, Kommoss, additional, Heublein, S, additional, Kommoss, F, additional, JN, McAlpine, additional, Singh, N, additional, Bosse, T, additional, Köbel, M, additional, MS, Anglesio, additional, Staebler, A, additional, and Kommoss, S, additional

Published
2020
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25. P147 Long-term survival in women with high-grade serous ovarian cancer: interplay between RB1 and BRCA1/2

Author

Saner, FAM, primary, Garsed, DW, additional, Beach, JA, additional, Pandey, A, additional, Fereday, S, additional, Alsop, K, additional, Wouters, MCA, additional, Traficante, N, additional, Pearce, CL, additional, Pike, MC, additional, de Fazio, A, additional, Ramus, SJ, additional, Köbel, M, additional, Goode, EL, additional, Nelson, BH, additional, and Bowtell, DDL, additional

Published
2019
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28. Iatrogenic endometriosis harbors somatic cancer-driver mutations

Author

Lac, V, primary, Verhoef, L, additional, Aguirre-Hernandez, R, additional, Nazeran, T M, additional, Tessier-Cloutier, B, additional, Praetorius, T, additional, Orr, N L, additional, Noga, H, additional, Lum, A, additional, Khattra, J, additional, Prentice, L M, additional, Co, D, additional, Köbel, M, additional, Mijatovic, V, additional, Lee, A F, additional, Pasternak, J, additional, Bleeker, M C, additional, Krämer, B, additional, Brucker, S Y, additional, Kommoss, F, additional, Kommoss, S, additional, Horlings, H M, additional, Yong, P J, additional, Huntsman, D G, additional, and Anglesio, M S, additional

Published
2018
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30. Association of p16 expression with prognosis varies across ovarian carcinoma histotypes: an Ovarian Tumor Tissue Analysis consortium study

Author

Rambau, PF, Vierkant, RA, Intermaggio, MP, Kelemen, LE, Goodman, MT, Herpel, E, Pharoah, PD, Kommoss, S, Jimenez-Linan, M, Karlan, BY, Gentry-Maharaj, A, Menon, U, Polo, SH, Candido Dos Reis, FJ, Doherty, JA, Gayther, SA, Sharma, R, Larson, MC, Harnett, PR, Hatfield, E, de Andrade, JM, Nelson, GS, Steed, H, Schildkraut, JM, Carney, ME, Høgdall, E, Whittemore, AS, Widschwendter, M, Kennedy, CJ, Wang, F, Wang, Q, Wang, C, Armasu, SM, Daley, F, Coulson, P, Jones, ME, Anglesio, MS, Chow, C, de Fazio, A, García-Closas, M, Brucker, SY, Cybulski, C, Harris, HR, Hartkopf, AD, Huzarski, T, Jensen, A, Lubiński, J, Oszurek, O, Benitez, J, Mina, F, Staebler, A, Taran, FA, Pasternak, J, Talhouk, A, Rossing, MA, Hendley, J, Edwards, RP, Fereday, S, Modugno, F, Ness, RB, Sieh, W, El-Bahrawy, MA, Winham, SJ, Lester, J, Kjaer, SK, Gronwald, J, Sinn, P, Fasching, PA, Chang-Claude, J, Moysich, KB, Bowtell, DD, Hernandez, BY, Luk, H, Behrens, S, Shah, M, Jung, A, Ghatage, P, Alsop, J, Alsop, K, García-Donas, J, Thompson, PJ, Swerdlow, AJ, Karpinskyj, C, Cazorla-Jiménez, A, García, MJ, Deen, S, Wilkens, LR, Palacios, J, Berchuck, A, Koziak, JM, Brenton, JD, Cook, LS, Goode, EL, Huntsman, DG, Ramus, SJ, Köbel, M, Rambau, PF, Vierkant, RA, Intermaggio, MP, Kelemen, LE, Goodman, MT, Herpel, E, Pharoah, PD, Kommoss, S, Jimenez-Linan, M, Karlan, BY, Gentry-Maharaj, A, Menon, U, Polo, SH, Candido Dos Reis, FJ, Doherty, JA, Gayther, SA, Sharma, R, Larson, MC, Harnett, PR, Hatfield, E, de Andrade, JM, Nelson, GS, Steed, H, Schildkraut, JM, Carney, ME, Høgdall, E, Whittemore, AS, Widschwendter, M, Kennedy, CJ, Wang, F, Wang, Q, Wang, C, Armasu, SM, Daley, F, Coulson, P, Jones, ME, Anglesio, MS, Chow, C, de Fazio, A, García-Closas, M, Brucker, SY, Cybulski, C, Harris, HR, Hartkopf, AD, Huzarski, T, Jensen, A, Lubiński, J, Oszurek, O, Benitez, J, Mina, F, Staebler, A, Taran, FA, Pasternak, J, Talhouk, A, Rossing, MA, Hendley, J, Edwards, RP, Fereday, S, Modugno, F, Ness, RB, Sieh, W, El-Bahrawy, MA, Winham, SJ, Lester, J, Kjaer, SK, Gronwald, J, Sinn, P, Fasching, PA, Chang-Claude, J, Moysich, KB, Bowtell, DD, Hernandez, BY, Luk, H, Behrens, S, Shah, M, Jung, A, Ghatage, P, Alsop, J, Alsop, K, García-Donas, J, Thompson, PJ, Swerdlow, AJ, Karpinskyj, C, Cazorla-Jiménez, A, García, MJ, Deen, S, Wilkens, LR, Palacios, J, Berchuck, A, Koziak, JM, Brenton, JD, Cook, LS, Goode, EL, Huntsman, DG, Ramus, SJ, and Köbel, M

Abstract

We aimed to validate the prognostic association of p16 expression in ovarian high-grade serous carcinomas (HGSC) and to explore it in other ovarian carcinoma histotypes. p16 protein expression was assessed by clinical-grade immunohistochemistry in 6525 ovarian carcinomas including 4334 HGSC using tissue microarrays from 24 studies participating in the Ovarian Tumor Tissue Analysis consortium. p16 expression patterns were interpreted as abnormal (either overexpression referred to as block expression or absence) or normal (heterogeneous). CDKN2A (which encodes p16) mRNA expression was also analyzed in a subset (n = 2280) mostly representing HGSC (n = 2010). Association of p16 expression with overall survival (OS) was determined within histotypes as was CDKN2A expression for HGSC only. p16 block expression was most frequent in HGSC (56%) but neither protein nor mRNA expression was associated with OS. However, relative to heterogeneous expression, block expression was associated with shorter OS in endometriosis-associated carcinomas, clear cell [hazard ratio (HR): 2.02, 95% confidence (CI) 1.47-2.77, p < 0.001] and endometrioid (HR: 1.88, 95% CI 1.30-2.75, p = 0.004), while absence was associated with shorter OS in low-grade serous carcinomas (HR: 2.95, 95% CI 1.61-5.38, p = 0.001). Absence was most frequent in mucinous carcinoma (50%), and was not associated with OS in this histotype. The prognostic value of p16 expression is histotype-specific and pattern dependent. We provide definitive evidence against an association of p16 expression with survival in ovarian HGSC as previously suggested. Block expression of p16 in clear cell and endometrioid carcinoma should be further validated as a prognostic marker, and absence in low-grade serous carcinoma justifies CDK4 inhibition.

Published
2018

31. 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. (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), 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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32. Prognostic role and implications of mutation status of tumor suppressor gene ARID1A in cancer: A systematic review and meta-analysis

Author

Luchini, C. Veronese, N. Solmi, M. Cho, H. Kim, J.-H. Chou, A. Gill, A.J. Faraj, S.F. Chaux, A. Netto, G.J. Nakayama, K. Kyo, S. Lee, S.Y. Kim, D.-W. Yousef, G.M. Scorilas, A. Nelson, G.S. Köbel, M. Kalloger, S.E. Schaeffer, D.F. Yan, H.-B. Liu, F. Yokoyama, Y. Zhang, X. Pang, D. Lichner, Z. Sergi, G. Manzato, E. Capelli, P. Wood, L.D. Scarpa, A. Correll, C.U.

Abstract

Loss of the tumor suppressor gene AT-rich interactive domain-containing protein 1A (ARID1A) has been demonstrated in several cancers, but its prognostic role is unknown. We aimed to investigate the risk associated with loss of ARID1A (ARID1A-) for all-cause mortality, cancer-specific mortality and recurrence of disease in subjects with cancer. PubMed and SCOPUS search from database inception until 01/31/2015 without language restriction was conducted, contacting authors for unpublished data. Eligible were prospective studies reporting data on prognostic parameters in subjects with cancer, comparing participants with presence of ARID1A (ARID1A+) vs. ARID1A-, assessed either via immunohistochemistry (loss of expression) or with genetic testing (presence of mutation). Data were summarized using risk ratios (RR) for number of deaths/recurrences and hazard ratios (HR) for time-dependent risk related to ARID1A- adjusted for potential confounders. Of 136 hits, 25 studies with 5,651 participants (28 cohorts; ARID1A-: n = 1,701; ARID1A+: n = 3,950), with a mean follow-up period of 4.7 ± 1.8 years, were meta-analyzed. Compared to ARID1A+, ARID1A- significantly increased cancer-specific mortality (studies = 3; RR = 1.55, 95% confidence interval (CI) = 1.19-2.00, I2 = 31%). Using HRs adjusted for potential confounders, ARID1A- was associated with a greater risk of cancer-specific mortality (studies = 2; HR = 2.55, 95%CI = 1.19-5.45, I2 = 19%) and cancer recurrence (studies = 10; HR = 1.93, 95%CI = 1.22-3.05, I2 = 76%). On the basis of these results, we have demonstrated that loss of ARID1A shortened time to cancer-specific mortality, and to recurrence of cancer when adjusting for potential confounders. For its role, this gene should be considered as an important potential target for personalized medicine in cancer treatment.

Published
2015

33. An Immunohistochemical Algorithm for Ovarian Carcinoma Typing

Author

Köbel, M, Rahimi, K, Rambau, PF, Naugler, C, Le Page, C, Meunier, L, De Ladurantaye, M, Lee, S, Leung, S, Goode, EL, Ramus, SJ, Carlson, JW, Li, X, Ewanowich, CA, Kelemen, LE, Vanderhyden, B, Provencher, D, Huntsman, D, Lee, CH, Gilks, CB, Mes Masson, AM, Köbel, M, Rahimi, K, Rambau, PF, Naugler, C, Le Page, C, Meunier, L, De Ladurantaye, M, Lee, S, Leung, S, Goode, EL, Ramus, SJ, Carlson, JW, Li, X, Ewanowich, CA, Kelemen, LE, Vanderhyden, B, Provencher, D, Huntsman, D, Lee, CH, Gilks, CB, and Mes Masson, AM

Abstract

There are 5 major histotypes of ovarian carcinomas. Diagnostic typing criteria have evolved over time, and past cohorts may be misclassified by current standards. Our objective was to reclassify the recently assembled Canadian Ovarian Experimental Unified Resource and the Alberta Ovarian Tumor Type cohorts using immunohistochemical (IHC) biomarkers and to develop an IHC algorithm for ovarian carcinoma histotyping. A total of 1626 ovarian carcinoma samples from the Canadian Ovarian Experimental Unified Resource and the Alberta Ovarian Tumor Type were subjected to a reclassification by comparing the original with the predicted histotype. Histotype prediction was derived from a nominal logistic regression modeling using a previously reclassified cohort (N=784) with the binary input of 8 IHC markers. Cases with discordant original or predicted histotypes were subjected to arbitration. After reclassification, 1762 cases from all cohorts were subjected to prediction models (χ 2 Automatic Interaction Detection, recursive partitioning, and nominal logistic regression) with a variable IHC marker input. The histologic type was confirmed in 1521/1626 (93.5%) cases of the Canadian Ovarian Experimental Unified Resource and the Alberta Ovarian Tumor Type cohorts. The highest misclassification occurred in the endometrioid type, where most of the changes involved reclassification from endometrioid to high-grade serous carcinoma, which was additionally supported by mutational data and outcome. Using the reclassified histotype as the endpoint, a 4-marker prediction model correctly classified 88%, a 6-marker 91%, and an 8-marker 93% of the 1762 cases. This study provides statistically validated, inexpensive IHC algorithms, which have versatile applications in research, clinical practice, and clinical trials.

Published
2016

35. Iatrogenic endometriosis harbors somatic cancer-driver mutations.

Author

Lac, V, Verhoef, L, Aguirre-Hernandez, R, Nazeran, T M, Tessier-Cloutier, B, Praetorius, T, Orr, N L, Noga, H, Lum, A, Khattra, J, Prentice, L M, Co, D, Köbel, M, Mijatovic, V, Lee, A F, Pasternak, J, Bleeker, M C, Krämer, B, Brucker, S Y, and Kommoss, F

Abstract

Study Question: Does incisional endometriosis (IE) harbor somatic cancer-driver mutations?Summary Answer: We found that approximately one-quarter of IE cases harbor somatic-cancer mutations, which commonly affect components of the MAPK/RAS or PI3K-Akt-mTor signaling pathways.What Is Known Already: Despite the classification of endometriosis as a benign gynecological disease, it shares key features with cancers such as resistance to apoptosis and stimulation of angiogenesis and is well-established as the precursor of clear cell and endometrioid ovarian carcinomas. Our group has recently shown that deep infiltrating endometriosis (DE), a form of endometriosis that rarely undergoes malignant transformation, harbors recurrent somatic mutations.Study Design, Size, Duration: In a retrospective study comparing iatrogenically induced and endogenously occurring forms of endometriosis unlikely to progress to cancer, we examined endometriosis specimens from 40 women with IE and 36 women with DE. Specimens were collected between 2004 and 2017 from five hospital sites in either Canada, Germany or the Netherlands. IE and DE cohorts were age-matched and all women presented with histologically typical endometriosis without known history of malignancy.Participants/materials, Setting, Methods: Archival tissue specimens containing endometriotic lesions were macrodissected and/or laser-capture microdissected to enrich endometriotic stroma and epithelium and a hypersensitive cancer hotspot sequencing panel was used to assess for presence of somatic mutations. Mutations were subsequently validated using droplet digital PCR. PTEN and ARID1A immunohistochemistry (IHC) were performed as surrogates for somatic events resulting in functional loss of respective proteins.Main Results and the Role Of Chance: Overall, we detected somatic cancer-driver events in 11 of 40 (27.5%) IE cases and 13 of 36 (36.1%) DE cases, including hotspot mutations in KRAS, ERBB2, PIK3CA and CTNNB1. Heterogeneous PTEN loss occurred at similar rates in IE and DE (7/40 vs 5/36, respectively), whereas ARID1A loss only occurred in a single case of DE. While rates of detectable somatic cancer-driver events between IE and DE are not statistically significant (P > 0.05), KRAS activating mutations were more prevalent in DE.Limitations, Reasons For Caution: Detection of somatic cancer-driver events were limited to hotspots analyzed in our panel-based sequencing assay and loss of protein expression by IHC from archival tissue. Whole genome or exome sequencing, or epigenetic analysis may uncover additional somatic alterations. Moreover, because of the descriptive nature of this study, the functional roles of identified mutations within the context of endometriosis remain unclear and causality cannot be established.Wider Implications Of the Findings: The alterations we report may be important in driving the growth and survival of endometriosis in ectopic regions of the body. Given the frequency of mutation in surgically displaced endometrium (IE), examination of similar somatic events in eutopic endometrium, as well as clinically annotated cases of other forms of endometriosis, in particular endometriomas that are most commonly linked to malignancy, is warranted.Study Funding/competing Interest(s): This study was funded by a Canadian Cancer Society Impact Grant [701603, PI Huntsman], Canadian Institutes of Health Research Transitional Open Operating Grant [MOP-142273, PI Yong], the Canadian Institutes of Health Research Foundation Grant [FDN-154290, PI Huntsman], the Canadian Institutes of Health Research Project Grant [PJT-156084, PIs Yong and Anglesio], and the Janet D. Cottrelle Foundation through the BC Cancer Foundation [PI Huntsman]. D.G. Huntsman is a co-founder and shareholder of Contextual Genomics Inc., a for profit company that provides clinical reporting to assist in cancer patient treatment. R. Aguirre-Hernandez, J. Khattra and L.M. Prentice have a patent MOLECULAR QUALITY ASSURANCE METHODS FOR USE IN SEQUENCING pending and are current (or former) employees of Contextual Genomics Inc. The remaining authors have no competing interests to declare.Trial Registration Number: Not applicable. [ABSTRACT FROM AUTHOR]

Published
2019
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37. Evidence for a time-dependent association between FOLR1 expression and survival from ovarian carcinoma:implications for clinical testing. An Ovarian Tumour Tissue Analysis consortium study

Author

Köbel, M, Madore, J, Ramus, S J, Clarke, B A, Pharoah, P D P, Deen, S, Bowtell, D D, Odunsi, K, Menon, U, Morrison, C, Lele, S, Bshara, W, Sucheston, L, Beckmann, M W, Hein, A, Thiel, F C, Hartmann, A, Wachter, D L, Anglesio, M S, Høgdall, E, Jensen, A, Høgdall, C, Kalli, K R, Fridley, B L, Keeney, G L, Fogarty, Z C, Vierkant, R A, Liu, S, Cho, S, Nelson, G, Ghatage, P, Gentry-Maharaj, A, Gayther, S A, Benjamin, E, Widschwendter, M, Intermaggio, M P, Rosen, B, Bernardini, M Q, Mackay, H, Oza, A, Shaw, P, Jimenez-Linan, M, Driver, K E, Alsop, J, Mack, M, Koziak, J M, Steed, H, Ewanowich, C, DeFazio, A, Kjær, S K, Köbel, M, Madore, J, Ramus, S J, Clarke, B A, Pharoah, P D P, Deen, S, Bowtell, D D, Odunsi, K, Menon, U, Morrison, C, Lele, S, Bshara, W, Sucheston, L, Beckmann, M W, Hein, A, Thiel, F C, Hartmann, A, Wachter, D L, Anglesio, M S, Høgdall, E, Jensen, A, Høgdall, C, Kalli, K R, Fridley, B L, Keeney, G L, Fogarty, Z C, Vierkant, R A, Liu, S, Cho, S, Nelson, G, Ghatage, P, Gentry-Maharaj, A, Gayther, S A, Benjamin, E, Widschwendter, M, Intermaggio, M P, Rosen, B, Bernardini, M Q, Mackay, H, Oza, A, Shaw, P, Jimenez-Linan, M, Driver, K E, Alsop, J, Mack, M, Koziak, J M, Steed, H, Ewanowich, C, DeFazio, A, and Kjær, S K

Abstract

BACKGROUND: Folate receptor 1 (FOLR1) is expressed in the majority of ovarian carcinomas (OvCa), making it an attractive target for therapy. However, clinical trials testing anti-FOLR1 therapies in OvCa show mixed results and require better understanding of the prognostic relevance of FOLR1 expression. We conducted a large study evaluating FOLR1 expression with survival in different histological types of OvCa.METHODS: Tissue microarrays composed of tumour samples from 2801 patients in the Ovarian Tumour Tissue Analysis (OTTA) consortium were assessed for FOLR1 expression by centralised immunohistochemistry. We estimated associations for overall (OS) and progression-free (PFS) survival using adjusted Cox regression models. High-grade serous ovarian carcinomas (HGSC) from The Cancer Genome Atlas (TCGA) were evaluated independently for association between FOLR1 mRNA upregulation and survival.RESULTS: FOLR1 expression ranged from 76% in HGSC to 11% in mucinous carcinomas in OTTA. For HGSC, the association between FOLR1 expression and OS changed significantly during the years following diagnosis in OTTA (Pinteraction=0.01, N=1422) and TCGA (Pinteraction=0.01, N=485). In OTTA, particularly for FIGO stage I/II tumours, patients with FOLR1-positive HGSC showed increased OS during the first 2 years only (hazard ratio=0.44, 95% confidence interval=0.20-0.96) and patients with FOLR1-positive clear cell carcinomas (CCC) showed decreased PFS independent of follow-up time (HR=1.89, 95% CI=1.10-3.25, N=259). In TCGA, FOLR1 mRNA upregulation in HGSC was also associated with increased OS during the first 2 years following diagnosis irrespective of tumour stage (HR: 0.48, 95% CI: 0.25-0.94).CONCLUSIONS: FOLR1-positive HGSC tumours were associated with an increased OS in the first 2 years following diagnosis. Patients with FOLR1-negative, poor prognosis HGSC would be unlikely to benefit from anti-FOLR1 therapies. In contrast, a decreased PFS interval was observ

Published
2014

38. Recent alcohol consumption and risk of incident ovarian carcinoma: A pooled analysis of 5,342 cases and 10,358 controls from the Ovarian Cancer Association Consortium

Author

Kelemen, LE, Bandera, EV, Terry, KL, Rossing, MA, Brinton, LA, Doherty, JA, Ness, RB, Kjær, SK, Chang-Claude, J, Köbel, M, Lurie, G, Thompson, PJ, Carney, ME, Moysich, K, Edwards, R, Bunker, C, Jensen, A, Høgdall, E, Cramer, DW, Vitonis, AF, Olson, SH, King, M, Chandran, U, Lissowska, J, Garcia-Closas, M, Yang, H, Webb, PM, Schildkraut, JM, Goodman, MT, Risch, HA, Kelemen, LE, Bandera, EV, Terry, KL, Rossing, MA, Brinton, LA, Doherty, JA, Ness, RB, Kjær, SK, Chang-Claude, J, Köbel, M, Lurie, G, Thompson, PJ, Carney, ME, Moysich, K, Edwards, R, Bunker, C, Jensen, A, Høgdall, E, Cramer, DW, Vitonis, AF, Olson, SH, King, M, Chandran, U, Lissowska, J, Garcia-Closas, M, Yang, H, Webb, PM, Schildkraut, JM, Goodman, MT, and Risch, HA

Abstract

Background: Studies evaluating the association between alcohol intake and ovarian carcinoma (OC) are inconsistent. Because OC and ovarian borderline tumor histologic types differ genetically, molecularly and clinically, large numbers are needed to estimate risk associations.Methods: We pooled data from 12 case-control studies in the Ovarian Cancer Association Consortium comprising 5,342 OC cases, 1,455 borderline tumors and 10,358 controls with quantitative information on recent alcohol intake to estimate odds ratios (OR) and 95% confidence intervals (CI) according to frequencies of average daily intakes of beer, wine, liquor and total alcohol.Results: Total alcohol intake was not associated with all OC: consumption of >3 drinks per day compared to none, OR=0.92, 95% CI=0.76-1.10, P trend=0.27. Among beverage types, a statistically non-significant decreased risk was observed among women who consumed >8 oz/d of wine compared to none (OR=0.83, 95% CI=0.68-1.01, P trend=0.08). This association was more apparent among women with clear cell OC (OR, 0.43; 95% CI, 0.22-0.83; P trend=0.02), although based on only 10 cases and not statistically different from the other histologic types (P value for statistical heterogeneity between histologic types = 0.09). Statistical heterogeneity of the alcohol- and wine-OC associations was seen among three European studies, but not among eight North American studies. No statistically significant associations were observed in separate analyses evaluating risk with borderline tumors of serous or mucinous histology. Smoking status did not significantly modify any of the associations.Conclusions: We found no evidence that recent moderate alcohol drinking is associated with increased risk for overall OC, or that variation in risk is associated strongly with specific histologic types. Understanding modifiable causes of these elusive and deadly cancers remains a priority for the research community. © 2013 Kelemen et al.; licensee BioMed Central

Published
2013

39. Mutation of FOXL2 in granulosa-cell tumors of the ovary

Author

Shah, S., Köbel, M., Senz, J., Morin, R., Clarke, B., Wiegand, K., Leung, G., Zayed, A., Mehl, E., Kalloger, S., Sun, M., Giuliany, R., Yorida, E., Jones, S., Varhol, Richard, Swenerton, K., Miller, D., Clement, P., Crane, C., Madore, J., Provencher, D., Leung, P., DeFazio, A., Khattra, J., Turashvili, G., Zhao, Y., Zeng, T., Glover, J., Vanderhyden, B., Zhao, C., Parkinson, C., Jimenez-Linan, M., Bowtell, D., Mes-Masson, A., Brenton, J., Aparicio, S., Boyd, N., Hirst, M., Gilks, C., Marra, M., Huntsman, D., Shah, S., Köbel, M., Senz, J., Morin, R., Clarke, B., Wiegand, K., Leung, G., Zayed, A., Mehl, E., Kalloger, S., Sun, M., Giuliany, R., Yorida, E., Jones, S., Varhol, Richard, Swenerton, K., Miller, D., Clement, P., Crane, C., Madore, J., Provencher, D., Leung, P., DeFazio, A., Khattra, J., Turashvili, G., Zhao, Y., Zeng, T., Glover, J., Vanderhyden, B., Zhao, C., Parkinson, C., Jimenez-Linan, M., Bowtell, D., Mes-Masson, A., Brenton, J., Aparicio, S., Boyd, N., Hirst, M., Gilks, C., Marra, M., and Huntsman, D.

Abstract

BACKGROUND: Granulosa-cell tumors (GCTs) are the most common type of malignant ovarian sex cord-stromal tumor (SCST). The pathogenesis of these tumors is unknown. Moreover, their histopathological diagnosis can be challenging, and there is no curative treatment beyond surgery. METHODS: We analyzed four adult-type GCTs using whole-transcriptome paired-end RNA sequencing. We identified putative GCT-specific mutations that were present in at least three of these samples but were absent from the transcriptomes of 11 epithelial ovarian tumors, published human genomes, and databases of single-nucleotide polymorphisms. We confirmed these variants by direct sequencing of complementary DNA and genomic DNA. We then analyzed additional tumors and matched normal genomic DNA, using a combination of direct sequencing, analyses of restriction-fragment-length polymorphisms, and TaqMan assays. RESULTS: All four index GCTs had a missense point mutation, 402C?G (C134W), in FOXL2, a gene encoding a transcription factor known to be critical for granulosa-cell development. The FOXL2 mutation was present in 86 of 89 additional adult-type GCTs (97%), in 3 of 14 thecomas (21%), and in 1 of 10 juvenile-type GCTs (10%). The mutation was absent in 49 SCSTs of other types and in 329 unrelated ovarian or breast tumors. CONCLUSIONS: Whole-transcriptome sequencing of four GCTs identified a single, recurrent somatic mutation (402C?G) in FOXL2 that was present in almost all morphologically identified adult-type GCTs. Mutant FOXL2 is a potential driver in the pathogenesis of adult-type GCTs. Copyright © 2009 Massachusetts Medical Society. All rights reserved.

Published
2009

47. Evidence for a time-dependent association between FOLR1 expression and survival from ovarian carcinoma: implications for clinical testing. An Ovarian Tumour Tissue Analysis consortium study.

Author

Köbel, M, Madore, J, Ramus, S J, Clarke, B A, Pharoah, P D P, Deen, S, Bowtell, D D, Odunsi, K, Menon, U, Morrison, C, Lele, S, Bshara, W, Sucheston, L, Beckmann, M W, Hein, A, Thiel, F C, Hartmann, A, Wachter, D L, Anglesio, M S, and Høgdall, E

Subjects
*FOLIC acid, *CELL receptors, *PROTEIN expression, *OVARIAN cancer treatment, *CLINICAL trials, *IMMUNOHISTOCHEMISTRY
Abstract

Background:Folate receptor 1 (FOLR1) is expressed in the majority of ovarian carcinomas (OvCa), making it an attractive target for therapy. However, clinical trials testing anti-FOLR1 therapies in OvCa show mixed results and require better understanding of the prognostic relevance of FOLR1 expression. We conducted a large study evaluating FOLR1 expression with survival in different histological types of OvCa.Methods:Tissue microarrays composed of tumour samples from 2801 patients in the Ovarian Tumour Tissue Analysis (OTTA) consortium were assessed for FOLR1 expression by centralised immunohistochemistry. We estimated associations for overall (OS) and progression-free (PFS) survival using adjusted Cox regression models. High-grade serous ovarian carcinomas (HGSC) from The Cancer Genome Atlas (TCGA) were evaluated independently for association between FOLR1 mRNA upregulation and survival.Results:FOLR1 expression ranged from 76% in HGSC to 11% in mucinous carcinomas in OTTA. For HGSC, the association between FOLR1 expression and OS changed significantly during the years following diagnosis in OTTA (Pinteraction=0.01, N=1422) and TCGA (Pinteraction=0.01, N=485). In OTTA, particularly for FIGO stage I/II tumours, patients with FOLR1-positive HGSC showed increased OS during the first 2 years only (hazard ratio=0.44, 95% confidence interval=0.20-0.96) and patients with FOLR1-positive clear cell carcinomas (CCC) showed decreased PFS independent of follow-up time (HR=1.89, 95% CI=1.10-3.25, N=259). In TCGA, FOLR1 mRNA upregulation in HGSC was also associated with increased OS during the first 2 years following diagnosis irrespective of tumour stage (HR: 0.48, 95% CI: 0.25-0.94).Conclusions:FOLR1-positive HGSC tumours were associated with an increased OS in the first 2 years following diagnosis. Patients with FOLR1-negative, poor prognosis HGSC would be unlikely to benefit from anti-FOLR1 therapies. In contrast, a decreased PFS interval was observed for FOLR1-positive CCC. The clinical efficacy of FOLR1-targeted interventions should therefore be evaluated according to histology, stage and time following diagnosis. [ABSTRACT FROM AUTHOR]

Published
2014
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48. Mucinous carcinomas of the ovary and colorectum: different organ, same dilemma.

Author

Kelemen LE and Köbel M

Subjects
*TUMOR treatment, *COLON tumors, *DIFFERENTIAL diagnosis, *OVARIAN tumors, *TUMORS, RECTUM tumors
Abstract

Mucinous carcinomas are uncommon histological types that affect several organ sites. Primary mucinous carcinomas of the ovary are distinct from other ovarian carcinoma types, but they can pose a particular challenge for correct diagnosis from metastases, which most usually originate from the colorectum. Correct diagnosis is the mainstay of treatment, because standard practice states that protocols are tailored to the primary organ site. Little is known of mutational alterations in primary and metastatic mucinous carcinomas of the ovary, and few markers exist that can discriminate between them. We reviewed commonalities between ovarian and colorectal mucinous carcinomas with respect to aetiology, molecular alterations, differential diagnosis, and implications for treatment. Although primary mucinous carcinomas of the ovary and colorectum share similar mutational patterns and unfavourable outcomes at advanced stage, compared with their non-mucinous counterparts, important differences exist with respect to mucin localisation and specific molecular alterations. Technologies-eg, next-generation sequencing-could aid identification of additional driver molecular changes that will help clarify the relation between mucinous carcinomas from different organ sites. Perhaps, then, we can consider moving towards testing and adoption of therapeutic approaches tailored to molecular characteristics of mucinous carcinomas, irrespective of organ site, so patients' survival can be optimised. [ABSTRACT FROM AUTHOR]

Published
2011

49. Case report: Hydropic leiomyoma of the uterus presenting in pregnancy: imaging features.

Author

HEFFERNAN, E., KÖBEL, M., and SPIELMANN, A.

Abstract

Uterine leiomyomas commonly undergo degenerative change, which can lead to variable imaging features. Diffuse hydropic change is an unusual form of degeneration that presents a considerable diagnostic challenge to both radiologists and pathologists, as it can mimic a malignant neoplasm on imaging and at histological analysis. We present the case of a giant diffuse hydropic leiomyoma presenting in the first trimester of pregnancy in a 36-year-old woman, the imaging features of which were suggestive of a more aggressive neoplasm. The sonographic and MRI appearances of the lesion are discussed, and the varied imaging features of leiomyomas are reviewed. [ABSTRACT FROM AUTHOR]

Published
2009
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50. Expression of lysophosphatidic acid acyltransferase beta (LPAAT-ß) in ovarian carcinoma: correlation with tumour grading and prognosis.

Author

Niesporek, S., Denkert, C., Weichert, W., Köbel, M., Noske, A., Sehouli, J., Singer, J. W., Dietel, M., and Hauptmann, S.

Subjects
PHOSPHOLIPIDS, TUMORS, POLYMERASE chain reaction, MESSENGER RNA, LYSOPHOSPHOLIPIDS, ENZYMES
Abstract

Lysophosphatidic acid acyltransferase beta (LPAAT-ß) is an enzyme involved in lipid biosynthesis whose role in tumour progression has been of emerging interest in the last few years. We investigated the expression of LPAAT-ßby reverse transcriptase-polymerase chain reaction and immunohistochemistry in 10 ovarian cell lines as well as in a cohort of 106 ovarian tumours and normal ovaries. Lysophosphatidic acid acyltransferase beta mRNA was found in all cell lines and ovarian tumours examined. Expression of LPAAT-ßprotein was significantly increased in ovarian carcinomas compared to benign ovarian tissue (?2 test P-value=0.001, Kruskal-Wallis test P-value<0.0001). Furthermore, LPAAT-ßexpression was positively associated with higher tumour grade (P=0.044), higher mitotic index (P<0.0001) and tumour stage (P=0.032). Expression of LPAAT-ßwas significantly linked to reduced overall survival time (P=0.024) as well as to shorter progression-free survival time (P=0.012) in patients younger than 60 years. Our study shows that LPAAT-ßis upregulated in ovarian cancer and is more prevalent in poorly differentiated tumours. In addition, LPAAT-ßexpression is a predictor of a worse prognosis in patients younger than 60 years. Further studies are needed to investigate if LPAAT-ßmay serve as a therapeutic target for certain subgroups of patients.British Journal of Cancer (2005) 92, 1729-1736. doi:10.1038/sj.bjc.6602528 www.bjcancer.com Published online 19 April 2005 [ABSTRACT FROM AUTHOR]

Published
2005
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