8 results on '"Hildebrandt, M.A."'
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2. Polymorphisms within Autophagy-Related Genes as Susceptibility Biomarkers for Multiple Myeloma: A Meta-Analysis of Three Large Cohorts and Functional Characterization.
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Clavero, E., Sanchez-Maldonado, J.M., Macauda, A., Horst, R. ter, Sampaio-Marques, B., Jurczyszyn, A., Clay-Gilmour, A., Stein, A., Hildebrandt, M.A., Weinhold, N., Buda, G., García-Sanz, R., Tomczak, W., Vogel, U., Jerez, A., Zawirska, D., Wątek, M., Hofmann, J.N., Landi, S., Spinelli, J.J., Butrym, A., Kumar, A., Martínez-López, J., Galimberti, S., Sarasquete, M.E., Subocz, E., Iskierka-Jażdżewska, E., Giles, G.G., Rybicka-Ramos, M., Kruszewski, M., Abildgaard, N., Verdejo, F.G., Sánchez Rovira, P., Silva Filho, M.I. da, Kadar, K., Razny, M., Cozen, W., Pelosini, M., Jurado, M., Bhatti, P., Dudzinski, M., Druzd-Sitek, A., Orciuolo, E., Li, Y., Norman, A.D., Zaucha, J.M., Reis, R.M., Markiewicz, M., Rodríguez Sevilla, J.J., Andersen, V., Jamroziak, K., Hemminki, K., Berndt, S.I., Rajkumar, V., Mazur, G., Kumar, S.K., Ludovico, P., Nagler, A., Chanock, S.J., Dumontet, C., Machiela, M.J., Varkonyi, J., Camp, N.J., Ziv, E., Vangsted, A.J., Brown, E.E., Campa, D., Vachon, C.M., Netea, M.G., Canzian, F., Försti, A., Sainz, J., Clavero, E., Sanchez-Maldonado, J.M., Macauda, A., Horst, R. ter, Sampaio-Marques, B., Jurczyszyn, A., Clay-Gilmour, A., Stein, A., Hildebrandt, M.A., Weinhold, N., Buda, G., García-Sanz, R., Tomczak, W., Vogel, U., Jerez, A., Zawirska, D., Wątek, M., Hofmann, J.N., Landi, S., Spinelli, J.J., Butrym, A., Kumar, A., Martínez-López, J., Galimberti, S., Sarasquete, M.E., Subocz, E., Iskierka-Jażdżewska, E., Giles, G.G., Rybicka-Ramos, M., Kruszewski, M., Abildgaard, N., Verdejo, F.G., Sánchez Rovira, P., Silva Filho, M.I. da, Kadar, K., Razny, M., Cozen, W., Pelosini, M., Jurado, M., Bhatti, P., Dudzinski, M., Druzd-Sitek, A., Orciuolo, E., Li, Y., Norman, A.D., Zaucha, J.M., Reis, R.M., Markiewicz, M., Rodríguez Sevilla, J.J., Andersen, V., Jamroziak, K., Hemminki, K., Berndt, S.I., Rajkumar, V., Mazur, G., Kumar, S.K., Ludovico, P., Nagler, A., Chanock, S.J., Dumontet, C., Machiela, M.J., Varkonyi, J., Camp, N.J., Ziv, E., Vangsted, A.J., Brown, E.E., Campa, D., Vachon, C.M., Netea, M.G., Canzian, F., Försti, A., and Sainz, J.
- Abstract
Item does not contain fulltext, Multiple myeloma (MM) arises following malignant proliferation of plasma cells in the bone marrow, that secrete high amounts of specific monoclonal immunoglobulins or light chains, resulting in the massive production of unfolded or misfolded proteins. Autophagy can have a dual role in tumorigenesis, by eliminating these abnormal proteins to avoid cancer development, but also ensuring MM cell survival and promoting resistance to treatments. To date no studies have determined the impact of genetic variation in autophagy-related genes on MM risk. We performed meta-analysis of germline genetic data on 234 autophagy-related genes from three independent study populations including 13,387 subjects of European ancestry (6863 MM patients and 6524 controls) and examined correlations of statistically significant single nucleotide polymorphisms (SNPs; p < 1 × 10(-9)) with immune responses in whole blood, peripheral blood mononuclear cells (PBMCs), and monocyte-derived macrophages (MDM) from a large population of healthy donors from the Human Functional Genomic Project (HFGP). We identified SNPs in six loci, CD46, IKBKE, PARK2, ULK4, ATG5, and CDKN2A associated with MM risk (p = 4.47 × 10(-4)-5.79 × 10(-14)). Mechanistically, we found that the ULK4(rs6599175) SNP correlated with circulating concentrations of vitamin D3 (p = 4.0 × 10(-4)), whereas the IKBKE(rs17433804) SNP correlated with the number of transitional CD24(+)CD38(+) B cells (p = 4.8 × 10(-4)) and circulating serum concentrations of Monocyte Chemoattractant Protein (MCP)-2 (p = 3.6 × 10(-4)). We also found that the CD46(rs1142469) SNP correlated with numbers of CD19(+) B cells, CD19(+)CD3(-) B cells, CD5(+)IgD(-) cells, IgM(-) cells, IgD(-)IgM(-) cells, and CD4(-)CD8(-) PBMCs (p = 4.9 × 10(-4)-8.6 × 10(-4)) and circulating concentrations of interleukin (IL)-20 (p = 0.00082). Finally, we observed that the CDKN2A(rs2811710) SNP correlated with levels of CD4(+)EMCD45RO(+)CD27(-) cells (p = 9.3 × 10(-4)). These results s
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- 2023
3. Identification of novel genetic loci for risk of multiple myeloma by functional annotation.
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Macauda, A., Briem, K., Clay-Gilmour, A., Cozen, W., Försti, A., Giaccherini, M., Corradi, C., Sainz, J., Niazi, Y., Horst, R. ter, Li, Y., Netea, M.G., Vogel, U., Hemminki, K., Slager, S.L., Varkonyi, J., Andersen, V., Iskierka-Jazdzewska, E., Mártinez-Lopez, J., Zaucha, J., Camp, N.J., Rajkumar, S.V., Druzd-Sitek, A., Bhatti, P., Chanock, S.J., Kumar, S.K., Subocz, E., Mazur, G., Landi, S., Machiela, M.J., Jerez, A., Norman, A.D., Hildebrandt, M.A., Kadar, K., Berndt, S.I., Ziv, E., Buda, G., Nagler, A., Dumontet, C., Raźny, M., Watek, M., Butrym, A., Grzasko, N., Dudzinski, M., Rybicka-Ramos, M., Matera, E.L., García-Sanz, R., Goldschmidt, H., Jamroziak, K., Jurczyszyn, A., Clavero, E., Giles, G.G., Pelosini, M., Zawirska, D., Kruszewski, M., Marques, H., Haastrup, E., Sánchez-Maldonado, J.M., Bertsch, U., Rymko, M., Raab, M.S., Brown, E.E., Hofmann, J.N., Vachon, C., Campa, D., Canzian, F., Macauda, A., Briem, K., Clay-Gilmour, A., Cozen, W., Försti, A., Giaccherini, M., Corradi, C., Sainz, J., Niazi, Y., Horst, R. ter, Li, Y., Netea, M.G., Vogel, U., Hemminki, K., Slager, S.L., Varkonyi, J., Andersen, V., Iskierka-Jazdzewska, E., Mártinez-Lopez, J., Zaucha, J., Camp, N.J., Rajkumar, S.V., Druzd-Sitek, A., Bhatti, P., Chanock, S.J., Kumar, S.K., Subocz, E., Mazur, G., Landi, S., Machiela, M.J., Jerez, A., Norman, A.D., Hildebrandt, M.A., Kadar, K., Berndt, S.I., Ziv, E., Buda, G., Nagler, A., Dumontet, C., Raźny, M., Watek, M., Butrym, A., Grzasko, N., Dudzinski, M., Rybicka-Ramos, M., Matera, E.L., García-Sanz, R., Goldschmidt, H., Jamroziak, K., Jurczyszyn, A., Clavero, E., Giles, G.G., Pelosini, M., Zawirska, D., Kruszewski, M., Marques, H., Haastrup, E., Sánchez-Maldonado, J.M., Bertsch, U., Rymko, M., Raab, M.S., Brown, E.E., Hofmann, J.N., Vachon, C., Campa, D., and Canzian, F.
- Abstract
Contains fulltext : 299996.pdf (Publisher’s version ) (Open Access), 01 november 2023
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- 2023
4. Polygenic risk modeling for prediction of epithelial ovarian cancer risk
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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.
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- 2022
5. Copy Number Variants Are Ovarian Cancer Risk Alleles at Known and Novel Risk Loci
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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.
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- 2022
6. rs495139 in the TYMS-ENOSF1 Region and Risk of Ovarian Carcinoma of Mucinous Histology
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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.
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- 2018
7. Shared genetics underlying epidemiological association between endometriosis and ovarian cancer
- Author
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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
8. Cis-eQTL analysis and functional validation of candidate susceptibility genes for high-grade serous ovarian cancer
- Author
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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
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