Citations 2
Copy Number Variants Are Ovarian Cancer Risk Alleles at Known and Novel Risk Loci
DeVries, Amber A , Peng, Pei-Chen , Reyes, Alberto Luiz P., Plummer, Jasmine , Davis, Brian , Chen, Stephanie S., Dezem, Felipe Segato , Antonenkova, Natalia, Beckmann, Matthias W. , Beeghly‐Fadiel, Alicia, Bogdanova, Natalia , Bogdanova-Markov, Nadja, Brenton, James D. , Chang‐Claude, Jenny , Dörk, Thilo , Eccles, Diana M, Fasching, Peter A. , Goode, Ellen L. , Goodman, Marc T. , Group, OPAL Study, Grant, Peter , Nagle, C.A., Chevenix-Trench, G, Bowtell, D, Blomfield, Penny, Davis, Alison , Leung, Yee , Livingstone, Karen, O’Neill, Helen C. , Black, Amanda , Hadley, Alison , Shannon, Colleen, Neesham, Deborah, Otton, Geoffrey, Au‐Yeung, George , Goss, Geraldine , Wain, Gerard, Gard, Grace , Robertson, G S M, Lombard, Janine , Tan, Joanne , McNeilage, Jane, Power, J. , Miller, Jessica A., Lamont, John, Wong, Kit Man , Reid, Kate , Milishkin, L, Buck, Martin , Bunting, Michael W, McNally, Orla , Awad, Reda, Mohan, Rahul , Farrell, Rhonda , McIntosh, Rachel, Rome, Robert, Houghton, R., Hogg, Russell , Land, R., Baron‐Hay, Sally , Paramasivum, S, Pather, Selvan , Hyde, Samuel M. , Salfinger, Stuart , Valmadre, Susan, Jobling, Thomas W., Manolitsas, Tom, Bonaventura, T, Group, AOCS, Bowtell, D, Green, A, Webb, P, Gertig, DM, Moore, S., Hung, Jillian A., Harrap, Karen L. , Sadkowsky, T., Malt, M. , Robertson, R. Paul , Bergh, T. Vanden, Jones, Michelle R. , Nattress, K., Chiew, Yoke-Eng, Stenlake, Annie, Ashover, P., Corrish, T., Jackman, Louisa, Ferguson, Kaltin , Martin, Kara, Martyn, Amanda C. , White, Jonathan, Jayde, V., Bowes, Laura, Mamers, Pamela, Galletta, Laura, Giles, Daniel A., Hendley, Joy , Shirley, H., Ball, C., Young, Christian D. , Viduka, S., Bilic, Sanela , Glavinas, Lydia, Brooks, Jacqueline D., Stuart‐Harris, R., Kirsten, Fred, Rutovitz, J , Clingan, P., Proietto, Anthony , Braye, Stephen, Shannon, J., Bonaventura, T, Begbie, Stephen , Hildebrandt, Michelle A.T., Huff, Chad D. , Huntsman, David G., Kar, Siddhartha , Labrie, Marilyne , Lambrechts, Diether , Le, Nhu D. , May, Taymaa, Menon, Usha , Moysich, Kirsten B. , Odunsi, Kunle , Olsson, Håkan , Pearce, Celeste Leigh , Ramus, Susan J. , Ríboli, Elio , Riggan, Marjorie J. , Romieu, Isabelle , Schildkraut, Joellen M. , Sieh, Weiva , Song, Honglin , Sutphen, Rebecca , Terry, Kathryn L. , Thompson, Pamela J., Titus, Linda , Tworoger, Shelley S. , Nieuwenhuysen, Els Van , Edwards, Digna Velez, Wentzensen, Nicolas , Whittemore, Alice S. , Wu, Anna H. , Freedman, Matthew L., Lawrenson, Kate , Easton, Douglas F. , Gayther, Simon A. , Eccles, Diana , Bowtell, David D.L. , Lambrechts, Diether , Dennis, Joe , Plummer, Jasmine T , Anton-Culver, Hoda , Campbell, Ian G , Chenevix-Trench, Georgia , Eliassen, A Heather , Jensen, Allan , Kar, Siddhartha , Menon, Usha , Riboli, Elio , Sieh, Weiva , Webb, Penelope M , Wentzensen, Nicolas , Wolk, Alicja , Ziogas, Argyrios , Lawrenson, Kate , Jones, Michelle R , Dörk, Thilo , Lambrechts, Diether , Ramus, Susan J , Tworoger, Shelley S , Eccles, Diana , Brenton, James D , Moysich, Kirsten , Lambrechts, Diether , Bogdanova, Natalia V , Bowtell, David D , Goodman, Marc T , Tyrer, Jonathan P. , Coetzee, Simon G. , Aben, Katja K.H. , Anton‐Culver, Hoda , Beeghly‐Fadiel, Alicia , Berchuck, Andrew , Bützow, Ralf C. , Campbell, Ian , Chenevix‐Trench, Georgia , Cook, Linda S. , DeFazio, Anna , Doherty, Jennifer A. , Eliassen, A. Heather , Fortner, Renée T. , Giles, Graham G. , Gronwald, Jacek , Group, OPAL Study, Friedländer, Michael , Obermair, Andreas , Nagle, C, Beesley, Vanessa L. , Bowtell, D, Brand, Alison H. , Nicklin, James , Quinn, Michael A. , Williams, M, Hadley, A, Glasgow, A, Garrett, A, Rao, A, Steer, Christopher , Allen, Deborah Emma , Robertson, G, Power, J, Coward, Jermaine , Carter, Jonathan , Lamont, J, Wong, K M, Perrin, Lewis C , Nascimento, M, Buck, M, Harrison, Michelle , Chetty, Naven , Hacker, Neville F. , Harnett, Paul R. , Beale, Philip James , Awad, R, McIntosh, R, Sayer, R, Hogg, R, Hyde, S, Bonaventura, T, Arora, Vivek , Group, AOCS, Bowtell, D, Webb, P, Gertig, Dorota M., Traficante, Nadia , Fereday, Sián , Pandeya, Nirmala , Robertson, R, McKenzie, P, Maidens, J, Sullivan, Helen T. , Alexander, Brian M. , Brown, S, Green, L, Jackman, L, Martyn, A, Ranieri, B, White, J, Giles, D, Alsop, Kathryn , Schmidt, T, Young, C, Tran, H, Rutovitz, J, Glasgow, A, Shannon, J, Bonaventura, T, Stewart, James , Håkansson, Niclas , Hildebrandt, Michelle A.T. , Jensen, Allan , Karlan, Beth Y. , Хуснутдинова, Э. К. , Kiemeney, Lambertus A. , Kjær, Susanne K. , Kupryjańczyk, Jolanta , Lubiński, Jan , Milne, Roger L. , Modugno, Francesmary , Monteiro, Álvaro N.A. , Pejovic, Tanja B. , Sandler, Dale P. , Setiawan, Veronica Wendy , Edwards, Digna R. Velez , Webb, Penelope M. , Wolk, Alicja , Ziogas, Argyrios , Pharoah, Paul D.P.
JNCI: Journal of the National Cancer Institute | October 10, 2022 | Volume: 114 | Issue: 11 | Pages: 1533-1544
AbstractBackgroundKnown 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.MethodsSingle 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.ResultsWe 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.ConclusionsCNVs 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.
Identification of a Locus Near ULK1 Associated With Progression-Free Survival in Ovarian Cancer
Quinn, Michael C. , McCue, Karen, Shi, Wei , Johnatty, Sharon E. , Beesley, Jonathan, Civitarese, Andrew, O’Mara, Tracy A. , Glubb, Dylan M. , Armasu, Sebastian M. , Ong, Jue‐Sheng , Lu, Yi , Gao, Bo , Patch, Ann‐Marie , Fasching, Peter A. , Beckmann, Matthias W. , Lambrechts, Diether , Vergote, Ignace , Beeghly‐Fadiel, Alicia, García, María J. , Goodman, Marc T. , Dörk, Thilo , Moysich, Kirsten B. , Pfisterer, Jacobus , Bauman, Klaus, Lester, Jenny , Cunningham, Julie M. , McCauley, Bryan M. , Høgdall, Claus , Schildkraut, Joellen M. , Riggan, Marjorie J. , Terry, Kathryn L. , Webb, Penelope M. , May, Taymaa, Ene, Gabrielle, Huntsman, David G., Woo, Michelle, Carney, Michael E. , Fereday, Sián , Kennedy, Catherine J. , Edwards, Stacey L. , DeFazio, Anna , Goode, Ellen L. , MacGregor, Stuart , Chenevix‐Trench, Georgia , Lambrechts, Diether , Quinn, Michael C J , Ong, Jue-Sheng , Gharahkhani, Puya , Lu, Yi , Fasching, Peter A , Lambrechts, Diether , Vergote, Ignace , Dörk, Thilo , Dürst, Matthias , Modugno, Francesmary , Bois, Andreas du , Karlan, Beth Y , Cunningham, Julie M , Kjaer, Susanne K , Webb, Penelope M , Friedlander, Michael , Glasspool, Rosalind , Hinsley, Samantha , Heitz, Florian , Kennedy, Catherine J , Winham, Stacey J , Fazio, Anna de , Pharoah, Paul D P , MacGregor, Stuart , Lambrechts, Diether , Moysich, Kirsten , O'Mara, Tracy A , Chenevix-Trench, Georgia , Høgdall, Claus K , Fereday, Sian , Goodman, Marc T , Beesley, Jonathan, Tyrer, Jonathan P. , Gharahkhani, Puya , Edwards, Digna R. Velez , Beeghly‐Fadiel, Alicia , Benı́tez, Javier , Modugno, Francesmary , Karlan, Beth Y. , Larson, Melissa C. , Kjær, Susanne K. , Jensen, Allan , Høgdall, Estrid , Berchuck, Andrew , Cramer, Daniel W. , Bjørge, Line , Friedländer, Michael , Pejovic, Tanja B. , Moffitt, Melissa , Glasspool, Rosalind , Heitz, Florian , Winham, Stacey J. , Pharoah, Paul D.P.
Cancer Epidemiology, Biomarkers & Prevention | June 23, 2021 | Volume: 30 | Issue: 9 | Pages: 1669-1680
Abstract Background: Many loci have been found to be associated with risk of epithelial ovarian cancer (EOC). However, although there is considerable variation in progression-free survival (PFS), no loci have been found to be associated with outcome at genome-wide levels of significance. Methods: We carried out a genome-wide association study (GWAS) of PFS in 2,352 women with EOC who had undergone cytoreductive surgery and standard carboplatin/paclitaxel chemotherapy. Results: We found seven SNPs at 12q24.33 associated with PFS (P < 5 × 10–8), the top SNP being rs10794418 (HR = 1.24; 95% CI, 1.15–1.34; P = 1.47 × 10–8). High expression of a nearby gene, ULK1, is associated with shorter PFS in EOC, and with poor prognosis in other cancers. SNP rs10794418 is also associated with expression of ULK1 in ovarian tumors, with the allele associated with shorter PFS being associated with higher expression, and chromatin interactions were detected between the ULK1 promoter and associated SNPs in serous and endometrioid EOC cell lines. ULK1 knockout ovarian cancer cell lines showed significantly increased sensitivity to carboplatin in vitro. Conclusions: The locus at 12q24.33 represents one of the first genome-wide significant loci for survival for any cancer. ULK1 is a plausible candidate for the target of this association. Impact: This finding provides insight into genetic markers associated with EOC outcome and potential treatment options. See related commentary by Peres and Monteiro, p. 1604