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.
Genetic Risk Score Mendelian Randomization Shows that Obesity Measured as Body Mass Index, but not Waist:Hip Ratio, Is Causal for Endometrial Cancer
Painter, Jodie N. , O’Mara, Tracy A. , Marquart, Louise , Webb, Penelope M. , Medland, Sarah E. , Cheng, Timothy, Holliday, Elizabeth , McEvoy, Mark , Scott, Rodney J. , Healey, Catherine S., Shah, Mitul , Gorman, Maggie, Martin, Lynn , Hodgson, Shirley V. , Beckmann, Matthias W. , Ekici, Arif B. , Fasching, Peter A. , Hein, Alexander , Rübner, Matthias, Darabi, Hatef, Li, Jingmei , Dörk, Thilo , Hillemanns, Peter , Runnebaum, Ingo B. , Annibali, Daniela , Depreeuw, Jeroen, Lambrechts, Diether , Neven, Patrick , Cunningham, Julie M. , Dowdy, Sean C. , Goode, Ellen L. , Winham, Stacey J. , Njølstad, Tormund S. , Salvesen, Helga B., Trovik, Jone , Werner, Henrica M.J., Ashton, Katie A. , Otton, Geoffrey, Proietto, Anthony , Mints, Miriam, Tham, Emma , Bolla, Manjeet K. , Michailidou, Kyriaki , Wang, Qin , Hopper, John L. , Peto, Julian , Swerdlow, Anthony J. , Burwinkel, Barbara , Brenner, Hermann , Meindl, Alfons, Brauch, Hiltrud , Lindblom, Annika , Chang‐Claude, Jenny , Couch, Fergus J. , Kristensen, Vessela N. , Tomlinson, Ian M., Dunning, Alison M. , Easton, Douglas F. , Thompson, Deborah J. , Lambrechts, Diether , Attia, John , Dennis, Joe , Ahmed, Shahana , Czene, Kamila , Hall, Per N , Dürst, Matthias , Amant, Frédéric , Fridley, Brooke L. , Mints, Miriam , Tyrer, Jonathan P. , Meindl, Alfons, Couch, Fergus J. , Giles, Graham G. , Cox, Angela , Pharoah, Paul D.P. , Spurdle, Amanda B. , Winham, Stacey J , Dörk, Thilo , Lambrechts, Diether , Webb, Penelope M , Hein, Alexander , Hillemanns, Peter , Swerdlow, Anthony J , Medland, Sarah E , O'Mara, Tracy A , Dunning, Alison M , Lambrechts, Diether , Brenner, Hermann , Li, Jingmei , Ekici, Arif B , Michailidou, Kyriaki , Brauch, Hiltrud , Lindblom, Annika
Cancer Epidemiology, Biomarkers & Prevention | August 22, 2016 | Volume: 25 | Issue: 11 | Pages: 1503-1510
Abstract Background: The strongest known risk factor for endometrial cancer is obesity. To determine whether SNPs associated with increased body mass index (BMI) or waist–hip ratio (WHR) are associated with endometrial cancer risk, independent of measured BMI, we investigated relationships between 77 BMI and 47 WHR SNPs and endometrial cancer in 6,609 cases and 37,926 country-matched controls. Methods: Logistic regression analysis and fixed effects meta-analysis were used to test for associations between endometrial cancer risk and (i) individual BMI or WHR SNPs, (ii) a combined weighted genetic risk score (wGRS) for BMI or WHR. Causality of BMI for endometrial cancer was assessed using Mendelian randomization, with BMIwGRS as instrumental variable. Results: The BMIwGRS was significantly associated with endometrial cancer risk (P = 3.4 × 10−17). Scaling the effect of the BMIwGRS on endometrial cancer risk by its effect on BMI, the endometrial cancer OR per 5 kg/m2 of genetically predicted BMI was 2.06 [95% confidence interval (CI), 1.89–2.21], larger than the observed effect of BMI on endometrial cancer risk (OR = 1.55; 95% CI, 1.44–1.68, per 5 kg/m2). The association attenuated but remained significant after adjusting for BMI (OR = 1.22; 95% CI, 1.10–1.39; P = 5.3 × 10−4). There was evidence of directional pleiotropy (P = 1.5 × 10−4). BMI SNP rs2075650 was associated with endometrial cancer at study-wide significance (P < 4.0 × 10−4), independent of BMI. Endometrial cancer was not significantly associated with individual WHR SNPs or the WHRwGRS. Conclusions: BMI, but not WHR, is causally associated with endometrial cancer risk, with evidence that some BMI-associated SNPs alter endometrial cancer risk via mechanisms other than measurable BMI. Impact: The causal association between BMI SNPs and endometrial cancer has possible implications for endometrial cancer risk modeling. Cancer Epidemiol Biomarkers Prev; 25(11); 1503–10. ©2016 AACR.