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.
Disruption of Glycogen Utilization Markedly Improves the Efficacy of Carboplatin against Preclinical Models of Clear Cell Ovarian Carcinoma
Khan, Tashbib , He, Yaowu , Kryza, Thomas , Harrington, Brittney S. , Gunter, Jennifer H. , Sullivan, Mitchell A. , Cuda, Tahleesa , Rogers, Rebecca F. , Davies, Claire M. , Broomfield, Amy, Gough, Madeline , Wu, Andy , McGann, Thomas , Weroha, S. John , Forbes, Josephine M. , Armes, Jane E., Barry, Sinead , Coward, Jermaine , Jagasia, Nisha , Snell, Cameron , Hooper, John D. , Wu, Andy C , Haluska, Paul , Forbes, Josephine M , Hooper, John D , Rogers, Rebecca, Chetty, Naven , Lourie, Rohan , Perrin, Lewis C
Cancers | April 3, 2020 | Volume: 12 | Issue: 4 | Pages: 869
High stage and recurrent ovarian clear cell carcinoma (OCC) are associated with poor prognosis and resistance to chemotherapy. A distinguishing histological feature of OCC is abundant cytoplasmic stores of glucose, in the form of glycogen, that can be mobilized for cellular metabolism. Here, we report the effect on preclinical models of OCC of disrupting glycogen utilization using the glucose analogue 2-deoxy-D-glucose (2DG). At concentrations significantly lower than previously reported for other cancers, 2DG markedly improves the efficacy in vitro of carboplatin chemotherapy against chemo-sensitive TOV21G and chemo-resistant OVTOKO OCC cell lines, and this is accompanied by the depletion of glycogen. Of note, 2DG doses—of more than 10-fold lower than previously reported for other cancers—significantly improve the efficacy of carboplatin against cell line and patient-derived xenograft models in mice that mimic the chemo-responsiveness of OCC. These findings are encouraging, in that 2DG doses, which are substantially lower than previously reported to cause adverse events in cancer patients, can safely and significantly improve the efficacy of carboplatin against OCC. Our results thus justify clinical trials to evaluate whether low dose 2DG improves the efficacy of carboplatin in OCC patients.