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1. Epithelial-Mesenchymal Transition (EMT) Gene Variants and Epithelial Ovarian Cancer (EOC) Risk

Author

Amankwah, EK, Lin, HY, Tyrer, JP, Lawrenson, K, Dennis, J, Chornokur, G, Aben, KKH, Anton-Culver, H, Antonenkova, N, Bruinsma, F, Bandera, EV, Bean, YT, Beckmann, MW, Bisogna, M, Bjorge, L, Bogdanova, N, Brinton, LA, Brooks-Wilson, A, Bunker, CH, Butzow, R, Campbell, IG, Carty, K, Chen, Z, Chen, YA, Chang-Claude, J, Cook, LS, Cramer, DW, Cunningham, JM, Cybulski, C, Dansonka-Mieszkowska, A, du Bois, A, Despierre, E, Dicks, E, Doherty, JA, Dörk, T, Dürst, M, Easton, DF, Eccles, DM, Edwards, RP, Ekici, AB, Fasching, PA, Fridley, BL, Gao, YT, Gentry-Maharaj, A, Giles, GG, Glasspool, R, Goodman, MT, Gronwald, J, Harrington, P, Harter, P, Hasmad, HN, Hein, A, Heitz, F, Hildebrandt, MAT, Hillemanns, P, Hogdall, CK, Hogdall, E, Hosono, S, Iversen, ES, Jakubowska, A, Jensen, A, Ji, BT, Karlan, BY, Jim, H, Kellar, M, Kiemeney, LA, Krakstad, C, Kjaer, SK, Kupryjanczyk, J, Lambrechts, D, Lambrechts, S, Le, ND, Lee, AW, Lele, S, Leminen, A, Lester, J, Levine, DA, Liang, D, Lim, BK, Lissowska, J, Lu, K, Lubinski, J, Lundvall, L, Massuger, LFAG, Matsuo, K, Mcguire, V, Mclaughlin, JR, Mcneish, I, Menon, U, Milne, RL, Modugno, F, Moysich, KB, Ness, RB, Nevanlinna, H, Eilber, U, Odunsi, K, Olson, SH, Orlow, I, Orsulic, S, and Weber, RP

Subjects
Epidemiology, Public Health and Health Services, Genetics
Abstract

Epithelial-mesenchymal transition (EMT) is a process whereby epithelial cells assume mesenchymal characteristics to facilitate cancer metastasis. However, EMT also contributes to the initiation and development of primary tumors. Prior studies that explored the hypothesis that EMT gene variants contribute to epithelial ovarian carcinoma (EOC) risk have been based on small sample sizes and none have sought replication in an independent population. We screened 15,816 single-nucleotide polymorphisms (SNPs) in 296 genes in a discovery phase using data from a genome-wide association study of EOC among women of European ancestry (1,947 cases and 2,009 controls) and identified 793 variants in 278 EMT-related genes that were nominally (P < 0.05) associated with invasive EOC. These SNPs were then genotyped in a larger study of 14,525 invasive-cancer patients and 23,447 controls. A P-value

Published
2015

2. Obesity and survival among women with ovarian cancer: results from the Ovarian Cancer Association Consortium

Author

Nagle, CM, Dixon, SC, Jensen, A, Kjaer, SK, Modugno, F, deFazio, A, Fereday, S, Hung, J, Johnatty, SE, Fasching, PA, Beckmann, MW, Lambrechts, D, Vergote, I, Van Nieuwenhuysen, E, Lambrechts, S, Risch, HA, Rossing, MA, Doherty, JA, Wicklund, KG, Chang-Claude, J, Goodman, MT, Ness, RB, Moysich, K, Heitz, F, du Bois, A, Harter, P, Schwaab, I, Matsuo, K, Hosono, S, Goode, EL, Vierkant, RA, Larson, MC, Fridley, BL, Høgdall, C, Schildkraut, JM, Weber, RP, Cramer, DW, Terry, KL, Bandera, EV, Paddock, L, Rodriguez-Rodriguez, L, Wentzensen, N, Yang, HP, Brinton, LA, Lissowska, J, Høgdall, E, Lundvall, L, Whittemore, A, McGuire, V, Sieh, W, Rothstein, J, Sutphen, R, Anton-Culver, H, Ziogas, A, Pearce, CL, Wu, AH, and Webb, PM

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Prevention, Nutrition, Ovarian Cancer, Obesity, Rare Diseases, Cancer, Body Mass Index, Carcinoma, Ovarian Epithelial, Disease-Free Survival, Female, Humans, Kaplan-Meier Estimate, Neoplasms, Glandular and Epithelial, Ovarian Neoplasms, ovarian cancer, obesity, overall survival, progression-free survival, ovarian cancer-specific survival, Australian Ovarian Cancer Study Group, Ovarian Cancer Association Consortium, Public Health and Health Services, Oncology & Carcinogenesis, Oncology and carcinogenesis
Abstract

BackgroundObservational studies have reported a modest association between obesity and risk of ovarian cancer; however, whether it is also associated with survival and whether this association varies for the different histologic subtypes are not clear. We undertook an international collaborative analysis to assess the association between body mass index (BMI), assessed shortly before diagnosis, progression-free survival (PFS), ovarian cancer-specific survival and overall survival (OS) among women with invasive ovarian cancer.MethodsWe used original data from 21 studies, which included 12 390 women with ovarian carcinoma. We combined study-specific adjusted hazard ratios (HRs) using random-effects models to estimate pooled HRs (pHR). We further explored associations by histologic subtype.ResultsOverall, 6715 (54%) deaths occurred during follow-up. A significant OS disadvantage was observed for women who were obese (BMI: 30-34.9, pHR: 1.10 (95% confidence intervals (CIs): 0.99-1.23); BMI: ⩾35, pHR: 1.12 (95% CI: 1.01-1.25)). Results were similar for PFS and ovarian cancer-specific survival. In analyses stratified by histologic subtype, associations were strongest for women with low-grade serous (pHR: 1.12 per 5 kg m(-2)) and endometrioid subtypes (pHR: 1.08 per 5 kg m(-2)), and more modest for the high-grade serous (pHR: 1.04 per 5 kg m(-2)) subtype, but only the association with high-grade serous cancers was significant.ConclusionsHigher BMI is associated with adverse survival among the majority of women with ovarian cancer.

Published
2015

3. Integrated genomic analyses of ovarian carcinoma

Author

Bell, D, Berchuck, A, Birrer, M, Chien, J, Cramer, DW, Dao, F, Dhir, R, DiSaia, P, Gabra, H, Glenn, P, Godwin, AK, Gross, J, Hartmann, L, Huang, M, Huntsman, DG, Iacocca, M, Imielinski, M, Kalloger, S, Karlan, BY, Levine, DA, Mills, GB, Morrison, C, Mutch, D, Olvera, N, Orsulic, S, Park, K, Petrelli, N, Rabeno, B, Rader, JS, Sikic, BI, Smith-McCune, K, Sood, AK, Bowtell, D, Penny, R, Testa, JR, Chang, K, Creighton, CJ, Dinh, HH, Drummond, JA, Fowler, G, Gunaratne, P, Hawes, AC, Kovar, CL, Lewis, LR, Morgan, MB, Newsham, IF, Santibanez, J, Reid, JG, Trevino, LR, Wu, Y-Q, Wang, M, Muzny, DM, Wheeler, DA, Gibbs, RA, Getz, G, Lawrence, MS, Cibulskis, K, Sivachenko, AY, Sougnez, C, Voet, D, Wilkinson, J, Bloom, T, Ardlie, K, Fennell, T, Baldwin, J, Nichol, R, Fisher, S, Gabriel, S, Lander, ES, Ding, L, Fulton, RS, Koboldt, DC, McLellan, MD, Wylie, T, Walker, J, O’Laughlin, M, Dooling, DJ, Fulton, L, Abbott, R, Dees, ND, Zhang, Q, Kandoth, C, Wendl, M, Schierding, W, Shen, D, Harris, CC, Schmidt, H, Kalicki, J, Delehaunty, KD, Fronick, CC, Demeter, R, Cook, L, Wallis, JW, Lin, L, Magrini, VJ, Hodges, JS, Eldred, JM, Smith, SM, Pohl, CS, and Vandin, F

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Oncology and Carcinogenesis, Biotechnology, Rare Diseases, Human Genome, Ovarian Cancer, Cancer, Aged, Carcinoma, DNA Methylation, Female, Gene Dosage, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Genomics, Humans, MicroRNAs, Middle Aged, Mutation, Ovarian Neoplasms, RNA, Messenger, Cancer Genome Atlas Research Network, General Science & Technology
Abstract

A catalogue of molecular aberrations that cause ovarian cancer is critical for developing and deploying therapies that will improve patients' lives. The Cancer Genome Atlas project has analysed messenger RNA expression, microRNA expression, promoter methylation and DNA copy number in 489 high-grade serous ovarian adenocarcinomas and the DNA sequences of exons from coding genes in 316 of these tumours. Here we report that high-grade serous ovarian cancer is characterized by TP53 mutations in almost all tumours (96%); low prevalence but statistically recurrent somatic mutations in nine further genes including NF1, BRCA1, BRCA2, RB1 and CDK12; 113 significant focal DNA copy number aberrations; and promoter methylation events involving 168 genes. Analyses delineated four ovarian cancer transcriptional subtypes, three microRNA subtypes, four promoter methylation subtypes and a transcriptional signature associated with survival duration, and shed new light on the impact that tumours with BRCA1/2 (BRCA1 or BRCA2) and CCNE1 aberrations have on survival. Pathway analyses suggested that homologous recombination is defective in about half of the tumours analysed, and that NOTCH and FOXM1 signalling are involved in serous ovarian cancer pathophysiology.

Published
2011

4. Evaluation of candidate stromal epithelial cross-talk genes identifies association between risk of serous ovarian cancer and TERT, a cancer susceptibility "hot-spot".

Author

Johnatty, SE, Beesley, J, Chen, X, Macgregor, S, Duffy, DL, Spurdle, AB, deFazio, A, Gava, N, Webb, PM, Rossing, MA, Doherty, JA, Goodman, MT, Lurie, G, Thompson, PJ, Wilkens, LR, Ness, RB, Moysich, KB, Chang-Claude, J, Wang-Gohrke, S, Cramer, DW, Terry, KL, Hankinson, SE, Tworoger, SS, Garcia-Closas, M, Yang, H, Lissowska, J, Chanock, SJ, Pharoah, PD, Song, H, Whitemore, AS, Pearce, CL, Stram, DO, Wu, AH, Pike, MC, Gayther, SA, Ramus, SJ, Menon, U, Gentry-Maharaj, A, Anton-Culver, H, Ziogas, A, Hogdall, E, Kjaer, SK, Hogdall, C, Berchuck, A, Schildkraut, JM, Iversen, ES, Moorman, PG, Phelan, CM, Sellers, TA, Cunningham, JM, Vierkant, RA, Rider, DN, Goode, EL, Haviv, I, Chenevix-Trench, G, Ovarian, CAC, Australian, OCSG, and Australian, CSOC

Abstract

We hypothesized that variants in genes expressed as a consequence of interactions between ovarian cancer cells and the host micro-environment could contribute to cancer susceptibility. We therefore used a two-stage approach to evaluate common single nucleotide polymorphisms (SNPs) in 173 genes involved in stromal epithelial interactions in the Ovarian Cancer Association Consortium (OCAC). In the discovery stage, cases with epithelial ovarian cancer (n=675) and controls (n=1,162) were genotyped at 1,536 SNPs using an Illumina GoldenGate assay. Based on Positive Predictive Value estimates, three SNPs-PODXL rs1013368, ITGA6 rs13027811, and MMP3 rs522616-were selected for replication using TaqMan genotyping in up to 3,059 serous invasive cases and 8,905 controls from 16 OCAC case-control studies. An additional 18 SNPs with Pper-alleleor=0.5). However genotypes at TERT rs7726159 were associated with ovarian cancer risk in the smaller, five-study replication study (Pper-allele=0.03). Combined analysis of the discovery and replication sets for this TERT SNP showed an increased risk of serous ovarian cancer among non-Hispanic whites [adj. ORper-allele 1.14 (1.04-1.24) p=0.003]. Our study adds to the growing evidence that, like the 8q24 locus, the telomerase reverse transcriptase locus at 5p15.33, is a general cancer susceptibility locus.

Published
2010

5. Validating genetic risk associations for ovarian cancer through the international Ovarian Cancer Association Consortium.

Author

Pearce, CL, Near, AM, Van Den Berg, DJ, Ramus, SJ, Gentry-Maharaj, A, Menon, U, Gayther, SA, Anderson, AR, Edlund, CK, Wu, AH, Chen, X, Beesley, J, Webb, PM, Holt, SK, Chen, C, Doherty, JA, Rossing, MA, Whittemore, AS, McGuire, V, DiCioccio, RA, Goodman, MT, Lurie, G, Carney, ME, Wilkens, LR, Ness, RB, Moysich, KB, Edwards, R, Jennison, E, Kjaer, SK, Hogdall, E, Hogdall, CK, Goode, EL, Sellers, TA, Vierkant, RA, Cunningham, JM, Schildkraut, JM, Berchuck, A, Moorman, PG, Iversen, ES, Cramer, DW, Terry, KL, Vitonis, AF, Titus-Ernstoff, L, Song, H, Pharoah, PDP, Spurdle, AB, Anton-Culver, H, Ziogas, A, Brewster, W, Galitovskiy, V, Chenevix-Trench, G, Australian Cancer Study, and Australian Ovarian Cancer Study Group

Subjects
Australian Cancer Study, Australian Ovarian Cancer Study Group, Humans, Ovarian Neoplasms, Neoplasm Invasiveness, Genetic Predisposition to Disease, DNA Ligases, DNA-Binding Proteins, Risk Factors, Case-Control Studies, Cohort Studies, Genotype, Heterozygote, Homozygote, Polymorphism, Single Nucleotide, Adult, Aged, Middle Aged, Female, Cytochrome P-450 CYP3A, DNA Ligase ATP, ovarian cancer, genetic susceptibility, oestrogen metabolism, CYP3A4, pooled-analyses, Polymorphism, Single Nucleotide, Ovarian Cancer, Genetics, Clinical Research, Cancer, Rare Diseases, 2.1 Biological and endogenous factors, Oncology & Carcinogenesis, Oncology and Carcinogenesis, Public Health and Health Services
Abstract

The search for genetic variants associated with ovarian cancer risk has focused on pathways including sex steroid hormones, DNA repair, and cell cycle control. The Ovarian Cancer Association Consortium (OCAC) identified 10 single-nucleotide polymorphisms (SNPs) in genes in these pathways, which had been genotyped by Consortium members and a pooled analysis of these data was conducted. Three of the 10 SNPs showed evidence of an association with ovarian cancer at P< or =0.10 in a log-additive model: rs2740574 in CYP3A4 (P=0.011), rs1805386 in LIG4 (P=0.007), and rs3218536 in XRCC2 (P=0.095). Additional genotyping in other OCAC studies was undertaken and only the variant in CYP3A4, rs2740574, continued to show an association in the replication data among homozygous carriers: OR(homozygous(hom))=2.50 (95% CI 0.54-11.57, P=0.24) with 1406 cases and 2827 controls. Overall, in the combined data the odds ratio was 2.81 among carriers of two copies of the minor allele (95% CI 1.20-6.56, P=0.017, p(het) across studies=0.42) with 1969 cases and 3491 controls. There was no association among heterozygous carriers. CYP3A4 encodes a key enzyme in oestrogen metabolism and our finding between rs2740574 and risk of ovarian cancer suggests that this pathway may be involved in ovarian carcinogenesis. Additional follow-up is warranted.

Published
2009

6. CCNE1 and survival of patients with tubo-ovarian high-grade serous carcinoma: An Ovarian Tumor Tissue Analysis consortium study

Author

Kang, E-Y, Weir, A, Meagher, NS, Farrington, K, Nelson, GS, Ghatage, P, Lee, C-H, Riggan, MJ, Bolithon, A, Popovic, G, Leung, B, Tang, K, Lambie, N, Millstein, J, Alsop, J, Anglesio, MS, Ataseven, B, Barlow, E, Beckmann, MW, Berger, J, Bisinotto, C, Boesmueller, H, Boros, J, Brand, AH, Brooks-Wilson, A, Brucker, SY, Carney, ME, Casablanca, Y, Cazorla-Jimenez, A, Cohen, PA, Conrads, TP, Cook, LS, Coulson, P, Courtney-Brooks, M, Cramer, DW, Crowe, P, Cunningham, JM, Cybulski, C, Darcy, KM, El-Bahrawy, MA, Elishaev, E, Erber, R, Farrell, R, Fereday, S, Fischer, A, Garcia, MJ, Gayther, SA, Gentry-Maharaj, A, Gilks, CB, Grube, M, Harnett, PR, Harrington, SP, Harter, P, Hartmann, A, Hecht, JL, Heikaus, S, Hein, A, Heitz, F, Hendley, J, Hernandez, BY, Hernando Polo, S, Heublein, S, Hirasawa, A, Hogdall, E, Hogdall, CK, Horlings, HM, Huntsman, DG, Huzarski, T, Jewell, A, Jimenez-Linan, M, Jones, ME, Kaufmann, SH, Kennedy, CJ, Khabele, D, Kommoss, FKF, Kruitwagen, RFPM, Lambrechts, D, Le, ND, Lener, M, Lester, J, Leung, Y, Linder, A, Loverix, L, Lubinski, J, Madan, R, Maxwell, GL, Modugno, F, Neuhausen, SL, Olawaiye, A, Olbrecht, S, Orsulic, S, Palacios, J, Pearce, CL, Pike, MC, Quinn, CM, Mohan, GR, Rodriguez-Antona, C, Ruebner, M, Ryan, A, Salfinger, SG, Sasamoto, N, Schildkraut, JM, Schoemaker, MJ, Shah, M, Sharma, R, Shvetsov, YB, Singh, N, Sonke, GS, Steele, L, Stewart, CJR, Sundfeldt, K, Swerdlow, AJ, Talhouk, A, Tan, A, Taylor, SE, Terry, KL, Toloczko, A, Traficante, N, Van de Vijver, KK, van der Aa, MA, Van Gorp, T, Van Nieuwenhuysen, E, Van-Wagensveld, L, Vergote, I, Vierkant, RA, Wang, C, Wilkens, LR, Winham, SJ, Wu, AH, Benitez, J, Berchuck, A, Candido Dos Reis, FJ, DeFazio, A, Fasching, PA, Goode, EL, Goodman, MT, Gronwald, J, Karlan, BY, Kommoss, S, Menon, U, Sinn, H-P, Staebler, A, Brenton, JD, Bowtell, DD, Pharoah, PDP, Ramus, SJ, Kobel, M, Kang, E-Y, Weir, A, Meagher, NS, Farrington, K, Nelson, GS, Ghatage, P, Lee, C-H, Riggan, MJ, Bolithon, A, Popovic, G, Leung, B, Tang, K, Lambie, N, Millstein, J, Alsop, J, Anglesio, MS, Ataseven, B, Barlow, E, Beckmann, MW, Berger, J, Bisinotto, C, Boesmueller, H, Boros, J, Brand, AH, Brooks-Wilson, A, Brucker, SY, Carney, ME, Casablanca, Y, Cazorla-Jimenez, A, Cohen, PA, Conrads, TP, Cook, LS, Coulson, P, Courtney-Brooks, M, Cramer, DW, Crowe, P, Cunningham, JM, Cybulski, C, Darcy, KM, El-Bahrawy, MA, Elishaev, E, Erber, R, Farrell, R, Fereday, S, Fischer, A, Garcia, MJ, Gayther, SA, Gentry-Maharaj, A, Gilks, CB, Grube, M, Harnett, PR, Harrington, SP, Harter, P, Hartmann, A, Hecht, JL, Heikaus, S, Hein, A, Heitz, F, Hendley, J, Hernandez, BY, Hernando Polo, S, Heublein, S, Hirasawa, A, Hogdall, E, Hogdall, CK, Horlings, HM, Huntsman, DG, Huzarski, T, Jewell, A, Jimenez-Linan, M, Jones, ME, Kaufmann, SH, Kennedy, CJ, Khabele, D, Kommoss, FKF, Kruitwagen, RFPM, Lambrechts, D, Le, ND, Lener, M, Lester, J, Leung, Y, Linder, A, Loverix, L, Lubinski, J, Madan, R, Maxwell, GL, Modugno, F, Neuhausen, SL, Olawaiye, A, Olbrecht, S, Orsulic, S, Palacios, J, Pearce, CL, Pike, MC, Quinn, CM, Mohan, GR, Rodriguez-Antona, C, Ruebner, M, Ryan, A, Salfinger, SG, Sasamoto, N, Schildkraut, JM, Schoemaker, MJ, Shah, M, Sharma, R, Shvetsov, YB, Singh, N, Sonke, GS, Steele, L, Stewart, CJR, Sundfeldt, K, Swerdlow, AJ, Talhouk, A, Tan, A, Taylor, SE, Terry, KL, Toloczko, A, Traficante, N, Van de Vijver, KK, van der Aa, MA, Van Gorp, T, Van Nieuwenhuysen, E, Van-Wagensveld, L, Vergote, I, Vierkant, RA, Wang, C, Wilkens, LR, Winham, SJ, Wu, AH, Benitez, J, Berchuck, A, Candido Dos Reis, FJ, DeFazio, A, Fasching, PA, Goode, EL, Goodman, MT, Gronwald, J, Karlan, BY, Kommoss, S, Menon, U, Sinn, H-P, Staebler, A, Brenton, JD, Bowtell, DD, Pharoah, PDP, Ramus, SJ, and Kobel, M

Abstract

BACKGROUND: Cyclin E1 (CCNE1) is a potential predictive marker and therapeutic target in tubo-ovarian high-grade serous carcinoma (HGSC). Smaller studies have revealed unfavorable associations for CCNE1 amplification and CCNE1 overexpression with survival, but to date no large-scale, histotype-specific validation has been performed. The hypothesis was that high-level amplification of CCNE1 and CCNE1 overexpression, as well as a combination of the two, are linked to shorter overall survival in HGSC. METHODS: Within the Ovarian Tumor Tissue Analysis consortium, amplification status and protein level in 3029 HGSC cases and mRNA expression in 2419 samples were investigated. RESULTS: High-level amplification (>8 copies by chromogenic in situ hybridization) was found in 8.6% of HGSC and overexpression (>60% with at least 5% demonstrating strong intensity by immunohistochemistry) was found in 22.4%. CCNE1 high-level amplification and overexpression both were linked to shorter overall survival in multivariate survival analysis adjusted for age and stage, with hazard stratification by study (hazard ratio [HR], 1.26; 95% CI, 1.08-1.47, p = .034, and HR, 1.18; 95% CI, 1.05-1.32, p = .015, respectively). This was also true for cases with combined high-level amplification/overexpression (HR, 1.26; 95% CI, 1.09-1.47, p = .033). CCNE1 mRNA expression was not associated with overall survival (HR, 1.00 per 1-SD increase; 95% CI, 0.94-1.06; p = .58). CCNE1 high-level amplification is mutually exclusive with the presence of germline BRCA1/2 pathogenic variants and shows an inverse association to RB1 loss. CONCLUSION: This study provides large-scale validation that CCNE1 high-level amplification is associated with shorter survival, supporting its utility as a prognostic biomarker in HGSC.

Published
2023

7. Lifetime ovulatory years and risk of epithelial ovarian cancer: a multinational pooled analysis

Author

Fu, Z, Brooks, MM, Irvin, S, Jordan, S, Aben, KKH, Anton-Culver, H, Bandera, E, Beckmann, MW, Berchuck, A, Brooks-Wilson, A, Chang-Claude, J, Cook, LS, Cramer, DW, Cushing-Haugen, KL, Doherty, JA, Ekici, AB, Fasching, PA, Fortner, RT, Gayther, SA, Gentry-Maharaj, A, Giles, GG, Goode, EL, Goodman, MT, Harris, HR, Hein, A, Kaaks, R, Kiemeney, LA, Koebel, M, Kotsopoulos, J, Le, ND, Lee, AW, Matsuo, K, McGuire, V, McLaughlin, JR, Menon, U, Milne, RL, Moysich, KB, Pearce, CL, Pike, MC, Qin, B, Ramus, SJ, Riggan, MJ, Rothstein, JH, Schildkraut, JM, Sieh, W, Sutphen, R, Terry, KL, Thompson, PJ, Titus, L, van Altena, AM, White, E, Whittemore, AS, Wu, AH, Zheng, W, Ziogas, A, Taylor, SE, Tang, L, Songer, T, Wentzensen, N, Webb, PM, Risch, HA, Modugno, F, Fu, Z, Brooks, MM, Irvin, S, Jordan, S, Aben, KKH, Anton-Culver, H, Bandera, E, Beckmann, MW, Berchuck, A, Brooks-Wilson, A, Chang-Claude, J, Cook, LS, Cramer, DW, Cushing-Haugen, KL, Doherty, JA, Ekici, AB, Fasching, PA, Fortner, RT, Gayther, SA, Gentry-Maharaj, A, Giles, GG, Goode, EL, Goodman, MT, Harris, HR, Hein, A, Kaaks, R, Kiemeney, LA, Koebel, M, Kotsopoulos, J, Le, ND, Lee, AW, Matsuo, K, McGuire, V, McLaughlin, JR, Menon, U, Milne, RL, Moysich, KB, Pearce, CL, Pike, MC, Qin, B, Ramus, SJ, Riggan, MJ, Rothstein, JH, Schildkraut, JM, Sieh, W, Sutphen, R, Terry, KL, Thompson, PJ, Titus, L, van Altena, AM, White, E, Whittemore, AS, Wu, AH, Zheng, W, Ziogas, A, Taylor, SE, Tang, L, Songer, T, Wentzensen, N, Webb, PM, Risch, HA, and Modugno, F

Abstract

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

8. High Prediagnosis Inflammation-Related Risk Score Associated with Decreased Ovarian Cancer Survival

Author

Brieger, KK, Phung, MT, Mukherjee, B, Bakulski, KM, Anton-Culver, H, Bandera, E, Bowtell, DDL, Cramer, DW, DeFazio, A, Doherty, JA, Fereday, S, Fortner, RT, Gentry-Maharaj, A, Goode, EL, Goodman, MT, Harris, HR, Matsuo, K, Menon, U, Modugno, F, Moysich, KB, Qin, B, Ramus, SJ, Risch, HA, Rossing, MA, Schildkraut, JM, Trabert, B, Vierkant, RA, Winham, SJ, Wentzensen, N, Wu, AH, Ziogas, A, Khoja, L, Cho, KR, McLean, K, Richardson, J, Grout, B, Chase, A, Deurloo, CM, Odunsi, K, Nelson, BH, Brenton, JD, Terry, KL, Pharoah, PDP, Berchuck, A, Hanley, GE, Webb, PM, Pike, MC, Pearce, CL, Brieger, KK, Phung, MT, Mukherjee, B, Bakulski, KM, Anton-Culver, H, Bandera, E, Bowtell, DDL, Cramer, DW, DeFazio, A, Doherty, JA, Fereday, S, Fortner, RT, Gentry-Maharaj, A, Goode, EL, Goodman, MT, Harris, HR, Matsuo, K, Menon, U, Modugno, F, Moysich, KB, Qin, B, Ramus, SJ, Risch, HA, Rossing, MA, Schildkraut, JM, Trabert, B, Vierkant, RA, Winham, SJ, Wentzensen, N, Wu, AH, Ziogas, A, Khoja, L, Cho, KR, McLean, K, Richardson, J, Grout, B, Chase, A, Deurloo, CM, Odunsi, K, Nelson, BH, Brenton, JD, Terry, KL, Pharoah, PDP, Berchuck, A, Hanley, GE, Webb, PM, Pike, MC, and Pearce, CL

Abstract

BACKGROUND: There is suggestive evidence that inflammation is related to ovarian cancer survival. However, more research is needed to identify inflammation-related factors that are associated with ovarian cancer survival and to determine their combined effects. METHODS: This analysis used pooled data on 8,147 women with invasive epithelial ovarian cancer from the Ovarian Cancer Association Consortium. The prediagnosis inflammation-related exposures of interest included alcohol use; aspirin use; other nonsteroidal anti-inflammatory drug use; body mass index; environmental tobacco smoke exposure; history of pelvic inflammatory disease, polycystic ovarian syndrome, and endometriosis; menopausal hormone therapy use; physical inactivity; smoking status; and talc use. Using Cox proportional hazards models, the relationship between each exposure and survival was assessed in 50% of the data. A weighted inflammation-related risk score (IRRS) was developed, and its association with survival was assessed using Cox proportional hazards models in the remaining 50% of the data. RESULTS: There was a statistically significant trend of increasing risk of death per quartile of the IRRS [HR = 1.09; 95% confidence interval (CI), 1.03-1.14]. Women in the upper quartile of the IRRS had a 31% higher death rate compared with the lowest quartile (95% CI, 1.11-1.54). CONCLUSIONS: A higher prediagnosis IRRS was associated with an increased mortality risk after an ovarian cancer diagnosis. Further investigation is warranted to evaluate whether postdiagnosis exposures are also associated with survival. IMPACT: Given that pre- and postdiagnosis exposures are often correlated and many are modifiable, our study results can ultimately motivate the development of behavioral recommendations to enhance survival among patients with ovarian cancer.

Published
2022

9. Identification of a Locus Near ULK1 Associated With Progression-Free Survival in Ovarian Cancer

Author

Quinn, MCJ, McCue, K, Shi, W, Johnatty, SE, Beesley, J, Civitarese, A, O'Mara, TA, Glubb, DM, Tyrer, JP, Armasu, SM, Ong, J-S, Gharahkhani, P, Lu, Y, Gao, B, Patch, A-M, Fasching, PA, Beckmann, MW, Lambrechts, D, Vergote, I, Edwards, DRV, Beeghly-Fadiel, A, Benitez, J, Garcia, MJ, Goodman, MT, Doerk, T, Duerst, M, Modugno, F, Moysich, K, du Bois, A, Pfisterer, J, Bauman, K, Karlan, BY, Lester, J, Cunningham, JM, Larson, MC, McCauley, BM, Kjaer, SK, Jensen, A, Hogdall, CK, Hogdall, E, Schildkraut, JM, Riggan, MJ, Berchuck, A, Cramer, DW, Terry, KL, Bjorge, L, Webb, PM, Friedlander, M, Pejovic, T, Moffitt, M, Glasspool, R, May, T, Ene, GE, Huntsman, DG, Woo, M, Carney, ME, Hinsley, S, Heitz, F, Fereday, S, Kennedy, CJ, Edwards, SL, Winham, SJ, deFazio, A, Pharoah, PDP, Goode, EL, MacGregor, S, Chenevix-Trench, G, Quinn, MCJ, McCue, K, Shi, W, Johnatty, SE, Beesley, J, Civitarese, A, O'Mara, TA, Glubb, DM, Tyrer, JP, Armasu, SM, Ong, J-S, Gharahkhani, P, Lu, Y, Gao, B, Patch, A-M, Fasching, PA, Beckmann, MW, Lambrechts, D, Vergote, I, Edwards, DRV, Beeghly-Fadiel, A, Benitez, J, Garcia, MJ, Goodman, MT, Doerk, T, Duerst, M, Modugno, F, Moysich, K, du Bois, A, Pfisterer, J, Bauman, K, Karlan, BY, Lester, J, Cunningham, JM, Larson, MC, McCauley, BM, Kjaer, SK, Jensen, A, Hogdall, CK, Hogdall, E, Schildkraut, JM, Riggan, MJ, Berchuck, A, Cramer, DW, Terry, KL, Bjorge, L, Webb, PM, Friedlander, M, Pejovic, T, Moffitt, M, Glasspool, R, May, T, Ene, GE, Huntsman, DG, Woo, M, Carney, ME, Hinsley, S, Heitz, F, Fereday, S, Kennedy, CJ, Edwards, SL, Winham, SJ, deFazio, A, Pharoah, PDP, Goode, EL, MacGregor, S, and Chenevix-Trench, G

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.

Published
2021

10. Evaluation of vitamin D biosynthesis and pathway target genes reveals UGT2A1/2 and EGFR polymorphisms associated with epithelial ovarian cancer in African American Women

Author

Grant, DJ, Manichaikul, A, Alberg, AJ, Bandera, E, Barnholtz-Sloan, J, Bondy, M, Cote, ML, Funkhouser, E, Moorman, PG, Peres, LC, Peters, ES, Schwartz, AG, Terry, PD, Wang, X-Q, Keku, TO, Hoyo, C, Berchuck, A, Sandler, DP, Taylor, JA, O'Brien, KM, Edwards, DRV, Edwards, TL, Beeghly-Fadiel, A, Wentzensen, N, Pearce, CL, Wu, AH, Whittemore, AS, McGuire, V, Sieh, W, Rothstein, JH, Modugno, F, Ness, R, Moysich, K, Rossing, MA, Doherty, JA, Sellers, TA, Permuth-Way, JB, Monteiro, AN, Levine, DA, Setiawan, VW, Haiman, CA, LeMarchand, L, Wilkens, LR, Karlan, BY, Menon, U, Ramus, S, Gayther, S, Gentry-Maharaj, A, Terry, KL, Cramer, DW, Goode, EL, Larson, MC, Kaufmann, SH, Cannioto, R, Odunsi, K, Etter, JL, Huang, R-Y, Bernardini, MQ, Tone, AA, May, T, Goodman, MT, Thompson, PJ, Carney, ME, Tworoger, SS, Poole, EM, Lambrechts, D, Vergote, I, Vanderstichele, A, Van Nieuwenhuysen, E, Anton-Culver, H, Ziogas, A, Brenton, JD, Bjorge, L, Salvensen, HB, Kiemeney, LA, Massuger, LFAG, Pejovic, T, Bruegl, A, Moffitt, M, Cook, L, Le, ND, Brooks-Wilson, A, Kelemen, LE, Pharoah, PDP, Song, H, Campbell, I, Eccles, D, DeFazio, A, Kennedy, CJ, Schildkraut, JM, Grant, DJ, Manichaikul, A, Alberg, AJ, Bandera, E, Barnholtz-Sloan, J, Bondy, M, Cote, ML, Funkhouser, E, Moorman, PG, Peres, LC, Peters, ES, Schwartz, AG, Terry, PD, Wang, X-Q, Keku, TO, Hoyo, C, Berchuck, A, Sandler, DP, Taylor, JA, O'Brien, KM, Edwards, DRV, Edwards, TL, Beeghly-Fadiel, A, Wentzensen, N, Pearce, CL, Wu, AH, Whittemore, AS, McGuire, V, Sieh, W, Rothstein, JH, Modugno, F, Ness, R, Moysich, K, Rossing, MA, Doherty, JA, Sellers, TA, Permuth-Way, JB, Monteiro, AN, Levine, DA, Setiawan, VW, Haiman, CA, LeMarchand, L, Wilkens, LR, Karlan, BY, Menon, U, Ramus, S, Gayther, S, Gentry-Maharaj, A, Terry, KL, Cramer, DW, Goode, EL, Larson, MC, Kaufmann, SH, Cannioto, R, Odunsi, K, Etter, JL, Huang, R-Y, Bernardini, MQ, Tone, AA, May, T, Goodman, MT, Thompson, PJ, Carney, ME, Tworoger, SS, Poole, EM, Lambrechts, D, Vergote, I, Vanderstichele, A, Van Nieuwenhuysen, E, Anton-Culver, H, Ziogas, A, Brenton, JD, Bjorge, L, Salvensen, HB, Kiemeney, LA, Massuger, LFAG, Pejovic, T, Bruegl, A, Moffitt, M, Cook, L, Le, ND, Brooks-Wilson, A, Kelemen, LE, Pharoah, PDP, Song, H, Campbell, I, Eccles, D, DeFazio, A, Kennedy, CJ, and Schildkraut, JM

Abstract

An association between genetic variants in the vitamin D receptor (VDR) gene and epithelial ovarian cancer (EOC) was previously reported in women of African ancestry (AA). We sought to examine associations between genetic variants in VDR and additional genes from vitamin D biosynthesis and pathway targets (EGFR, UGT1A, UGT2A1/2, UGT2B, CYP3A4/5, CYP2R1, CYP27B1, CYP24A1, CYP11A1, and GC). Genotyping was performed using the custom-designed 533,631 SNP Illumina OncoArray with imputation to the 1,000 Genomes Phase 3 v5 reference set in 755 EOC cases, including 537 high-grade serous (HGSOC), and 1,235 controls. All subjects are of African ancestry (AA). Logistic regression was performed to estimate odds ratios (OR) and 95% confidence intervals (CI). We further evaluated statistical significance of selected SNPs using the Bayesian False Discovery Probability (BFDP). A significant association with EOC was identified in the UGT2A1/2 region for the SNP rs10017134 (per allele OR = 1.4, 95% CI = 1.2-1.7, P = 1.2 × 10-6 , BFDP = 0.02); and an association with HGSOC was identified in the EGFR region for the SNP rs114972508 (per allele OR = 2.3, 95% CI = 1.6-3.4, P = 1.6 × 10-5 , BFDP = 0.29) and in the UGT2A1/2 region again for rs1017134 (per allele OR = 1.4, 95% CI = 1.2-1.7, P = 2.3 × 10-5 , BFDP = 0.23). Genetic variants in the EGFR and UGT2A1/2 may increase susceptibility of EOC in AA women. Future studies to validate these findings are warranted. Alterations in EGFR and UGT2A1/2 could perturb enzyme efficacy, proliferation in ovaries, impact and mark susceptibility to EOC.

Published
2019

11. A comprehensive gene-environment interaction analysis in Ovarian Cancer using genome-wide significant common variants

Author

Kim, S, Wang, M, Tyrer, JP, Jensen, A, Wiensch, A, Liu, G, Lee, AW, Ness, RB, Salvatore, M, Tworoger, SS, Whittemore, AS, Anton-Culver, H, Sieh, W, Olson, SH, Berchuck, A, Goode, EL, Goodman, MT, Doherty, JA, Chenevix-Trench, G, Rossing, MA, Webb, PM, Giles, GG, Terry, KL, Ziogas, A, Fortner, RT, Menon, U, Gayther, SA, Wu, AH, Song, H, Brooks-Wilson, A, Bandera, E, Cook, LS, Cramer, DW, Milne, RL, Winham, SJ, Kjaer, SK, Modugno, F, Thompson, PJ, Chang-Claude, J, Harris, HR, Schildkraut, JM, Le, ND, Wentzensen, N, Trabert, B, Hogdall, E, Huntsman, D, Pike, MC, Pharoah, PDP, Pearce, CL, Mukherjee, B, Kim, S, Wang, M, Tyrer, JP, Jensen, A, Wiensch, A, Liu, G, Lee, AW, Ness, RB, Salvatore, M, Tworoger, SS, Whittemore, AS, Anton-Culver, H, Sieh, W, Olson, SH, Berchuck, A, Goode, EL, Goodman, MT, Doherty, JA, Chenevix-Trench, G, Rossing, MA, Webb, PM, Giles, GG, Terry, KL, Ziogas, A, Fortner, RT, Menon, U, Gayther, SA, Wu, AH, Song, H, Brooks-Wilson, A, Bandera, E, Cook, LS, Cramer, DW, Milne, RL, Winham, SJ, Kjaer, SK, Modugno, F, Thompson, PJ, Chang-Claude, J, Harris, HR, Schildkraut, JM, Le, ND, Wentzensen, N, Trabert, B, Hogdall, E, Huntsman, D, Pike, MC, Pharoah, PDP, Pearce, CL, and Mukherjee, B

Abstract

As a follow-up to genome-wide association analysis of common variants associated with ovarian carcinoma (cancer), our study considers seven well-known ovarian cancer risk factors and their interactions with 28 genome-wide significant common genetic variants. The interaction analyses were based on data from 9971 ovarian cancer cases and 15,566 controls from 17 case-control studies. Likelihood ratio and Wald tests for multiplicative interaction and for relative excess risk due to additive interaction were used. The top multiplicative interaction was noted between oral contraceptive pill (OCP) use (ever vs. never) and rs13255292 (p value = 3.48 × 10-4 ). Among women with the TT genotype for this variant, the odds ratio for OCP use was 0.53 (95% CI = 0.46-0.60) compared to 0.71 (95%CI = 0.66-0.77) for women with the CC genotype. When stratified by duration of OCP use, women with 1-5 years of OCP use exhibited differential protective benefit across genotypes. However, no interaction on either the multiplicative or additive scale was found to be statistically significant after multiple testing correction. The results suggest that OCP use may offer increased benefit for women who are carriers of the T allele in rs13255292. On the other hand, for women carrying the C allele in this variant, longer (5+ years) use of OCP may reduce the impact of carrying the risk allele of this SNP. Replication of this finding is needed. The study presents a comprehensive analytic framework for conducting gene-environment analysis in ovarian cancer.

Published
2019

12. A transcriptome-wide association study among 97,898 women to identify candidate susceptibility genes for epithelial ovarian cancer risk

Author

Lu, Y, Beeghly-Fadiel, A, Wu, L, Guo, X, Li, B, Schildkraut, JM, Im, HK, Chen, YA, Permuth, JB, Reid, BM, Teer, JK, Moysich, KB, Andrulis, IL, Anton-Culver, H, Arun, BK, Bandera, EV, Barkardottir, RB, Barnes, DR, Benitez, J, Bjorge, L, Brenton, J, Butzow, R, Caldes, T, Caligo, MA, Campbell, I, Chang-Claude, J, Claes, KBM, Couch, FJ, Cramer, DW, Daly, MB, DeFazio, A, Dennis, J, Diez, O, Domchek, SM, D rk, T, Easton, DF, Eccles, DM, Fasching, PA, Fortner, RET, Fountzilas, G, Friedman, E, Ganz, PA, Garber, J, Giles, GG, Godwin, AK, Goldgar, DE, Goodman, MT, Greene, MH, Gronwald, J, Hamann, U, Heitz, F, Hildebrandt, MAT, Høgdall, CK, Hollestelle, A, Hulick, PJ, Huntsman, DG, Imyanitov, EN, Isaacs, C, Jakubowska, A, James, P, Karlan, BY, Kelemen, LE, Kiemeney, LA, Kjaer, SK, Kwong, A, Le, ND, Leslie, G, Lesueur, F, Levine, DA, Mattiello, A, May, T, McGuffog, L, and McNeish, IA

Subjects
endocrine system diseases, female genital diseases and pregnancy complications
Abstract

© 2018 American Association for Cancer Research. Large-scale genome-wide association studies (GWAS) have identified approximately 35 loci associated with epithelial ovarian cancer (EOC) risk. The majority of GWAS-identified disease susceptibility variants are located in noncoding regions, and causal genes underlying these associations remain largely unknown. Here, we performed a transcriptome-wide association study to search for novel genetic loci and plausible causal genes at known GWAS loci. We used RNA sequencing data (68 normal ovarian tissue samples from 68 individuals and 6,124 cross-tissue samples from 369 individuals) and high-density genotyping data from European descendants of the Genotype-Tissue Expression (GTEx V6) project to build ovarian and cross-tissue models of genetically regulated expression using elastic net methods. We evaluated 17,121 genes for their cis-predicted gene expression in relation to EOC risk using summary statistics data from GWAS of 97,898 women, including 29,396 EOC cases. With a Bonferroni-corrected significance level of P < 2.2 106, we identified 35 genes, including FZD4 at 11q14.2 (Z ¼ 5.08, P ¼ 3.83 107, the cross-tissue model; 1 Mb away from any GWAS-identified EOC risk variant), a potential novel locus for EOC risk. All other 34 significantly associated genes were located within 1 Mb of known GWAS-identified loci, including 23 genes at 6 loci not previously linked to EOC risk. Upon conditioning on nearby known EOC GWAS-identified variants, the associations for 31 genes disappeared and three genes remained (P < 1.47 103). These data identify one novel locus (FZD4) and 34 genes at 13 known EOC risk loci associated with EOC risk, providing new insights into EOC carcinogenesis.

Published
2018

13. Variants in genes encoding small GTPases and association with epithelial ovarian cancer susceptibility

Author

Earp, M, Tyrer, JP, Winham, SJ, Lin, HY, Chornokur, G, Dennis, J, Aben, KKH, Anton-Culver, H, Antonenkova, N, Bandera, EV, Bean, YT, Beckmann, MW, Bjorge, L, Bogdanova, N, Brinton, LA, Brooks-Wilson, A, Bruinsma, F, Bunker, CH, Butzow, R, Campbell, IG, Carty, K, Chang-Claude, J, Cook, LS, Cramer, DW, Cunningham, JM, Cybulski, C, Dansonka-Mieszkowska, A, Despierre, E, Doherty, JA, Dörk, T, Du Bois, A, Dürst, M, Easton, DF, Eccles, DM, Edwards, RP, Ekici, AB, Fasching, PA, Fridley, BL, Gentry-Maharaj, A, Giles, GG, Glasspool, R, Goodman, MT, Gronwald, J, Harter, P, Hein, A, Heitz, F, Hildebrandt, MAT, Hillemanns, P, Hogdall, CK, Høgdall, E, Hosono, S, Iversen, ES, Jakubowska, A, Jensen, A, Ji, BT, Jung, AY, Karlan, BY, Kellar, M, Kiemeney, LA, Lim, BK, Kjaer, SK, Krakstad, C, Kupryjanczyk, J, Lambrechts, D, Lambrechts, S, Le, ND, Lele, S, Lester, J, Levine, DA, Li, Z, Liang, D, Lissowska, J, Lu, K, Lubinski, J, Lundvall, L, Massuger, LFAG, Matsuo, K, and McGuire, V

Subjects
endocrine system diseases, female genital diseases and pregnancy complications
Abstract

© This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication. Epithelial ovarian cancer (EOC) is the fifth leading cause of cancer mortality in American women. Normal ovarian physiology is intricately connected to small GTP binding proteins of the Ras superfamily (Ras, Rho, Rab, Arf, and Ran) which govern processes such as signal transduction, cell proliferation, cell motility, and vesicle transport. We hypothesized that common germline variation in genes encoding small GTPases is associated with EOC risk. We investigated 322 variants in 88 small GTPase genes in germline DNA of 18,736 EOC patients and 26,138 controls of European ancestry using a custom genotype array and logistic regression fitting log-additive models. Functional annotation was used to identify bio-features and expression quantitative trait loci that intersect with risk variants. One variant, ARHGEF10L (Rho guanine nucleotide exchange factor 10 like) rs2256787, was associated with increased endometrioid EOC risk (OR = 1.33, p = 4.46 x 10−6). Other variants of interest included another in ARHGEF10L, rs10788679, which was associated with invasive serous EOC risk (OR = 1.07, p = 0.00026) and two variants in AKAP6 (A-kinase anchoring protein 6) which were associated with risk of invasive EOC (rs1955513, OR = 0.90, p = 0.00033; rs927062, OR = 0.94, p = 0.00059). Functional annotation revealed that the two ARHGEF10L variants were located in super-enhancer regions and that AKAP6 rs927062 was associated with expression of GTPase gene ARHGAP5 (Rho GTPase activating protein 5). Inherited variants in ARHGEF10L and AKAP6, with potential transcriptional regulatory function and association with EOC risk, warrant investigation in independent EOC study populations.

Published
2018

14. Adult height is associated with increased risk of ovarian cancer: A Mendelian randomisation study

Author

Dixon-Suen, SC, Nagle, CM, Thrift, AP, Pharoah, PDP, Ewing, A, Pearce, CL, Zheng, W, Chenevix-Trench, G, Fasching, PA, Beckmann, MW, Lambrechts, D, Vergote, I, Lambrechts, S, Van Nieuwenhuysen, E, Rossing, MA, Doherty, JA, Wicklund, KG, Chang-Claude, J, Jung, AY, Moysich, KB, Odunsi, K, Goodman, MT, Wilkens, LR, Thompson, PJ, Shvetsov, YB, Dörk, T, Park-Simon, TW, Hillemanns, P, Bogdanova, N, Butzow, R, Nevanlinna, H, Pelttari, LM, Leminen, A, Modugno, F, Ness, RB, Edwards, RP, Kelley, JL, Heitz, F, Du Bois, A, Harter, P, Schwaab, I, Karlan, BY, Lester, J, Orsulic, S, Rimel, BJ, Kjær, SK, Høgdall, E, Jensen, A, Goode, EL, Fridley, BL, Cunningham, JM, Winham, SJ, Giles, GG, Bruinsma, F, Milne, RL, Southey, MC, Hildebrandt, MAT, Wu, X, Lu, KH, Liang, D, Levine, DA, Bisogna, M, Schildkraut, JM, Berchuck, A, Cramer, DW, Terry, KL, Bandera, EV, Olson, SH, Salvesen, HB, Thomsen, LCV, Kopperud, RK, Bjorge, L, Kiemeney, LA, Massuger, LFAG, and Pejovic, T

Subjects
Australian Ovarian Cancer Study Group, Ovarian Cancer Association Consortium
Abstract

© 2018 Cancer Research UK. Background: Observational studies suggest greater height is associated with increased ovarian cancer risk, but cannot exclude bias and/or confounding as explanations for this. Mendelian randomisation (MR) can provide evidence which may be less prone to bias. Methods: We pooled data from 39 Ovarian Cancer Association Consortium studies (16,395 cases; 23,003 controls). We applied two-stage predictor-substitution MR, using a weighted genetic risk score combining 609 single-nucleotide polymorphisms. Study-specific odds ratios (OR) and 95% confidence intervals (CI) for the association between genetically predicted height and risk were pooled using random-effects meta-analysis. Results: Greater genetically predicted height was associated with increased ovarian cancer risk overall (pooled-OR (pOR) = 1.06; 95% CI: 1.01-1.11 per 5 cm increase in height), and separately for invasive (pOR = 1.06; 95% CI: 1.01-1.11) and borderline (pOR = 1.15; 95% CI: 1.02-1.29) tumours. Conclusions: Women with a genetic propensity to being taller have increased risk of ovarian cancer. This suggests genes influencing height are involved in pathways promoting ovarian carcinogenesis.

Published
2018

15. Adult height is associated with increased risk of ovarian cancer: A Mendelian randomisation study

Author

Dixon-Suen, Suzanne, Nagle, CM, Thrift, AP, Pharoah, PDP, Ewing, A, Pearce, CL, Zheng, W, Chenevix-Trench, G, Fasching, PA, Beckmann, MW, Lambrechts, D, Vergote, I, Lambrechts, S, Van Nieuwenhuysen, E, Rossing, MA, Doherty, JA, Wicklund, KG, Chang-Claude, J, Jung, AY, Moysich, KB, Odunsi, K, Goodman, MT, Wilkens, LR, Thompson, PJ, Shvetsov, YB, Dörk, T, Park-Simon, TW, Hillemanns, P, Bogdanova, N, Butzow, R, Nevanlinna, H, Pelttari, LM, Leminen, A, Modugno, F, Ness, RB, Edwards, RP, Kelley, JL, Heitz, F, Du Bois, A, Harter, P, Schwaab, I, Karlan, BY, Lester, J, Orsulic, S, Rimel, BJ, Kjær, SK, Høgdall, E, Jensen, A, Goode, EL, Fridley, BL, Cunningham, JM, Winham, SJ, Giles, GG, Bruinsma, F, Milne, RL, Southey, MC, Hildebrandt, MAT, Wu, X, Lu, KH, Liang, D, Levine, DA, Bisogna, M, Schildkraut, JM, Berchuck, A, Cramer, DW, Terry, KL, Bandera, EV, Olson, SH, Salvesen, HB, Thomsen, LCV, Kopperud, RK, Bjorge, L, Kiemeney, LA, Massuger, LFAG, Pejovic, T, Bruegl, A, Cook, LS, Le, ND, Swenerton, KD, Brooks-Wilson, A, Kelemen, LE, Lubiński, J, Huzarski, T, Gronwald, J, Menkiszak, J, Wentzensen, N, Brinton, L, Yang, H, Lissowska, J, Høgdall, CK, Lundvall, L, Song, H, Tyrer, JP, Campbell, I, Eccles, D, Paul, J, Glasspool, R, Siddiqui, N, Whittemore, AS, Sieh, W, Dixon-Suen, Suzanne, Nagle, CM, Thrift, AP, Pharoah, PDP, Ewing, A, Pearce, CL, Zheng, W, Chenevix-Trench, G, Fasching, PA, Beckmann, MW, Lambrechts, D, Vergote, I, Lambrechts, S, Van Nieuwenhuysen, E, Rossing, MA, Doherty, JA, Wicklund, KG, Chang-Claude, J, Jung, AY, Moysich, KB, Odunsi, K, Goodman, MT, Wilkens, LR, Thompson, PJ, Shvetsov, YB, Dörk, T, Park-Simon, TW, Hillemanns, P, Bogdanova, N, Butzow, R, Nevanlinna, H, Pelttari, LM, Leminen, A, Modugno, F, Ness, RB, Edwards, RP, Kelley, JL, Heitz, F, Du Bois, A, Harter, P, Schwaab, I, Karlan, BY, Lester, J, Orsulic, S, Rimel, BJ, Kjær, SK, Høgdall, E, Jensen, A, Goode, EL, Fridley, BL, Cunningham, JM, Winham, SJ, Giles, GG, Bruinsma, F, Milne, RL, Southey, MC, Hildebrandt, MAT, Wu, X, Lu, KH, Liang, D, Levine, DA, Bisogna, M, Schildkraut, JM, Berchuck, A, Cramer, DW, Terry, KL, Bandera, EV, Olson, SH, Salvesen, HB, Thomsen, LCV, Kopperud, RK, Bjorge, L, Kiemeney, LA, Massuger, LFAG, Pejovic, T, Bruegl, A, Cook, LS, Le, ND, Swenerton, KD, Brooks-Wilson, A, Kelemen, LE, Lubiński, J, Huzarski, T, Gronwald, J, Menkiszak, J, Wentzensen, N, Brinton, L, Yang, H, Lissowska, J, Høgdall, CK, Lundvall, L, Song, H, Tyrer, JP, Campbell, I, Eccles, D, Paul, J, Glasspool, R, Siddiqui, N, Whittemore, AS, and Sieh, W

Published
2018

16. Ovarian cancer early detection by circulating CA125 in the context of anti-CA125 autoantibody levels: Results from the EPIC cohort

Author

Fortner, RT, Schock, H, Le Cornet, C, Huesing, A, Vitonis, AF, Johnson, TS, Fichorova, RN, Fashemi, T, Yamamoto, HS, Tjonneland, A, Hansen, L, Overvad, K, Boutron-Ruault, M-C, Kvaskoff, M, Severi, G, Boeing, H, Trichopoulou, A, Papatesta, E-M, La Vecchia, C, Palli, D, Sieri, S, Tumino, R, Sacerdote, C, Mattiello, A, Onland-Moret, NC, Peeters, PH, Bueno-de-Mesquita, HBA, Weiderpass, E, Ramon Quiros, J, Duell, EJ, Sanchez, M-J, Navarro, C, Ardanaz, E, Larranaga, N, Nodin, B, Jirstrom, K, Idahl, A, Lundin, E, Khaw, K-T, Travis, RC, Gunter, M, Johansson, M, Dossus, L, Merritt, MA, Riboli, E, Terry, KL, Cramer, DW, Kaaks, R, Fortner, RT, Schock, H, Le Cornet, C, Huesing, A, Vitonis, AF, Johnson, TS, Fichorova, RN, Fashemi, T, Yamamoto, HS, Tjonneland, A, Hansen, L, Overvad, K, Boutron-Ruault, M-C, Kvaskoff, M, Severi, G, Boeing, H, Trichopoulou, A, Papatesta, E-M, La Vecchia, C, Palli, D, Sieri, S, Tumino, R, Sacerdote, C, Mattiello, A, Onland-Moret, NC, Peeters, PH, Bueno-de-Mesquita, HBA, Weiderpass, E, Ramon Quiros, J, Duell, EJ, Sanchez, M-J, Navarro, C, Ardanaz, E, Larranaga, N, Nodin, B, Jirstrom, K, Idahl, A, Lundin, E, Khaw, K-T, Travis, RC, Gunter, M, Johansson, M, Dossus, L, Merritt, MA, Riboli, E, Terry, KL, Cramer, DW, and Kaaks, R

Abstract

CA125 is the best ovarian cancer early detection marker to date; however, sensitivity is limited and complementary markers are required to improve discrimination between ovarian cancer cases and non-cases. Anti-CA125 autoantibodies are observed in circulation. Our objective was to evaluate whether these antibodies (1) can serve as early detection markers, providing evidence of an immune response to a developing tumor, and (2) modify the discriminatory capacity of CA125 by either masking CA125 levels (resulting in lower discrimination) or acting synergistically to improve discrimination between cases and non-cases. We investigated these objectives using a nested case-control study within the European Prospective Investigation into Cancer and Nutrition cohort (EPIC) including 250 cases diagnosed within 4 years of blood collection and up to four matched controls. Circulating CA125 antigen and antibody levels were quantified using an electrochemiluminescence assay. Adjusted areas under the curve (aAUCs) by 2-year lag-time intervals were calculated using conditional logistic regression calibrated toward the absolute risk estimates from a pre-existing epidemiological risk model as an offset-variable. Anti-CA125 levels alone did not discriminate cases from controls. For cases diagnosed <2 years after blood collection, discrimination by CA125 antigen was suggestively higher with higher anti-CA125 levels (aAUC, highest antibody tertile: 0.84 [0.76-0.92]; lowest tertile: 0.76 [0.67-0.86]; phet = 0.06). We provide the first evidence of potentially synergistic discrimination effects of CA125 and anti-CA125 antibodies in ovarian early detection. If these findings are replicated, evaluating CA125 in the context of its antibody may improve ovarian cancer early detection.

Published
2018

17. rs495139 in the TYMS-ENOSF1 Region and Risk of Ovarian Carcinoma of Mucinous Histology

Author

Kelemen, LE, Earp, M, Fridley, BL, Chenevix-Trench, G, Fasching, PA, Beckmann, MW, Ekici, AB, Hein, A, Lambrechts, D, Lambrechts, S, Van Nieuwenhuysen, E, Vergote, I, Rossing, MA, Doherty, JA, Chang-Claude, J, Behrens, S, Moysich, KB, Cannioto, R, Lele, S, Odunsi, K, Goodman, MT, Shvetsov, YB, Thompson, PJ, Wilkens, LR, Doerk, T, Antonenkova, N, Bogdanova, N, Hillemanns, P, Runnebaum, IB, du Bois, A, Harter, P, Heitz, F, Schwaab, I, Butzow, R, Pelttari, LM, Nevanlinna, H, Modugno, F, Edwards, RP, Kelley, JL, Ness, RB, Karlan, BY, Lester, J, Orsulic, S, Walsh, C, Kjaer, SK, Jensen, A, Cunningham, JM, Vierkant, RA, Giles, GG, Bruinsma, F, Southey, MC, Hildebrandt, MAT, Liang, D, Lu, K, Wu, X, Sellers, TA, Levine, DA, Schildkraut, JM, Iversen, ES, Terry, KL, Cramer, DW, Tworoger, SS, Poole, EM, Bandera, EV, Olson, SH, Orlow, I, Thomsen, LCV, Bjorge, L, Krakstad, C, Tangen, IL, Kiemeney, LA, Aben, KKH, Massuger, LFAG, van Altena, AM, Pejovic, T, Bean, Y, Kellar, M, Cook, LS, Le, ND, Brooks-Wilson, A, Gronwald, J, Cybulski, C, Jakubowska, A, Lubinski, J, Wentzensen, N, Brinton, LA, Lissowska, J, Hogdall, E, Engelholm, SA, Hogdall, C, Lundvall, L, Nedergaard, L, Pharoah, PDP, Dicks, E, Song, H, Tyrer, JP, McNeish, I, Siddiqui, N, Carty, K, Glasspool, R, Paul, J, Campbell, IG, Eccles, D, Whittemore, AS, McGuire, V, Rothstein, JH, Sieh, W, Narod, SA, Phelan, CM, McLaughlin, JR, Risch, HA, Anton-Culver, H, Ziogas, A, Menon, U, Gayther, SA, Gentry-Maharaj, A, Ramus, SJ, Wu, AH, Pearce, CL, Lee, AW, Pike, MC, Kupryjanczyk, J, Podgorska, A, Plisiecka-Halasa, J, Sawicki, W, Goode, EL, Berchuck, A, Kelemen, LE, Earp, M, Fridley, BL, Chenevix-Trench, G, Fasching, PA, Beckmann, MW, Ekici, AB, Hein, A, Lambrechts, D, Lambrechts, S, Van Nieuwenhuysen, E, Vergote, I, Rossing, MA, Doherty, JA, Chang-Claude, J, Behrens, S, Moysich, KB, Cannioto, R, Lele, S, Odunsi, K, Goodman, MT, Shvetsov, YB, Thompson, PJ, Wilkens, LR, Doerk, T, Antonenkova, N, Bogdanova, N, Hillemanns, P, Runnebaum, IB, du Bois, A, Harter, P, Heitz, F, Schwaab, I, Butzow, R, Pelttari, LM, Nevanlinna, H, Modugno, F, Edwards, RP, Kelley, JL, Ness, RB, Karlan, BY, Lester, J, Orsulic, S, Walsh, C, Kjaer, SK, Jensen, A, Cunningham, JM, Vierkant, RA, Giles, GG, Bruinsma, F, Southey, MC, Hildebrandt, MAT, Liang, D, Lu, K, Wu, X, Sellers, TA, Levine, DA, Schildkraut, JM, Iversen, ES, Terry, KL, Cramer, DW, Tworoger, SS, Poole, EM, Bandera, EV, Olson, SH, Orlow, I, Thomsen, LCV, Bjorge, L, Krakstad, C, Tangen, IL, Kiemeney, LA, Aben, KKH, Massuger, LFAG, van Altena, AM, Pejovic, T, Bean, Y, Kellar, M, Cook, LS, Le, ND, Brooks-Wilson, A, Gronwald, J, Cybulski, C, Jakubowska, A, Lubinski, J, Wentzensen, N, Brinton, LA, Lissowska, J, Hogdall, E, Engelholm, SA, Hogdall, C, Lundvall, L, Nedergaard, L, Pharoah, PDP, Dicks, E, Song, H, Tyrer, JP, McNeish, I, Siddiqui, N, Carty, K, Glasspool, R, Paul, J, Campbell, IG, Eccles, D, Whittemore, AS, McGuire, V, Rothstein, JH, Sieh, W, Narod, SA, Phelan, CM, McLaughlin, JR, Risch, HA, Anton-Culver, H, Ziogas, A, Menon, U, Gayther, SA, Gentry-Maharaj, A, Ramus, SJ, Wu, AH, Pearce, CL, Lee, AW, Pike, MC, Kupryjanczyk, J, Podgorska, A, Plisiecka-Halasa, J, Sawicki, W, Goode, EL, and Berchuck, A

Abstract

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 × 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.

Published
2018

18. Analyses of germline variants associated with ovarian cancer survival identify functional candidates at the 1q22 and 19p12 outcome loci

Author

Glubb, DM, Johnatty, SE, Quinn, MCJ, O'Mara, TA, Tyrer, JP, Gao, B, Fasching, PA, Beckmann, MW, Lambrechts, D, Vergote, I, Edwards, DRV, Beeghly-Fadiel, A, Benitez, J, Garcia, MJ, Goodman, MT, Thompson, PJ, Doerk, T, Duerst, M, Modungo, F, Moysich, K, Heitz, F, du Bois, A, Pfisterer, J, Hillemanns, P, Karlan, BY, Lester, J, Goode, EL, Cunningham, JM, Winham, SJ, Larson, MC, McCauley, BM, Kjaer, SK, Jensen, A, Schildkraut, JM, Berchuck, A, Cramer, DW, Terry, KL, Salvesen, HB, Bjorge, L, Webb, PM, Grant, P, Pejovic, T, Moffitt, M, Hogdall, CK, Hogdall, E, Paul, J, Glasspool, R, Bernardini, M, Tone, A, Huntsman, D, Woo, M, deFazio, A, Kennedy, CJ, Pharoah, PDP, MacGregor, S, Chenevix-Trench, G, Grp, AGOS, Grp, AOCS, Tyrer, Jonathan [0000-0003-3724-4757], Pharoah, Paul [0000-0001-8494-732X], and Apollo - University of Cambridge Repository

Subjects
meta-analysis, genetic association, Oncology and Carcinogenesis, AGO Study Group, ovarian cancer outcome, gene regulation, health care economics and organizations
Abstract

We previously identified associations with ovarian cancer outcome at five genetic loci. To identify putatively causal genetic variants and target genes, we prioritized two ovarian outcome loci (1q22 and 19p12) for further study. Bioinformatic and functional genetic analyses indicated that MEF2D and ZNF100 are targets of candidate outcome variants at 1q22 and 19p12, respectively. At 19p12, the chromatin interaction of a putative regulatory element with the ZNF100 promoter region correlated with candidate outcome variants. At 1q22, putative regulatory elements enhanced MEF2D promoter activity and haplotypes containing candidate outcome variants modulated these effects. In a public dataset, MEF2D and ZNF100 expression were both associated with ovarian cancer progression-free or overall survival time. In an extended set of 6,162 epithelial ovarian cancer patients, we found that functional candidates at the 1q22 and 19p12 loci, as well as other regional variants, were nominally associated with patient outcome; however, no associations reached our threshold for statistical significance (p

Published
2017

19. History of hypertension, heart disease, and diabetes and ovarian cancer patient survival: evidence from the ovarian cancer association consortium

Author

Minlikeeva, AN, Freudenheim, JL, Cannioto, RA, Szender, JB, Eng, KH, Modugno, F, Ness, RB, LaMonte, MJ, Friel, G, Segal, BH, Odunsi, K, Mayor, P, Zsiros, E, Schmalfeldt, B, Klapdor, R, Doerk, T, Hillemanns, P, Kelemen, LE, Kobel, M, Steed, H, de Fazio, A, Jordan, SJ, Nagle, CM, Risch, HA, Rossing, MA, Doherty, JA, Goodman, MT, Edwards, R, Matsuo, K, Mizuno, M, Karlan, BY, Kjaer, SK, Hogdall, E, Jensen, A, Schildkraut, JM, Terry, KL, Cramer, DW, Bandera, EV, Paddock, LE, Kiemeney, LA, Massuger, LF, Kupryjanczyk, J, Berchuck, A, Chang-Claude, J, Diergaarde, B, Webb, PM, Moysich, KB, Grp, AOCS, and Consortium, OCA

Subjects
Australian Ovarian Cancer Study Group, Risk, Adult, Heart Diseases, Epidemiology, Ovarian Cancer Association Consortium, Adrenergic beta-Antagonists, Oncology and Carcinogenesis, Medications, Cardiovascular, Disease-Free Survival, Rare Diseases, Clinical Research, Diabetes Mellitus, Genetics, Humans, Insulin, Hypoglycemic Agents, Mortality, Aged, Cancer, Ovarian Neoplasms, screening and diagnosis, Beta blockers, Ovarian cancer prognosis, Diabetes, Middle Aged, Ovarian Cancer, 4.1 Discovery and preclinical testing of markers and technologies, Survival Rate, Detection, Good Health and Well Being, Hypertension, Public Health and Health Services, Female
Abstract

PurposeSurvival following ovarian cancer diagnosis is generally low; understanding factors related to prognosis could be important to optimize treatment. The role of previously diagnosed comorbidities and use of medications for those conditions in relation to prognosis for ovarian cancer patients has not been studied extensively, particularly according to histological subtype.MethodsUsing pooled data from fifteen studies participating in the Ovarian Cancer Association Consortium, we examined the associations between history of hypertension, heart disease, diabetes, and medications taken for these conditions and overall survival (OS) and progression-free survival (PFS) among patients diagnosed with invasive epithelial ovarian carcinoma. We used Cox proportional hazards regression models adjusted for age and stage to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) overall and within strata of histological subtypes.ResultsHistory of diabetes was associated with increased risk of mortality (n = 7,674; HR = 1.12; 95% CI = 1.01-1.25). No significant mortality associations were observed for hypertension (n = 6,482; HR = 0.95; 95% CI = 0.88-1.02) or heart disease (n = 4,252; HR = 1.05; 95% CI = 0.87-1.27). No association of these comorbidities was found with PFS in the overall study population. However, among patients with endometrioid tumors, hypertension was associated with lower risk of progression (n = 339, HR = 0.54; 95% CI = 0.35-0.84). Comorbidity was not associated with OS or PFS for any of the other histological subtypes. Ever use of beta blockers, oral antidiabetic medications, and insulin was associated with increased mortality, HR = 1.20; 95% CI = 1.03-1.40, HR = 1.28; 95% CI = 1.05-1.55, and HR = 1.63; 95% CI = 1.20-2.20, respectively. Ever use of diuretics was inversely associated with mortality, HR = 0.71; 95% CI = 0.53-0.94.ConclusionsHistories of hypertension, diabetes, and use of diuretics, beta blockers, insulin, and oral antidiabetic medications may influence the survival of ovarian cancer patients. Understanding mechanisms for these observations could provide insight regarding treatment.

Published
2017

20. Identification of 12 new susceptibility loci for different histotypes of epithelial ovarian cancer

Author

Phelan, CM, Kuchenbaecker, KB, Tyrer, JP, Kar, SP, Lawrenson, K, Winham, SJ, Dennis, J, Pirie, A, Riggan, MJ, Chornokur, G, Earp, MA, Lyra, PC, Lee, JM, Coetzee, S, Beesley, J, McGuffog, L, Soucy, P, Dicks, E, Lee, A, Barrowdale, D, Lecarpentier, J, Leslie, G, Aalfs, CM, Aben, KKH, Adams, M, Adlard, J, Andrulis, IL, Anton-Culver, H, Antonenkova, N, Aravantinos, G, Arnold, N, Arun, BK, Arver, B, Azzollini, J, Balmaña, J, Banerjee, SN, Barjhoux, L, Barkardottir, RB, Bean, Y, Beckmann, MW, Beeghly-Fadiel, A, Benitez, J, Bermisheva, M, Bernardini, MQ, Birrer, MJ, Bjorge, L, Black, A, Blankstein, K, Blok, MJ, Bodelon, C, Bogdanova, N, Bojesen, A, Bonanni, B, Borg, Å, Bradbury, AR, Brenton, JD, Brewer, C, Brinton, L, Broberg, P, Brooks-Wilson, A, Bruinsma, F, Brunet, J, Buecher, B, Butzow, R, Buys, SS, Caldes, T, Caligo, MA, Campbell, I, Cannioto, R, Carney, ME, Cescon, T, Chan, SB, Chang-Claude, J, Chanock, S, Chen, XQ, Chiew, YE, Chiquette, J, Chung, WK, Claes, KBM, Conner, T, Cook, LS, Cook, J, Cramer, DW, Cunningham, JM, and D'Aloisio, AA

Subjects
endocrine system diseases, female genital diseases and pregnancy complications
Abstract

© 2017 Nature America, Inc., part of Springer Nature. All rights reserved. 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

21. Use of common analgesic medications and ovarian cancer survival: results from a pooled analysis in the Ovarian Cancer Association Consortium

Author

Dixon, SC, Nagle, CM, Wentzensen, N, Trabert, B, Beeghly-Fadiel, A, Schildkraut, JM, Moysich, KB, deFazio, A, Risch, HA, Rossing, MA, Doherty, JA, Wicklund, KG, Goodman, MT, Modugno, F, Ness, RB, Edwards, RP, Jensen, A, Kjaer, SK, Hogdall, E, Berchuck, A, Cramer, DW, Terry, KL, Poole, EM, Bandera, EV, Paddock, LE, Anton-Culver, H, Ziogas, A, Menon, U, Gayther, SA, Ramus, SJ, Gentry-Maharaj, A, Pearce, CL, Wu, AH, Pike, MC, Webb, PM, Grp, AOCS, and Consortium, OCA

Subjects
nonsteroidal anti-inflammatory drugs, ovarian cancer, aspirin, paracetamol, pooled analysis, survival, NSAID, acetaminophen
Published
2017

22. No evidence that genetic variation in the myeloid-derived suppressor cell pathway influences ovarian cancer survival

Author

Sucheston-Campbell, LE, Cannioto, R, Clay, AI, Etter, JL, Eng, KH, Liu, S, Battaglia, S, Hu, Q, Brian Szender, J, Minlikeeva, A, Joseph, JM, Mayor, P, Abrams, SI, Segal, BH, Wallace, PK, Soh, KT, Zsiros, E, Anton-Culver, H, Bandera, EV, Beckmann, MW, Berchuck, A, Bjorge, L, Bruegl, A, Campbell, IG, Campbell, SP, Chenevix-Trench, G, Cramer, DW, Mieszkowska, AD, Dao, F, Diergaarde, B, Doerk, T, Doherty, JA, Du Bois, A, Eccles, D, Engelholm, SA, Fasching, PA, Gayther, SA, Gentry-Maharaj, A, Glasspool, RM, Goodman, MT, Gronwald, J, Harter, P, Hein, A, Heitz, F, Hillemmanns, P, Høgdall, C, Høgdall, EVS, Huzarski, T, Jensen, A, Johnatty, SE, Jung, A, Karlan, BY, Klapdor, R, Kluz, T, Konopka, B, Kjer, SK, Kupryjanczyk, J, Lambrechts, D, Lester, J, Lubinski, J, Levine, DA, Lundvall, L, McGuire, V, McNeish, IA, Menon, U, Modugno, F, Ness, RB, Orsulic, S, Paul, J, Pearce, CL, Pejovic, T, Pharoah, P, Ramus, SJ, Rothstein, J, Rossing, MA, Rubner, M, Schildkraut, JM, Schmalfeldt, B, Schwaab, I, Siddiqui, N, and Sieh, W

Subjects
endocrine system diseases, female genital diseases and pregnancy complications
Abstract

© 2016 American Association for Cancer Research. Background: The precise mechanism by which the immune system is adversely affected in cancer patients remains poorly understood, but the accumulation of immunosuppressive/protumorigenic myeloid-derived suppressor cells (MDSCs) is thought to be a prominent mechanism contributing to immunologic tolerance of malignant cells in epithelial ovarian cancer (EOC). To this end, we hypothesized genetic variation in MDSC pathway genes would be associated with survival after EOC diagnoses. Methods: We measured the hazard of death due to EOC within 10 years of diagnosis, overall and by invasive subtype, attributable to SNPs in 24 genes relevant in the MDSC pathway in 10,751 women diagnosed with invasive EOC. Versatile Gene-based Association Study and the admixture likelihood method were used to test gene and pathway associations with survival. Results: We did not identify individual SNPs that were significantly associated with survival after correction for multiple testing (P < 3.5 × 10-5), nor did we identify significant associations between the MDSC pathway overall, or the 24 individual genes and EOC survival. Conclusions: In this well-powered analysis, we observed no evidence that inherited variations in MDSC-associated SNPs, individual genes, or the collective genetic pathway contributed to EOC survival outcomes. Impact: Common inherited variation in genes relevant to MDSCs was not associated with survival in women diagnosed with invasive EOC.

Published
2017

23. Use of common analgesic medications and ovarian cancer survival: Results from a pooled analysis in the Ovarian Cancer Association Consortium

Author

Dixon-Suen, Suzanne, Nagle, CM, Wentzensen, N, Trabert, B, Beeghly-Fadiel, A, Schildkraut, JM, Moysich, KB, DeFazio, A, Risch, HA, Rossing, MA, Doherty, JA, Wicklund, KG, Goodman, MT, Modugno, F, Ness, RB, Edwards, RP, Jensen, A, Kjær, SK, Høgdall, E, Berchuck, A, Cramer, DW, Terry, KL, Poole, EM, Bandera, EV, Paddock, LE, Anton-Culver, H, Ziogas, A, Menon, U, Gayther, SA, Ramus, SJ, Gentry-Maharaj, A, Pearce, CL, Wu, AH, Pike, MC, Webb, PM, Dixon-Suen, Suzanne, Nagle, CM, Wentzensen, N, Trabert, B, Beeghly-Fadiel, A, Schildkraut, JM, Moysich, KB, DeFazio, A, Risch, HA, Rossing, MA, Doherty, JA, Wicklund, KG, Goodman, MT, Modugno, F, Ness, RB, Edwards, RP, Jensen, A, Kjær, SK, Høgdall, E, Berchuck, A, Cramer, DW, Terry, KL, Poole, EM, Bandera, EV, Paddock, LE, Anton-Culver, H, Ziogas, A, Menon, U, Gayther, SA, Ramus, SJ, Gentry-Maharaj, A, Pearce, CL, Wu, AH, Pike, MC, and Webb, PM

Published
2017

24. History of thyroid disease and survival of ovarian cancer patients: results from the Ovarian Cancer Association Consortium, a brief report.

Author

Minlikeeva, AN, Freudenheim, JL, Cannioto, RA, Eng, KH, Szender, JB, Mayor, P, Etter, JL, Cramer, DW, Diergaarde, B, Doherty, JA, Dörk, T, Edwards, R, deFazio, A, Friel, G, Goodman, MT, Hillemanns, P, Høgdall, E, Jensen, A, Jordan, SJ, Karlan, BY, Kjær, SK, Klapdor, R, Matsuo, K, Mizuno, M, Nagle, CM, Odunsi, K, Paddock, L, Rossing, MA, Schildkraut, JM, Schmalfeldt, B, Segal, BH, Starbuck, K, Terry, KL, Webb, PM, Zsiros, E, Ness, RB, Modugno, F, Bandera, EV, Chang-Claude, J, Moysich, KB, Minlikeeva, AN, Freudenheim, JL, Cannioto, RA, Eng, KH, Szender, JB, Mayor, P, Etter, JL, Cramer, DW, Diergaarde, B, Doherty, JA, Dörk, T, Edwards, R, deFazio, A, Friel, G, Goodman, MT, Hillemanns, P, Høgdall, E, Jensen, A, Jordan, SJ, Karlan, BY, Kjær, SK, Klapdor, R, Matsuo, K, Mizuno, M, Nagle, CM, Odunsi, K, Paddock, L, Rossing, MA, Schildkraut, JM, Schmalfeldt, B, Segal, BH, Starbuck, K, Terry, KL, Webb, PM, Zsiros, E, Ness, RB, Modugno, F, Bandera, EV, Chang-Claude, J, and Moysich, KB

Abstract

BACKGROUND: Findings from in vitro studies suggest that increased exposure to thyroid hormones can influence progression of ovarian tumours. However, epidemiologic evidence on this topic is limited. METHODS: We pooled data from 11 studies from the Ovarian Cancer Association Consortium. Using multivariate Cox proportional hazards models, we estimated associations between hyper- and hypothyroidism and medications prescribed for these conditions with 5-year all-cause survival among women diagnosed with invasive ovarian cancer. RESULTS: Overall, there was a nonsignificant association with history of hyperthyroidism (n=160 cases) and mortality (HR=1.22; 95% CI=0.97-1.53). Furthermore, diagnosis of hyperthyroidism within the 5 years before ovarian cancer diagnosis was associated with an increased risk of death (HR=1.94; 95% CI=1.19-3.18). A more modest association was observed with history of hypothyroidism (n=624 cases) and mortality (HR=1.16; 95% CI=1.03-1.31). Neither duration of hypothyroidism nor use of thyroid medications was associated with survival. CONCLUSIONS: In this large study of women with ovarian cancer, we found that recent history of hyperthyroidism and overall history of hypothyroidism were associated with worse 5-year survival.

Published
2017

25. Enrichment of putative PAX8 target genes at serous epithelial ovarian cancer susceptibility loci

Author

Kar, SP, Adler, E, Tyrer, J, Hazelett, D, Anton-Culver, H, Bandera, EV, Beckmann, MW, Berchuck, A, Bogdanova, N, Brinton, L, Butzow, R, Campbell, I, Carty, K, Chang-Claude, J, Cook, LS, Cramer, DW, Cunningham, JM, Dansonka-Mieszkowska, A, Doherty, JA, Doerk, T, Duerst, M, Eccles, D, Fasching, PA, Flanagan, J, Gentry-Maharaj, A, Glasspool, R, Goode, EL, Goodman, MT, Gronwald, J, Heitz, F, Hildebrandt, MAT, Hogdall, E, Hogdall, CK, Huntsman, DG, Jensen, A, Karlan, BY, Kelemen, LE, Kiemeney, LA, Kjaer, SK, Kupryjanczyk, J, Lambrechts, D, Levine, DA, Li, Q, Lissowska, J, Lu, KH, Lubinski, J, Massuger, LFAG, McGuire, V, McNeish, I, Menon, U, Modugno, F, Monteiro, AN, Moysich, KB, Ness, RB, Nevanlinna, H, Paul, J, Pearce, CL, Pejovic, T, Permuth, JB, Phelan, C, Pike, MC, Poole, EM, Ramus, SJ, Risch, HA, Rossing, MA, Salvesen, HB, Schildkraut, JM, Sellers, TA, Sherman, M, Siddiqui, N, Sieh, W, Song, H, Southey, M, Terry, KL, Tworoger, SS, Walsh, C, Wentzensen, N, Whittemore, AS, Wu, AH, Yang, H, Zheng, W, Ziogas, A, Freedman, ML, Gayther, SA, Pharoah, PDP, Lawrenson, K, Kar, SP, Adler, E, Tyrer, J, Hazelett, D, Anton-Culver, H, Bandera, EV, Beckmann, MW, Berchuck, A, Bogdanova, N, Brinton, L, Butzow, R, Campbell, I, Carty, K, Chang-Claude, J, Cook, LS, Cramer, DW, Cunningham, JM, Dansonka-Mieszkowska, A, Doherty, JA, Doerk, T, Duerst, M, Eccles, D, Fasching, PA, Flanagan, J, Gentry-Maharaj, A, Glasspool, R, Goode, EL, Goodman, MT, Gronwald, J, Heitz, F, Hildebrandt, MAT, Hogdall, E, Hogdall, CK, Huntsman, DG, Jensen, A, Karlan, BY, Kelemen, LE, Kiemeney, LA, Kjaer, SK, Kupryjanczyk, J, Lambrechts, D, Levine, DA, Li, Q, Lissowska, J, Lu, KH, Lubinski, J, Massuger, LFAG, McGuire, V, McNeish, I, Menon, U, Modugno, F, Monteiro, AN, Moysich, KB, Ness, RB, Nevanlinna, H, Paul, J, Pearce, CL, Pejovic, T, Permuth, JB, Phelan, C, Pike, MC, Poole, EM, Ramus, SJ, Risch, HA, Rossing, MA, Salvesen, HB, Schildkraut, JM, Sellers, TA, Sherman, M, Siddiqui, N, Sieh, W, Song, H, Southey, M, Terry, KL, Tworoger, SS, Walsh, C, Wentzensen, N, Whittemore, AS, Wu, AH, Yang, H, Zheng, W, Ziogas, A, Freedman, ML, Gayther, SA, Pharoah, PDP, and Lawrenson, K

Abstract

BACKGROUND: Genome-wide association studies (GWAS) have identified 18 loci associated with serous ovarian cancer (SOC) susceptibility but the biological mechanisms driving these findings remain poorly characterised. Germline cancer risk loci may be enriched for target genes of transcription factors (TFs) critical to somatic tumorigenesis. METHODS: All 615 TF-target sets from the Molecular Signatures Database were evaluated using gene set enrichment analysis (GSEA) and three GWAS for SOC risk: discovery (2196 cases/4396 controls), replication (7035 cases/21 693 controls; independent from discovery), and combined (9627 cases/30 845 controls; including additional individuals). RESULTS: The PAX8-target gene set was ranked 1/615 in the discovery (PGSEA<0.001; FDR=0.21), 7/615 in the replication (PGSEA=0.004; FDR=0.37), and 1/615 in the combined (PGSEA<0.001; FDR=0.21) studies. Adding other genes reported to interact with PAX8 in the literature to the PAX8-target set and applying an alternative to GSEA, interval enrichment, further confirmed this association (P=0.006). Fifteen of the 157 genes from this expanded PAX8 pathway were near eight loci associated with SOC risk at P<10-5 (including six with P<5 × 10-8). The pathway was also associated with differential gene expression after shRNA-mediated silencing of PAX8 in HeyA8 (PGSEA=0.025) and IGROV1 (PGSEA=0.004) SOC cells and several PAX8 targets near SOC risk loci demonstrated in vitro transcriptomic perturbation. CONCLUSIONS: Putative PAX8 target genes are enriched for common SOC risk variants. This finding from our agnostic evaluation is of particular interest given that PAX8 is well-established as a specific marker for the cell of origin of SOC.

Published
2017

26. Correlates of circulating ovarian cancer early detection markers and their contribution to discrimination of early detection models: results from the EPIC cohort

Author

Fortner, RT, Vitonis, AF, Schock, H, Huesing, A, Johnson, T, Fichorova, RN, Fashemi, T, Yamamoto, HS, Tjonneland, A, Hansen, L, Overvad, K, Boutron-Ruault, M-C, Kvaskoff, M, Severi, G, Boeing, H, Trichopoulou, A, Benetou, V, La Vecchia, C, Palli, D, Sieri, S, Tumino, R, Matullo, G, Mattiello, A, Onland-Moret, NC, Peeters, PH, Weiderpass, E, Gram, IT, Jareid, M, Ramon Quiros, J, Duell, EJ, Sanchez, M-J, Dolores Chirlaque, M, Ardanaz, E, Larranaga, N, Nodin, B, Brandstedt, J, Idahl, A, Khaw, K-T, Allen, N, Gunter, M, Johansson, M, Dossus, L, Merritt, MA, Riboli, E, Cramer, DW, Kaaks, R, Terry, KL, Fortner, RT, Vitonis, AF, Schock, H, Huesing, A, Johnson, T, Fichorova, RN, Fashemi, T, Yamamoto, HS, Tjonneland, A, Hansen, L, Overvad, K, Boutron-Ruault, M-C, Kvaskoff, M, Severi, G, Boeing, H, Trichopoulou, A, Benetou, V, La Vecchia, C, Palli, D, Sieri, S, Tumino, R, Matullo, G, Mattiello, A, Onland-Moret, NC, Peeters, PH, Weiderpass, E, Gram, IT, Jareid, M, Ramon Quiros, J, Duell, EJ, Sanchez, M-J, Dolores Chirlaque, M, Ardanaz, E, Larranaga, N, Nodin, B, Brandstedt, J, Idahl, A, Khaw, K-T, Allen, N, Gunter, M, Johansson, M, Dossus, L, Merritt, MA, Riboli, E, Cramer, DW, Kaaks, R, and Terry, KL

Abstract

BACKGROUND: Ovarian cancer early detection markers CA125, CA15.3, HE4, and CA72.4 vary between healthy women, limiting their utility for screening. METHODS: We evaluated cross-sectional relationships between lifestyle and reproductive factors and these markers among controls (n = 1910) from a nested case-control study in the European Prospective Investigation into Cancer and Nutrition (EPIC). Improvements in discrimination of prediction models adjusting for correlates of the markers were evaluated among postmenopausal women in the nested case-control study (n = 590 cases). Generalized linear models were used to calculate geometric means of CA125, CA15.3, and HE4. CA72.4 above vs. below limit of detection was evaluated using logistic regression. Early detection prediction was modeled using conditional logistic regression. RESULTS: CA125 concentrations were lower, and CA15.3 higher, in post- vs. premenopausal women (p ≤ 0.02). Among postmenopausal women, CA125 was higher among women with higher parity and older age at menopause (ptrend ≤ 0.02), but lower among women reporting oophorectomy, hysterectomy, ever use of estrogen-only hormone therapy, or current smoking (p < 0.01). CA15.3 concentrations were higher among heavier women and in former smokers (p ≤ 0.03). HE4 was higher with older age at blood collection and in current smokers, and inversely associated with OC use duration, parity, and older age at menopause (≤ 0.02). No associations were observed with CA72.4. Adjusting for correlates of the markers in prediction models did not improve the discrimination. CONCLUSIONS: This study provides insights into sources of variation in ovarian cancer early detection markers in healthy women and informs about the utility of individualizing marker cutpoints based on epidemiologic factors.

Published
2017

27. Cigarette smoking is associated with adverse survival among women with ovarian cancer: Results from a pooled analysis of 19 studies

Author

Praestegaard, C, Jensen, A, Jensen, SM, Nielsen, TSS, Webb, PM, Nagle, CM, DeFazio, A, Hogdall, E, Rossing, MA, Doherty, JA, Wicklund, KG, Goodman, MT, Modugno, F, Moysich, K, Ness, RB, Edwards, R, Matsuo, K, Hosono, S, Goode, EL, Winham, SJ, Fridley, BL, Cramer, DW, Terry, KL, Schildkraut, JM, Berchuck, A, Bandera, EV, Paddock, LE, Massuger, LF, Wentzensen, N, Pharoah, P, Song, H, Whittemore, A, McGuire, V, Sieh, W, Rothstein, J, Anton-Culver, H, Ziogas, A, Menon, U, Gayther, SA, Ramus, SJ, Gentry-Maharaj, A, Wu, AH, Pearce, CL, Pike, M, Lee, AW, Sutphen, R, Chang-Claude, J, Risch, HA, Kjaer, SK, Praestegaard, C, Jensen, A, Jensen, SM, Nielsen, TSS, Webb, PM, Nagle, CM, DeFazio, A, Hogdall, E, Rossing, MA, Doherty, JA, Wicklund, KG, Goodman, MT, Modugno, F, Moysich, K, Ness, RB, Edwards, R, Matsuo, K, Hosono, S, Goode, EL, Winham, SJ, Fridley, BL, Cramer, DW, Terry, KL, Schildkraut, JM, Berchuck, A, Bandera, EV, Paddock, LE, Massuger, LF, Wentzensen, N, Pharoah, P, Song, H, Whittemore, A, McGuire, V, Sieh, W, Rothstein, J, Anton-Culver, H, Ziogas, A, Menon, U, Gayther, SA, Ramus, SJ, Gentry-Maharaj, A, Wu, AH, Pearce, CL, Pike, M, Lee, AW, Sutphen, R, Chang-Claude, J, Risch, HA, and Kjaer, SK

Abstract

Cigarette smoking is associated with an increased risk of developing mucinous ovarian tumors but whether it is associated with ovarian cancer survival overall or for the different histotypes is unestablished. Furthermore, it is unknown whether the association between cigarette smoking and survival differs according to strata of ovarian cancer stage at diagnosis. In a large pooled analysis, we evaluated the association between various measures of cigarette smoking and survival among women with epithelial ovarian cancer. We obtained data from 19 case-control studies in the Ovarian Cancer Association Consortium (OCAC), including 9,114 women diagnosed with ovarian cancer. Cox regression models were used to estimate adjusted study-specific hazard ratios (HRs), which were combined into pooled hazard ratios (pHR) with corresponding 95% confidence intervals (CIs) under random effects models. Overall, 5,149 (57%) women died during a median follow-up period of 7.0 years. Among women diagnosed with ovarian cancer, both current (pHR = 1.17, 95% CI: 1.08-1.28) and former smokers (pHR = 1.10, 95% CI: 1.02-1.18) had worse survival compared with never smoking women. In histotype-stratified analyses, associations were observed for mucinous (current smoking: pHR = 1.91, 95% CI: 1.01-3.65) and serous histotypes (current smoking: pHR = 1.11, 95% CI: 1.00-1.23; former smoking: pHR = 1.12, 95% CI: 1.04-1.20). Further, our results suggested that current smoking has a greater impact on survival among women with localized than disseminated disease. The identification of cigarette smoking as a modifiable factor associated with survival has potential clinical importance as a focus area to improve ovarian cancer prognosis.

Published
2017

28. Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus

Author

Lawrenson, K, Kar, S, McCue, K, Kuchenbaeker, K, Michailidou, K, Tyrer, J, Beesley, J, Ramus, SJ, Li, Q, Delgado, MK, Lee, JM, Aittomäki, K, Andrulis, IL, Anton-Culver, H, Arndt, V, Arun, BK, Arver, B, Bandera, EV, Barile, M, Barkardottir, RB, Barrowdale, D, Beckmann, MW, Benitez, J, Berchuck, A, Bisogna, M, Bjorge, L, Blomqvist, C, Blot, W, Bogdanova, N, Bojesen, A, Bojesen, SE, Bolla, MK, Bonanni, B, Børresen-Dale, AL, Brauch, H, Brennan, P, Brenner, H, Bruinsma, F, Brunet, J, Buhari, SA, Burwinkel, B, Butzow, R, Buys, SS, Cai, Q, Caldes, T, Campbell, I, Canniotto, R, Chang-Claude, J, Chiquette, J, Choi, JY, Claes, KBM, Cook, LS, Cox, A, Cramer, DW, Cross, SS, Cybulski, C, Czene, K, Daly, MB, Damiola, F, Dansonka-Mieszkowska, A, Darabi, H, Dennis, J, Devilee, P, Diez, O, Doherty, JA, Domchek, SM, Dorfling, CM, Dörk, T, Dumont, M, Ehrencrona, H, Ejlertsen, B, Ellis, S, Engel, C, Lee, E, Evans, DG, Fasching, PA, Feliubadalo, L, Figueroa, J, and Flesch-Janys, D

Abstract

© 2016 The Author(s). A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10-20), ER-negative BC (P=1.1 × 10-13), BRCA1-associated BC (P=7.7 × 10-16) and triple negative BC (P-diff=2 × 10-5). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10-3) and ABHD8 (P

Published
2016

29. Genome-wide meta-analyses of breast, ovarian, and prostate cancer association studies identify multiple new susceptibility loci shared by at least two cancer types

Author

Kar, SP, Beesley, J, Al Olama, AA, Michailidou, K, Tyrer, J, Kote-Jarai, ZA, Lawrenson, K, Lindstrom, S, Ramus, SJ, Thompson, DJ, Kibel, AS, Dansonka-Mieszkowska, A, Michael, A, Dieffenbach, AK, Gentry-Maharaj, A, Whittemore, AS, Wolk, A, Monteiro, A, Peixoto, A, Kierzek, A, Cox, A, Rudolph, A, Gonzalez-Neira, A, Wu, AH, Lindblom, A, Swerdlow, A, Ziogas, A, Ekici, AB, Burwinkel, B, Karlan, BY, Nordestgaard, BG, Blomqvist, C, Phelan, C, McLean, C, Pearce, CL, Vachon, C, Cybulski, C, Slavov, C, Stegmaier, C, Maier, C, Ambrosone, CB, Hogdall, CK, Teerlink, CC, Kang, D, Tessier, DC, Schaid, DJ, Stram, DO, Cramer, DW, Neal, DE, Eccles, D, Flesch-Janys, D, Velez Edwards, DR, Wokozorczyk, D, Levine, DA, Yannoukakos, D, Sawyer, EJ, Bandera, EV, Poole, EM, Goode, EL, Khusnutdinova, E, Hogdall, E, Song, F, Bruinsma, F, Heitz, F, Modugno, F, Hamdy, FC, Wiklund, F, Giles, GG, Olsson, H, Wildiers, H, and Ulmer, HU

Abstract

© 2016 American Association for Cancer Research. Breast, ovarian, and prostate cancers are hormone-related and may have a shared genetic basis, but this has not been investigated systematically by genome-wide association (GWA) studies. Meta-analyses combining the largest GWA meta-analysis data sets for these cancers totaling 112,349 cases and 116,421 controls of European ancestry, all together and in pairs, identified at P < 10−8 seven new cross-cancer loci: three associated with susceptibility to all three cancers (rs17041869/2q13/ BCL2L11; rs7937840/11q12/ INCENP; rs1469713/19p13/ GATAD2A), two breast and ovarian cancer risk loci (rs200182588/9q31/ SMC2; rs8037137/15q26/ RCCD1), and two breast and prostate cancer risk loci (rs5013329/1p34/ NSUN4; rs9375701/6q23/ L3MBTL3). Index variants in five additional regions previously associated with only one cancer also showed clear association with a second cancer type. Cell-type-specific expression quantitative trait locus and enhancer-gene interaction annotations suggested target genes with potential cross-cancer roles at the new loci. Pathway analysis revealed significant enrichment of death receptor signaling genes near loci with P < 10−5 in the three-cancer meta-analysis. SIGNIFICANCE: We demonstrate that combining large-scale GWA meta-analysis findings across cancer types can identify completely new risk loci common to breast, ovarian, and prostate cancers. We show that the identification of such cross-cancer risk loci has the potential to shed new light on the shared biology underlying these hormone-related cancers.

Published
2016

30. Inherited variants affecting RNA editing may contribute to ovarian cancer susceptibility: Results from a large-scale collaboration

Author

Permuth, JB, Reid, B, Earp, M, Chen, YA, Monteiro, ANA, Chen, Z, Chenevix-Trench, G, Fasching, PA, Beckmann, MW, Lambrechts, D, Vanderstichele, A, Van Niewenhuyse, E, Vergote, I, Rossing, MA, Doherty, JA, Chang-Claude, J, Moysich, K, Odunsi, K, Goodman, MT, Shvetsov, YB, Wilkens, LR, Thompson, PJ, Dörk, T, Bogdanova, N, Butzow, R, Nevanlinna, H, Pelttari, L, Leminen, A, Modugno, F, Edwards, RP, Ness, RB, Kelley, J, Heitz, F, Karlan, B, Lester, J, Kjaer, SK, Jensen, A, Giles, G, Hildebrandt, M, Liang, D, Lu, KH, Wu, X, Levine, DA, Bisogna, M, Berchuck, A, Cramer, DW, Terry, KL, Tworoger, SS, Poole, EM, Bandera, EV, Fridley, B, Cunningham, J, Winham, SJ, Olson, SH, Orlow, I, Bjorge, L, Kiemeney, LA, Massuger, L, Pejovic, T, Moffitt, M, Le, N, Cook, LS, Brooks-Wilson, A, Kelemen, LE, Gronwald, J, Lubinski, J, Wentzensen, N, Brinton, LA, Lissowska, J, Yang, H, Hogdall, E, Hogdall, C, Lundvall, L, Pharoah, PDP, Song, H, Campbell, I, Eccles, D, and McNeish, I

Abstract

RNA editing in mammals is a form of post-transcriptional modification in which adenosine is converted to inosine by the adenosine deaminases acting on RNA (ADAR) family of enzymes. Based on evidence of altered ADAR expression in epithelial ovarian cancers (EOC), we hypothesized that single nucleotide polymorphisms (SNPs) in ADAR genes modify EOC susceptibility, potentially by altering ovarian tissue gene expression. Using directly genotyped and imputed data from 10,891 invasive EOC cases and 21,693 controls, we evaluated the associations of 5,303 SNPs in ADAD1, ADAR, ADAR2, ADAR3, and SND1. Unconditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI), with adjustment for European ancestry. We conducted gene-level analyses using the Admixture Maximum Likelihood (AML) test and the Sequence-Kernel Association test for common and rare variants (SKAT-CR). Association analysis revealed top risk-associated SNP rs77027562 (OR (95% CI)= 1.39 (1.17-1.64), P=1.0x10-4) in ADAR3 and rs185455523 in SND1 (OR (95% CI)= 0.68 (0.56-0.83), P=2.0x10-4). When restricting to serous histology (n=6,500), the magnitude of association strengthened for rs185455523 (OR=0.60, P=1.0x10-4). Gene-level analyses revealed that variation in ADAR was associated (P

Published
2016

31. Assessment of variation in immunosuppressive pathway genes reveals TGFBR2 to be associated with risk of clear cell ovarian cancer

Author

Hampras, SS, Sucheston-Campbell, LE, Cannioto, R, Chang-Claude, J, Modugno, F, Dörk, T, Hillemanns, P, Preus, L, Knutson, KL, Wallace, PK, Hong, CC, Friel, G, Davis, W, Nesline, M, Pearce, CL, Kelemen, LE, Goodman, MT, Bandera, EV, Terry, KL, Schoof, N, Eng, KH, Clay, A, Singh, PK, Joseph, JM, Aben, KKH, Anton-Culver, H, Antonenkova, N, Baker, H, Bean, Y, Beckmann, MW, Bisogna, M, Bjorge, L, Bogdanova, N, Brinton, LA, Brooks-Wilson, A, Bruinsma, F, Butzow, R, Campbell, IG, Carty, K, Cook, LS, Cramer, DW, Cybulski, C, Dansonka-Mieszkowska, A, Dennis, J, Despierre, E, Dicks, E, Doherty, JA, du Bois, A, Dürst, M, Easton, D, Eccles, D, Edwards, RP, Ekici, AB, Fasching, PA, Fridley, BL, Gao, YT, Gentry-Maharaj, A, Giles, GG, Glasspool, R, Gronwald, J, Harrington, P, Harter, P, Hasmad, HN, Hein, A, Heitz, F, Hildebrandt, MAT, Hogdall, C, Hogdall, E, Hosono, S, Iversen, ES, Jakubowska, A, Jensen, A, Ji, BT, Karlan, BY, Kellar, M, Kelley, JL, Kiemeney, LA, Klapdor, R, Kolomeyevskaya, N, Krakstad, C, Kjaer, SK, Kruszka, B, Kupryjanczyk, J, Lambrechts, D, Lambrechts, S, Le, ND, Lee, AW, Lele, S, Leminen, A, Lester, J, Levine, DA, Liang, D, Lissowska, J, Liu, S, and Lu, K

Subjects
endocrine system diseases, female genital diseases and pregnancy complications
Abstract

Background: Regulatory T (Treg) cells, a subset of CD4+ T lymphocytes, are mediators of immunosuppression in cancer, and, thus, variants in genes encoding Treg cell immune molecules could be associated with ovarian cancer. Methods: In a population of 15,596 epithelial ovarian cancer (EOC) cases and 23,236 controls, we measured genetic associations of 1,351 SNPs in Treg cell pathway genes with odds of ovarian cancer and tested pathway and gene-level associations, overall and by histotype, for the 25 genes, using the admixture likelihood (AML) method. The most significant single SNP associations were tested for correlation with expression levels in 44 ovarian cancer patients. Results: The most significant global associations for all genes in the pathway were seen in endometrioid (p = 0.082) and clear cell (p = 0.083), with the most significant gene level association seen with TGFBR2 (p = 0.001) and clear cell EOC. Gene associations with histotypes at p < 0.05 included: IL12 (p = 0.005 and p = 0.008, serous and high-grade serous, respectively), IL8RA (p = 0.035, endometrioid and mucinous), LGALS1 (p = 0.03, mucinous), STAT5B (p = 0.022, clear cell), TGFBR1 (p = 0.021 endometrioid) and TGFBR2 (p = 0.017 and p = 0.025, endometrioid and mucinous, respectively). Conclusions: Common inherited gene variation in Treg cell pathways shows some evidence of germline genetic contribution to odds of EOC that varies by histologic subtype and may be associated with mRNA expression of immune-complex receptor in EOC patients.

Published
2016

32. Corrigendum: Common variants at 19p13 are associated with susceptibility to ovarian cancer

Author

Bolton, KL, Tyrer, J, Song, H, Ramus, SJ, Notaridou, M, Jones, C, Sher, T, Gentry-Maharaj, A, Wozniak, E, Tsai, Y-Y, Weidhaas, J, Paik, D, Van Den Berg, DJ, Stram, DO, Pearce, CL, Wu, AH, Brewster, W, Anton-Culver, H, Ziogas, A, Narod, SA, Levine, DA, Kaye, SB, Brown, R, Paul, J, Flanagan, J, Sieh, W, McGuire, V, Whittemore, AS, Campbell, I, Gore, ME, Lissowska, J, Yang, HP, Medrek, K, Gronwald, J, Lubinski, J, Jakubowska, A, Le, ND, Cook, LS, Kelemen, LE, Brooks-Wilson, A, Massuger, LFAG, Kiemeney, LA, Aben, KKH, van Altena, AM, Houlston, R, Tomlinson, I, Palmieri, RT, Moorman, PG, Schildkraut, J, Iversen, ES, Phelan, C, Vierkant, RA, Cunningham, JM, Goode, EL, Fridley, BL, Kruger-Kjaer, S, Blaeker, J, Hogdall, E, Hogdall, C, Gross, J, Karlan, BY, Ness, RB, Edwards, RP, Odunsi, K, Moyisch, KB, Baker, JA, Modugno, F, Heikkinenen, T, Butzow, R, Nevanlinna, H, Leminen, A, Bogdanova, N, Antonenkova, N, Doerk, T, Hillemanns, P, Dürst, M, Runnebaum, I, Thompson, PJ, Carney, ME, Goodman, MT, Lurie, G, Wang-Gohrke, S, Hein, R, Chang-Claude, J, Rossing, MA, Cushing-Haugen, KL, Doherty, J, Chen, C, Rafnar, T, Besenbacher, S, Sulem, P, Stefansson, K, Birrer, MJ, Terry, KL, Hernandez, D, Cramer, DW, Vergote, I, Amant, F, Lambrechts, D, Despierre, E, Fasching, PA, Beckmann, MW, Thiel, FC, Ekici, AB, Chen, X, Australian Ovarian Cancer Study Group, Johnatty, SE, Webb, PM, Beesley, J, Chanock, S, Garcia-Closas, M, Sellers, T, Easton, DF, Berchuck, A, Chenevix-Trench, G, Pharoah, PDP, and Gayther, SA

Subjects
Australian Ovarian Cancer Study Group
Published
2016

33. Cis-eQTL analysis and functional validation of candidate susceptibility genes for high-grade serous ovarian cancer

Author

Lawrenson, K, Li, Q, Kar, S, Seo, JH, Tyrer, J, Spindler, TJ, Lee, J, Chen, Y, Karst, A, Drapkin, R, Aben, KKH, Anton-Culver, H, Antonenkova, N, Baker, H, Bandera, EV, Bean, Y, Beckmann, MW, Berchuck, A, Bisogna, M, Bjorge, L, Bogdanova, N, Brinton, LA, Brooks-Wilson, A, Bruinsma, F, Butzow, R, Campbell, IG, Carty, K, Chang-Claude, J, Chenevix-Trench, G, Chen, A, Chen, Z, Cook, LS, Cramer, DW, Cunningham, JM, Cybulski, C, Dansonka-Mieszkowska, A, Dennis, J, Dicks, E, Doherty, JA, Dörk, T, Du Bois, A, Dürst, M, Eccles, D, Easton, DT, Edwards, RP, Eilber, U, Ekici, AB, Fasching, PA, Fridley, BL, Gao, YT, Gentry-Maharaj, A, Giles, GG, Glasspool, R, Goode, EL, Goodman, MT, Grownwald, J, Harrington, P, Harter, P, Hasmad, HN, Hein, A, Heitz, F, Hildebrandt, MAT, Hillemanns, P, Hogdall, E, Hogdall, C, Hosono, S, Iversen, ES, Jakubowska, A, James, P, Jensen, A, Ji, BT, Karlan, BY, Kjaer, SK, Kelemen, LE, Kellar, M, Kelley, JL, Kiemeney, LA, Krakstad, C, Kupryjanczyk, J, and Lambrechts, D

Abstract

© 2015 Macmillan Publishers Limited. All rights reserved. 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≤10-5). For three cis-eQTL associations (P

Published
2015

34. Cell-type-specific enrichment of risk-associated regulatory elements at ovarian cancer susceptibility loci

Author

Coetzee, SG, Shen, HC, Hazelett, DJ, Lawrenson, K, Kuchenbaecker, K, Tyrer, J, Rhie, SK, Levanon, K, Karst, A, Drapkin, R, Ramus, SJ, Couch, FJ, Offit, K, Chenevix-Trench, G, Monteiro, ANA, Antoniou, A, Freedman, M, Coetzee, GA, Pharoah, PDP, Noushmehr, H, Gayther, SA, Anton-Culver, H, Antonenkova, N, Baker, H, Bandera, EV, Bean, Y, Beckmann, MW, Berchuck, A, Bisogna, M, Bjorge, L, Bogdanova, N, Brinton, LA, Brooks-Wilson, A, Bruinsma, F, Butzow, R, Campbell, IG, Carty, K, Chang-Claude, J, Chen, A, Chen, Z, Cook, LS, Cramer, DW, Cunningham, JM, Cybulski, C, Dansonka-Mieszkowska, A, Dennis, J, Dicks, E, Doherty, JA, Dörk, T, Bois, AD, Dürst, M, Eccles, D, Easton, DF, Edwards, RP, Eilber, U, Ekici, AB, Fasching, PA, Fridley, BL, Gao, YT, Gentry-Maharaj, A, Giles, GG, Glasspool, R, Goode, EL, Goodman, MT, Grownwald, J, Harrington, P, Harter, P, Hasmad, HN, Hein, A, Heitz, F, Hildebrandt, MAT, Hillemanns, P, Hogdall, E, Hogdall, C, Hosono, S, Iversen, ES, Jakubowska, A, James, P, Jensen, A, Ji, BT, Karlan, BY, Kjaer, SK, Kelemen, LE, Kellar, M, Kelley, JL, Kiemeney, LA, Krakstad, C, Kupryjanczyk, J, Lambrechts, D, Lambrechts, S, Le, ND, Lele, S, Leminen, A, and Lester, J

Abstract

© The Author 2015. Published by Oxford University Press. All rights reserved. Understanding the regulatory landscape of the human genome is a central question in complex trait genetics. Most singlenucleotide polymorphisms (SNPs) associated with cancer risk lie in non-protein-coding regions, implicating regulatory DNA elements as functional targets of susceptibility variants. Here, we describe genome-wide annotation of regions of open chromatin and histone modification in fallopian tube and ovarian surface epithelial cells (FTSECs, OSECs), the debated cellular origins of high-grade serous ovarian cancers (HGSOCs) and in endometriosis epithelial cells (EECs), the likely precursor of clear cell ovarian carcinomas (CCOCs). The regulatory architecture of these cell types was compared with normal human mammary epithelial cells and LNCaP prostate cancer cells. We observed similar positional patterns of global enhancer signatures across the three different ovarian cancer precursor cell types, and evidence of tissue-specific regulatory signatures compared to nongynecological cell types. We found significant enrichment for risk-associated SNPs intersecting regulatory biofeatures at 17 known HGSOC susceptibility loci in FTSECs (P = 3.8 × 10-30), OSECs (P = 2.4 × 10-23) and HMECs (P = 6.7 × 10-15) but not for EECs (P = 0.45) or LNCaP cells (P = 0.88). Hierarchical clustering of risk SNPs conditioned on the six different cell types indicates FTSECs and OSECs are highly related (96% of samples using multi-scale bootstrapping) suggesting both cell types may be precursors of HGSOC. These data represent the first description of regulatory catalogues of normal precursor cells for different ovarian cancer subtypes, and provide unique insights into the tissue specific regulatory variation with respect to the likely functional targets of germline genetic susceptibility variants for ovarian cancer.

Published
2015

35. Common genetic variation in cellular transport genes and epithelial ovarian cancer (EOC) risk

Author

Chornokur, G, Lin, HY, Tyrer, JP, Lawrenson, K, Dennis, J, Amankwah, EK, Qu, X, Tsai, YY, Jim, HSL, Chen, Z, Chen, AY, Permuth-Wey, J, Aben, KKH, Anton-Culver, H, Antonenkova, N, Bruinsma, F, Bandera, EV, Bean, YT, Beckmann, MW, Bisogna, M, Bjorge, L, Bogdanova, N, Brinton, LA, Brooks-Wilson, A, Bunker, CH, Butzow, R, Campbell, IG, Carty, K, Chang-Claude, J, Cook, LS, Cramer, DW, Cunningham, JM, Cybulski, C, Dansonka-Mieszkowska, A, Du Bois, A, Despierre, E, Dicks, E, Doherty, JA, Dörk, T, Dürst, M, Easton, DF, Eccles, DM, Edwards, RP, Ekici, AB, Fasching, PA, Fridley, BL, Gao, YT, Gentry-Maharaj, A, Giles, GG, Glasspool, R, Goodman, MT, Gronwald, J, Harrington, P, Harter, P, Hein, A, Heitz, F, Hildebrandt, MAT, Hillemanns, P, Hogdall, CK, Hogdall, E, Hosono, S, Jakubowska, A, Jensen, A, Ji, BT, Karlan, BY, Kelemen, LE, Kellar, M, Kiemeney, LA, Krakstad, C, Kjaer, SK, Kupryjanczyk, J, Lambrechts, D, Lambrechts, S, Le, ND, Lee, AW, Lele, S, Leminen, A, and Lester, J

Abstract

© 2015 Chornokur et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Background: Defective cellular transport processes can lead to aberrant accumulation of trace elements, iron, small molecules and hormones in the cell, which in turn may promote the formation of reactive oxygen species, promoting DNA damage and aberrant expression of key regulatory cancer genes. As DNA damage and uncontrolled proliferation are hallmarks of cancer, including epithelial ovarian cancer (EOC), we hypothesized that inherited variation in the cellular transport genes contributes to EOC risk. Methods: In total, DNA samples were obtained from 14,525 case subjects with invasive EOC and from 23,447 controls from 43 sites in the Ovarian Cancer Association Consortium (OCAC). Two hundred seventy nine SNPs, representing 131 genes, were genotyped using an Illumina Infinium iSelect BeadChip as part of the Collaborative Oncological Gene-environment Study (COGS). SNP analyses were conducted using unconditional logistic regression under a log-additive model, and the FDR q-4). Conclusion: These results, generated on a large cohort of women, revealed associations between inherited cellular transport gene variants and risk of EOC histologic subtypes.

Published
2015

36. Genome-wide significant risk associations for mucinous ovarian carcinoma

Author

Kelemen, LE, Lawrenson, K, Tyrer, J, Li, Q, Lee, JM, Seo, JH, Phelan, CM, Beesley, J, Chen, X, Spindler, TJ, Aben, KKH, Anton-Culver, H, Antonenkova, N, Baker, H, Bandera, EV, Bean, Y, Beckmann, MW, Bisogna, M, Bjorge, L, Bogdanova, N, Brinton, LA, Brooks-Wilson, A, Bruinsma, F, Butzow, R, Campbell, IG, Carty, K, Chang-Claude, J, Chen, YA, Chen, Z, Cook, LS, Cramer, DW, Cunningham, JM, Cybulski, C, Dansonka-Mieszkowska, A, Dennis, J, Dicks, E, Doherty, JA, Dörk, T, Bois, AD, Dürst, M, Eccles, D, Easton, DT, Edwards, RP, Eilber, U, Ekici, AB, Engelholm, SA, Fasching, PA, Fridley, BL, Gao, YT, Gentry-Maharaj, A, Giles, GG, Glasspool, R, Goode, EL, Goodman, MT, Grownwald, J, Harrington, P, Harter, P, Hasmad, HN, Hein, A, Heitz, F, Hildebrandt, MAT, Hillemanns, P, Hogdall, E, Hogdall, C, Hosono, S, Iversen, ES, Jakubowska, A, Jensen, A, Ji, BT, Karlan, BY, Kellar, M, Kelley, JL, Kiemeney, LA, Krakstad, C, Kjaer, SK, Kupryjanczyk, J, Lambrechts, D, Lambrechts, S, and Le, ND

Abstract

© 2015 Nature America, Inc. All rights reserved. Genome-wide association studies have identified several risk associations for ovarian carcinomas but not for mucinous ovarian carcinomas (MOCs). Our analysis of 1,644 MOC cases and 21,693 controls with imputation identified 3 new risk associations: rs752590 at 2q13 (P = 3.3 × 10-8), rs711830 at 2q31.1 (P = 7.5 × 10-12) and rs688187 at 19q13.2 (P = 6.8 × 10-13). We identified significant expression quantitative trait locus (eQTL) associations for HOXD9 at 2q31.1 in ovarian (P = 4.95 × 10-4, false discovery rate (FDR) = 0.003) and colorectal (P = 0.01, FDR = 0.09) tumors and for PAX8 at 2q13 in colorectal tumors (P = 0.03, FDR = 0.09). Chromosome conformation capture analysis identified interactions between the HOXD9 promoter and risk-associated SNPs at 2q31.1. Overexpressing HOXD9 in MOC cells augmented the neoplastic phenotype. These findings provide the first evidence for MOC susceptibility variants and insights into the underlying biology of the disease.

Published
2015

37. Evaluating the ovarian cancer gonadotropin hypothesis: A candidate gene study

Author

Lee, AW, Tyrer, JP, Doherty, JA, Stram, DA, Kupryjanczyk, J, Dansonka-Mieszkowska, A, Plisiecka-Halasa, J, Spiewankiewicz, B, Myers, EJ, Chenevix-Trench, G, Fasching, PA, Beckmann, MW, Ekici, AB, Hein, A, Vergote, I, Van Nieuwenhuysen, E, Lambrechts, D, Wicklund, KG, Eilber, U, Wang-Gohrke, S, Chang-Claude, J, Rudolph, A, Sucheston-Campbell, L, Odunsi, K, Moysich, KB, Shvetsov, YB, Thompson, PJ, Goodman, MT, Wilkens, LR, Dörk, T, Hillemanns, P, Dürst, M, Runnebaum, IB, Bogdanova, N, Pelttari, LM, Nevanlinna, H, Leminen, A, Edwards, RP, Kelley, JL, Harter, P, Schwaab, I, Heitz, F, Du Bois, A, Orsulic, S, Lester, J, Walsh, C, Karlan, BY, Hogdall, E, Kjaer, SK, Jensen, A, Vierkant, RA, Cunningham, JM, Goode, EL, Fridley, BL, Southey, MC, Giles, GG, Bruinsma, F, Wu, X, Hildebrandt, MAT, Lu, K, Liang, D, Bisogna, M, Levine, DA, Weber, RP, Schildkraut, JM, Iversen, ES, Berchuck, A, Terry, KL, Cramer, DW, Tworoger, SS, Poole, EM, Olson, SH, Orlow, I, Bandera, EV, Bjorge, L, Tangen, IL, Salvesen, HB, Krakstad, C, and Massuger, LFAG

Subjects
endocrine system
Abstract

© 2014 Elsevier Inc. All rights reserved. Objective: Ovarian cancer is a hormone-related disease with a strong genetic basis. However, none of its high-penetrance susceptibility genes and GWAS-identified variants to date are known to be involved in hormonal pathways. Given the hypothesized etiologic role of gonadotropins, an assessment of how variability in genes involved in the gonadotropin signaling pathway impacts disease risk is warranted. Methods: Genetic data from 41 ovarian cancer study sites were pooled and unconditional logistic regression was used to evaluate whether any of the 2185 SNPs from 11 gonadotropin signaling pathway genes was associated with ovarian cancer risk. A burden test using the admixture likelihood (AML) method was also used to evaluate gene-level associations. Results: We did not find any genome-wide significant associations between individual SNPs and ovarian cancer risk. However, there was some suggestion of gene-level associations for four gonadotropin signaling pathway genes: INHBB (p = 0.045, mucinous), LHCGR (p = 0.046, high-grade serous), GNRH (p = 0.041, high-grade serous), and FSHB (p = 0.036, overall invasive). There was also suggestive evidence for INHA (p = 0.060, overall invasive). Conclusions: Ovarian cancer studies have limited sample numbers, thus fewer genome-wide susceptibility alleles, with only modest associations, have been identified relative to breast and prostate cancers. We have evaluated the majority of ovarian cancer studies with biological samples, to our knowledge, leaving no opportunity for replication. Using both our understanding of biology and powerful gene-level tests, we have identified four putative ovarian cancer loci near INHBB, LHCGR, GNRH, and FSHB that warrant a second look if larger sample sizes and denser genotype chips become available.

Published
2015

38. Adult body mass index and risk of ovarian cancer by subtype: A Mendelian randomization study

Author

Dixon-Suen, Suzanne, Nagle, CM, Thrift, AP, Pharoah, PDP, Pearce, CL, Zheng, W, Painter, JN, Chenevix-Trench, G, Fasching, PA, Beckmann, MW, Lambrechts, D, Vergote, I, Lambrechts, S, Van Nieuwenhuysen, E, Rossing, MA, Doherty, JA, GWicklund, K, Chang-Claude, J, Rudolph, A, Moysich, KB, Odunsi, K, Goodman, MT, Wilkens, LR, Thompson, PJ, Shvetsov, YB, Dörk, T, Park-Simon, TW, Hillemanns, P, Bogdanova, N, Butzow, R, Nevanlinna, H, Pelttari, LM, Leminen, A, Modugno, F, Ness, RB, Edwards, RP, Kelley, JL, Heitz, F, Karlan, BY, Kjær, SK, Høgdall, E, Jensen, A, Goode, EL, Fridley, BL, Cunningham, JM, Winham, SJ, Giles, GG, Bruinsma, F, Milne, RL, Southey, MC, Hildebrandt, MAT, Wu, X, Lu, KH, Liang, D, Levine, DA, Bisogna, M, Schildkraut, JM, Berchuck, A, Cramer, DW, Terry, KL, Bandera, EV, Olson, SH, Salvesen, HB, Thomsen, LC, Kopperud, RK, Bjorge, L, Kiemeney, LA, Massuger, LFAG, Pejovic, T, Cook, LS, Le, ND, Swenerton, KD, Brooks-Wilson, A, Kelemen, LE, Lubiński, J, Huzarski, T, Gronwald, J, Menkiszak, J, Wentzensen, N, Brinton, L, Yang, H, Lissowska, J, Høgdall, CK, Lundvall, L, Song, H, Tyrer, JP, Campbell, I, Eccles, D, Paul, J, Glasspool, R, Siddiqui, N, Whittemore, AS, Sieh, W, McGuire, V, Rothstein, JH, Narod, SA, Phelan, C, Risch, HA, McLaughlin, JR, Anton-Culver, H, Dixon-Suen, Suzanne, Nagle, CM, Thrift, AP, Pharoah, PDP, Pearce, CL, Zheng, W, Painter, JN, Chenevix-Trench, G, Fasching, PA, Beckmann, MW, Lambrechts, D, Vergote, I, Lambrechts, S, Van Nieuwenhuysen, E, Rossing, MA, Doherty, JA, GWicklund, K, Chang-Claude, J, Rudolph, A, Moysich, KB, Odunsi, K, Goodman, MT, Wilkens, LR, Thompson, PJ, Shvetsov, YB, Dörk, T, Park-Simon, TW, Hillemanns, P, Bogdanova, N, Butzow, R, Nevanlinna, H, Pelttari, LM, Leminen, A, Modugno, F, Ness, RB, Edwards, RP, Kelley, JL, Heitz, F, Karlan, BY, Kjær, SK, Høgdall, E, Jensen, A, Goode, EL, Fridley, BL, Cunningham, JM, Winham, SJ, Giles, GG, Bruinsma, F, Milne, RL, Southey, MC, Hildebrandt, MAT, Wu, X, Lu, KH, Liang, D, Levine, DA, Bisogna, M, Schildkraut, JM, Berchuck, A, Cramer, DW, Terry, KL, Bandera, EV, Olson, SH, Salvesen, HB, Thomsen, LC, Kopperud, RK, Bjorge, L, Kiemeney, LA, Massuger, LFAG, Pejovic, T, Cook, LS, Le, ND, Swenerton, KD, Brooks-Wilson, A, Kelemen, LE, Lubiński, J, Huzarski, T, Gronwald, J, Menkiszak, J, Wentzensen, N, Brinton, L, Yang, H, Lissowska, J, Høgdall, CK, Lundvall, L, Song, H, Tyrer, JP, Campbell, I, Eccles, D, Paul, J, Glasspool, R, Siddiqui, N, Whittemore, AS, Sieh, W, McGuire, V, Rothstein, JH, Narod, SA, Phelan, C, Risch, HA, McLaughlin, JR, and Anton-Culver, H

Published
2016

39. Recreational physical inactivity and mortality in women with invasive epithelial ovarian cancer: evidence from the Ovarian Cancer Association Consortium.

Author

Cannioto, RA, LaMonte, MJ, Kelemen, LE, Risch, HA, Eng, KH, Minlikeeva, AN, Hong, C-C, Szender, JB, Sucheston-Campbell, L, Joseph, JM, Berchuck, A, Chang-Claude, J, Cramer, DW, DeFazio, A, Diergaarde, B, Dörk, T, Doherty, JA, Edwards, RP, Fridley, BL, Friel, G, Goode, EL, Goodman, MT, Hillemanns, P, Hogdall, E, Hosono, S, Kelley, JL, Kjaer, SK, Klapdor, R, Matsuo, K, Odunsi, K, Nagle, CM, Olsen, CM, Paddock, LE, Pearce, CL, Pike, MC, Rossing, MA, Schmalfeldt, B, Segal, BH, Szamreta, EA, Thompson, PJ, Tseng, C-C, Vierkant, R, Schildkraut, JM, Wentzensen, N, Wicklund, KG, Winham, SJ, Wu, AH, Modugno, F, Ness, RB, Jensen, A, Webb, PM, Terry, K, Bandera, EV, Moysich, KB, Cannioto, RA, LaMonte, MJ, Kelemen, LE, Risch, HA, Eng, KH, Minlikeeva, AN, Hong, C-C, Szender, JB, Sucheston-Campbell, L, Joseph, JM, Berchuck, A, Chang-Claude, J, Cramer, DW, DeFazio, A, Diergaarde, B, Dörk, T, Doherty, JA, Edwards, RP, Fridley, BL, Friel, G, Goode, EL, Goodman, MT, Hillemanns, P, Hogdall, E, Hosono, S, Kelley, JL, Kjaer, SK, Klapdor, R, Matsuo, K, Odunsi, K, Nagle, CM, Olsen, CM, Paddock, LE, Pearce, CL, Pike, MC, Rossing, MA, Schmalfeldt, B, Segal, BH, Szamreta, EA, Thompson, PJ, Tseng, C-C, Vierkant, R, Schildkraut, JM, Wentzensen, N, Wicklund, KG, Winham, SJ, Wu, AH, Modugno, F, Ness, RB, Jensen, A, Webb, PM, Terry, K, Bandera, EV, and Moysich, KB

Abstract

BACKGROUND: Little is known about modifiable behaviours that may be associated with epithelial ovarian cancer (EOC) survival. We conducted a pooled analysis of 12 studies from the Ovarian Cancer Association Consortium to investigate the association between pre-diagnostic physical inactivity and mortality. METHODS: Participants included 6806 women with a primary diagnosis of invasive EOC. In accordance with the Physical Activity Guidelines for Americans, women reporting no regular, weekly recreational physical activity were classified as inactive. We utilised Cox proportional hazard models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) representing the associations of inactivity with mortality censored at 5 years. RESULTS: In multivariate analysis, inactive women had significantly higher mortality risks, with (HR=1.34, 95% CI: 1.18-1.52) and without (HR=1.22, 95% CI: 1.12-1.33) further adjustment for residual disease, respectively. CONCLUSION: In this large pooled analysis, lack of recreational physical activity was associated with increased mortality among women with invasive EOC.

Published
2016

40. A splicing variant of TERT identified by GWAS interacts with menopausal estrogen therapy in risk of ovarian cancer

Author

Lee, AW, Bomkamp, A, Bandera, EV, Jensen, A, Ramus, SJ, Goodman, MT, Rossing, MA, Modugno, F, Moysich, KB, Chang-Claude, J, Rudolph, A, Gentry-Maharaj, A, Terry, KL, Gayther, SA, Cramer, DW, Doherty, JA, Schildkraut, JM, Kjaer, SK, Ness, RB, Menon, U, Berchuck, A, Mukherjee, B, Roman, L, Pharoah, PD, Chenevix-Trench, G, Olson, S, Hogdall, E, Wu, AH, Pike, MC, Stram, DO, Pearce, CL, Lee, AW, Bomkamp, A, Bandera, EV, Jensen, A, Ramus, SJ, Goodman, MT, Rossing, MA, Modugno, F, Moysich, KB, Chang-Claude, J, Rudolph, A, Gentry-Maharaj, A, Terry, KL, Gayther, SA, Cramer, DW, Doherty, JA, Schildkraut, JM, Kjaer, SK, Ness, RB, Menon, U, Berchuck, A, Mukherjee, B, Roman, L, Pharoah, PD, Chenevix-Trench, G, Olson, S, Hogdall, E, Wu, AH, Pike, MC, Stram, DO, and Pearce, CL

Abstract

Menopausal estrogen-alone therapy (ET) is a well-established risk factor for serous and endometrioid ovarian cancer. Genetics also plays a role in ovarian cancer, which is partly attributable to 18 confirmed ovarian cancer susceptibility loci identified by genome-wide association studies. The interplay among these loci, ET use and ovarian cancer risk has yet to be evaluated. We analyzed data from 1,414 serous cases, 337 endometrioid cases and 4,051 controls across 10 case-control studies participating in the Ovarian Cancer Association Consortium (OCAC). Conditional logistic regression was used to determine the association between the confirmed susceptibility variants and risk of serous and endometrioid ovarian cancer among ET users and non-users separately and to test for statistical interaction. A splicing variant in TERT, rs10069690, showed a statistically significant interaction with ET use for risk of serous ovarian cancer (pint = 0.013). ET users carrying the T allele had a 51% increased risk of disease (OR = 1.51, 95% CI 1.19-1.91), which was stronger for long-term ET users of 10+ years (OR = 1.85, 95% CI 1.28-2.66, pint = 0.034). Non-users showed essentially no association (OR = 1.08, 95% CI 0.96-1.21). Two additional genomic regions harboring rs7207826 (C allele) and rs56318008 (T allele) also had significant interactions with ET use for the endometrioid histotype (pint = 0.021 and pint = 0.037, respectively). Hence, three confirmed susceptibility variants were identified whose associations with ovarian cancer risk are modified by ET exposure; follow-up is warranted given that these interactions are not adjusted for multiple comparisons. These findings, if validated, may elucidate the mechanism of action of these loci.

Published
2016

41. PALB2, CHEK2 and ATM rare variants and cancer risk: data from COGS

Author

Southey, MC, Goldgar, DE, Winqvist, R, Pylkas, K, Couch, F, Tischkowitz, M, Foulkes, WD, Dennis, J, Michailidou, K, van Rensburg, EJ, Heikkinen, T, Nevanlinna, H, Hopper, JL, Doerk, T, Claes, KBM, Reis-Filho, J, Teo, ZL, Radice, P, Catucci, I, Peterlongo, P, Tsimiklis, H, Odefrey, FA, Dowty, JG, Schmidt, MK, Broeks, A, Hogervorst, FB, Verhoef, S, Carpenter, J, Clarke, C, Scott, RJ, Fasching, PA, Haeberle, L, Ekici, AB, Beckmann, MW, Peto, J, dos-Santos-Silva, I, Fletcher, O, Johnson, N, Bolla, MK, Sawyer, EJ, Tomlinson, I, Kerin, MJ, Miller, N, Marme, F, Burwinkel, B, Yang, R, Guenel, P, Therese, T, Menegaux, F, Sanchez, M, Bojesen, S, Nielsen, SF, Flyger, H, Benitez, J, Pilar Zamora, M, Arias Perez, JI, Menendez, P, Anton-Culver, H, Neuhausen, S, Ziogas, A, Clarke, CA, Brenner, H, Arndt, V, Stegmaier, C, Brauch, H, Bruening, T, Ko, Y-D, Muranen, TA, Aittomaki, K, Blomqvist, C, Bogdanova, NV, Antonenkova, NN, Lindblom, A, Margolin, S, Mannermaa, A, Kataja, V, Kosma, V-M, Hartikainen, JM, Spurdle, AB, Wauters, E, Smeets, D, Beuselinck, B, Floris, G, Chang-Claude, J, Rudolph, A, Seibold, P, Flesch-Janys, D, Olson, JE, Vachon, C, Pankratz, VS, McLean, C, Haiman, CA, Henderson, BE, Schumacher, F, Le Marchand, L, Kristensen, V, Alnaes, GG, Zheng, W, Hunter, DJ, Lindstrom, S, Hankinson, SE, Kraft, P, Andrulis, I, Knight, JA, Glendon, G, Mulligan, AM, Jukkola-Vuorinen, A, Grip, M, Kauppila, S, Devilee, P, Tollenaar, RAEM, Seynaeve, C, Hollestelle, A, Garcia-Closas, M, Figueroa, J, Chanock, SJ, Lissowska, J, Czene, K, Darabi, H, Eriksson, M, Eccles, DM, Rafiq, S, Tapper, WJ, Gerty, SM, Hooning, MJ, Martens, JWM, Collee, JM, Tilanus-Linthorst, M, Hall, P, Li, J, Brand, JS, Humphreys, K, Cox, A, Reed, MWR, Luccarini, C, Baynes, C, Dunning, AM, Hamann, U, Torres, D, Ulmer, HU, Ruediger, T, Jakubowska, A, Lubinski, J, Jaworska, K, Durda, K, Slager, S, Toland, AE, Ambrosone, CB, Yannoukakos, D, Swerdlow, A, Ashworth, A, Orr, N, Jones, M, Gonzalez-Neira, A, Pita, G, Rosario Alonso, M, Alvarez, N, Herrero, D, Tessier, DC, Vincent, D, Bacot, F, Simard, J, Dumont, M, Soucy, P, Eeles, R, Muir, K, Wiklund, F, Gronberg, H, Schleutker, J, Nordestgaard, BG, Weischer, M, Travis, RC, Neal, D, Donovan, JL, Hamdy, FC, Khaw, K-T, Stanford, JL, Blot, WJ, Thibodeau, S, Schaid, DJ, Kelley, JL, Maier, C, Kibel, AS, Cybulski, C, Cannon-Albright, L, Butterbach, K, Park, J, Kaneva, R, Batra, J, Teixeira, MR, Kote-Jarai, Z, Al Olama, AA, Benlloch, S, Renner, SP, Hartmann, A, Hein, A, Ruebner, M, Lambrechts, D, Van Nieuwenhuysen, E, Vergote, I, Lambretchs, S, Doherty, JA, Rossing, MA, Nickels, S, Eilber, U, Wang-Gohrke, S, Odunsi, K, Sucheston-Campbell, LE, Friel, G, Lurie, G, Killeen, JL, Wilkens, LR, Goodman, MT, Runnebaum, I, Hillemanns, PA, Pelttari, LM, Butzow, R, Modugno, F, Edwards, RP, Ness, RB, Moysich, KB, du Bois, A, Heitz, F, Harter, P, Kommoss, S, Karlan, BY, Walsh, C, Lester, J, Jensen, A, Kjaer, SK, Hogdall, E, Peissel, B, Bonanni, B, Bernard, L, Goode, EL, Fridley, BL, Vierkant, RA, Cunningham, JM, Larson, MC, Fogarty, ZC, Kalli, KR, Liang, D, Lu, KH, Hildebrandt, MAT, Wu, X, Levine, DA, Dao, F, Bisogna, M, Berchuck, A, Iversen, ES, Marks, JR, Akushevich, L, Cramer, DW, Schildkraut, J, Terry, KL, Poole, EM, Stampfer, M, Tworoger, SS, Bandera, EV, Orlow, I, Olson, SH, Bjorge, L, Salvesen, HB, van Altena, AM, Aben, KKH, Kiemeney, LA, Massuger, LFAG, Pejovic, T, Bean, Y, Brooks-Wilson, A, Kelemen, LE, Cook, LS, Le, ND, Grski, B, Gronwald, J, Menkiszak, J, Hogdall, CK, Lundvall, L, Nedergaard, L, Engelholm, SA, Dicks, E, Tyrer, J, Campbell, I, McNeish, I, Paul, J, Siddiqui, N, Glasspool, R, Whittemore, AS, Rothstein, JH, McGuire, V, Sieh, W, Cai, H, Shu, X-O, Teten, RT, Sutphen, R, McLaughlin, JR, Narod, SA, Phelan, CM, Monteiro, AN, Fenstermacher, D, Lin, H-Y, Permuth, JB, Sellers, TA, Chen, YA, Tsai, Y-Y, Chen, Z, Gentry-Maharaj, A, Gayther, SA, Ramus, SJ, Menon, U, Wu, AH, Pearce, CL, Van den Berg, D, Pike, MC, Dansonka-Mieszkowska, A, Plisiecka-Halasa, J, Moes-Sosnowska, J, Kupryjanczyk, J, Pharoah, PDP, Song, H, Winship, I, Chenevix-Trench, G, Giles, GG, Tavtigian, SV, Easton, DF, Milne, RL, Southey, MC, Goldgar, DE, Winqvist, R, Pylkas, K, Couch, F, Tischkowitz, M, Foulkes, WD, Dennis, J, Michailidou, K, van Rensburg, EJ, Heikkinen, T, Nevanlinna, H, Hopper, JL, Doerk, T, Claes, KBM, Reis-Filho, J, Teo, ZL, Radice, P, Catucci, I, Peterlongo, P, Tsimiklis, H, Odefrey, FA, Dowty, JG, Schmidt, MK, Broeks, A, Hogervorst, FB, Verhoef, S, Carpenter, J, Clarke, C, Scott, RJ, Fasching, PA, Haeberle, L, Ekici, AB, Beckmann, MW, Peto, J, dos-Santos-Silva, I, Fletcher, O, Johnson, N, Bolla, MK, Sawyer, EJ, Tomlinson, I, Kerin, MJ, Miller, N, Marme, F, Burwinkel, B, Yang, R, Guenel, P, Therese, T, Menegaux, F, Sanchez, M, Bojesen, S, Nielsen, SF, Flyger, H, Benitez, J, Pilar Zamora, M, Arias Perez, JI, Menendez, P, Anton-Culver, H, Neuhausen, S, Ziogas, A, Clarke, CA, Brenner, H, Arndt, V, Stegmaier, C, Brauch, H, Bruening, T, Ko, Y-D, Muranen, TA, Aittomaki, K, Blomqvist, C, Bogdanova, NV, Antonenkova, NN, Lindblom, A, Margolin, S, Mannermaa, A, Kataja, V, Kosma, V-M, Hartikainen, JM, Spurdle, AB, Wauters, E, Smeets, D, Beuselinck, B, Floris, G, Chang-Claude, J, Rudolph, A, Seibold, P, Flesch-Janys, D, Olson, JE, Vachon, C, Pankratz, VS, McLean, C, Haiman, CA, Henderson, BE, Schumacher, F, Le Marchand, L, Kristensen, V, Alnaes, GG, Zheng, W, Hunter, DJ, Lindstrom, S, Hankinson, SE, Kraft, P, Andrulis, I, Knight, JA, Glendon, G, Mulligan, AM, Jukkola-Vuorinen, A, Grip, M, Kauppila, S, Devilee, P, Tollenaar, RAEM, Seynaeve, C, Hollestelle, A, Garcia-Closas, M, Figueroa, J, Chanock, SJ, Lissowska, J, Czene, K, Darabi, H, Eriksson, M, Eccles, DM, Rafiq, S, Tapper, WJ, Gerty, SM, Hooning, MJ, Martens, JWM, Collee, JM, Tilanus-Linthorst, M, Hall, P, Li, J, Brand, JS, Humphreys, K, Cox, A, Reed, MWR, Luccarini, C, Baynes, C, Dunning, AM, Hamann, U, Torres, D, Ulmer, HU, Ruediger, T, Jakubowska, A, Lubinski, J, Jaworska, K, Durda, K, Slager, S, Toland, AE, Ambrosone, CB, Yannoukakos, D, Swerdlow, A, Ashworth, A, Orr, N, Jones, M, Gonzalez-Neira, A, Pita, G, Rosario Alonso, M, Alvarez, N, Herrero, D, Tessier, DC, Vincent, D, Bacot, F, Simard, J, Dumont, M, Soucy, P, Eeles, R, Muir, K, Wiklund, F, Gronberg, H, Schleutker, J, Nordestgaard, BG, Weischer, M, Travis, RC, Neal, D, Donovan, JL, Hamdy, FC, Khaw, K-T, Stanford, JL, Blot, WJ, Thibodeau, S, Schaid, DJ, Kelley, JL, Maier, C, Kibel, AS, Cybulski, C, Cannon-Albright, L, Butterbach, K, Park, J, Kaneva, R, Batra, J, Teixeira, MR, Kote-Jarai, Z, Al Olama, AA, Benlloch, S, Renner, SP, Hartmann, A, Hein, A, Ruebner, M, Lambrechts, D, Van Nieuwenhuysen, E, Vergote, I, Lambretchs, S, Doherty, JA, Rossing, MA, Nickels, S, Eilber, U, Wang-Gohrke, S, Odunsi, K, Sucheston-Campbell, LE, Friel, G, Lurie, G, Killeen, JL, Wilkens, LR, Goodman, MT, Runnebaum, I, Hillemanns, PA, Pelttari, LM, Butzow, R, Modugno, F, Edwards, RP, Ness, RB, Moysich, KB, du Bois, A, Heitz, F, Harter, P, Kommoss, S, Karlan, BY, Walsh, C, Lester, J, Jensen, A, Kjaer, SK, Hogdall, E, Peissel, B, Bonanni, B, Bernard, L, Goode, EL, Fridley, BL, Vierkant, RA, Cunningham, JM, Larson, MC, Fogarty, ZC, Kalli, KR, Liang, D, Lu, KH, Hildebrandt, MAT, Wu, X, Levine, DA, Dao, F, Bisogna, M, Berchuck, A, Iversen, ES, Marks, JR, Akushevich, L, Cramer, DW, Schildkraut, J, Terry, KL, Poole, EM, Stampfer, M, Tworoger, SS, Bandera, EV, Orlow, I, Olson, SH, Bjorge, L, Salvesen, HB, van Altena, AM, Aben, KKH, Kiemeney, LA, Massuger, LFAG, Pejovic, T, Bean, Y, Brooks-Wilson, A, Kelemen, LE, Cook, LS, Le, ND, Grski, B, Gronwald, J, Menkiszak, J, Hogdall, CK, Lundvall, L, Nedergaard, L, Engelholm, SA, Dicks, E, Tyrer, J, Campbell, I, McNeish, I, Paul, J, Siddiqui, N, Glasspool, R, Whittemore, AS, Rothstein, JH, McGuire, V, Sieh, W, Cai, H, Shu, X-O, Teten, RT, Sutphen, R, McLaughlin, JR, Narod, SA, Phelan, CM, Monteiro, AN, Fenstermacher, D, Lin, H-Y, Permuth, JB, Sellers, TA, Chen, YA, Tsai, Y-Y, Chen, Z, Gentry-Maharaj, A, Gayther, SA, Ramus, SJ, Menon, U, Wu, AH, Pearce, CL, Van den Berg, D, Pike, MC, Dansonka-Mieszkowska, A, Plisiecka-Halasa, J, Moes-Sosnowska, J, Kupryjanczyk, J, Pharoah, PDP, Song, H, Winship, I, Chenevix-Trench, G, Giles, GG, Tavtigian, SV, Easton, DF, and Milne, RL

Abstract

BACKGROUND: The rarity of mutations in PALB2, CHEK2 and ATM make it difficult to estimate precisely associated cancer risks. Population-based family studies have provided evidence that at least some of these mutations are associated with breast cancer risk as high as those associated with rare BRCA2 mutations. We aimed to estimate the relative risks associated with specific rare variants in PALB2, CHEK2 and ATM via a multicentre case-control study. METHODS: We genotyped 10 rare mutations using the custom iCOGS array: PALB2 c.1592delT, c.2816T>G and c.3113G>A, CHEK2 c.349A>G, c.538C>T, c.715G>A, c.1036C>T, c.1312G>T, and c.1343T>G and ATM c.7271T>G. We assessed associations with breast cancer risk (42 671 cases and 42 164 controls), as well as prostate (22 301 cases and 22 320 controls) and ovarian (14 542 cases and 23 491 controls) cancer risk, for each variant. RESULTS: For European women, strong evidence of association with breast cancer risk was observed for PALB2 c.1592delT OR 3.44 (95% CI 1.39 to 8.52, p=7.1×10-5), PALB2 c.3113G>A OR 4.21 (95% CI 1.84 to 9.60, p=6.9×10-8) and ATM c.7271T>G OR 11.0 (95% CI 1.42 to 85.7, p=0.0012). We also found evidence of association with breast cancer risk for three variants in CHEK2, c.349A>G OR 2.26 (95% CI 1.29 to 3.95), c.1036C>T OR 5.06 (95% CI 1.09 to 23.5) and c.538C>T OR 1.33 (95% CI 1.05 to 1.67) (p≤0.017). Evidence for prostate cancer risk was observed for CHEK2 c.1343T>G OR 3.03 (95% CI 1.53 to 6.03, p=0.0006) for African men and CHEK2 c.1312G>T OR 2.21 (95% CI 1.06 to 4.63, p=0.030) for European men. No evidence of association with ovarian cancer was found for any of these variants. CONCLUSIONS: This report adds to accumulating evidence that at least some variants in these genes are associated with an increased risk of breast cancer that is clinically important.

Published
2016

42. Genome-wide association study of subtype-specific epithelial ovarian cancer risk alleles using pooled DNA

Author

Earp, MA, Kelemen, LE, Magliocco, AM, Swenerton, KD, Chenevix-Trench, G, Lu, Y, Hein, A, Ekici, AB, Beckmann, MW, Fasching, PA, Lambrechts, D, Despierre, E, Vergote, I, Lambrechts, S, Doherty, JA, Rossing, MA, Chang-Claude, J, Rudolph, A, Friel, G, Moysich, KB, Odunsi, K, Sucheston-Campbell, L, Lurie, G, Goodman, MT, Carney, ME, Thompson, PJ, Runnebaum, IB, Dürst, M, Hillemanns, P, Dörk, T, Antonenkova, N, Bogdanova, N, Leminen, A, Nevanlinna, H, Pelttari, LM, Butzow, R, Bunker, CH, Modugno, F, Edwards, RP, Ness, RB, Du Bois, A, Heitz, F, Schwaab, I, Harter, P, Karlan, BY, Walsh, C, Lester, J, Jensen, A, Kjær, SK, Høgdall, CK, Høgdall, E, Lundvall, L, Sellers, TA, Fridley, BL, Goode, EL, Cunningham, JM, Vierkant, RA, Giles, GG, Baglietto, L, Severi, G, Southey, MC, Liang, D, Wu, X, Lu, K, Hildebrandt, MAT, Levine, DA, Bisogna, M, Schildkraut, JM, Iversen, ES, Weber, RP, Berchuck, A, Cramer, DW, Terry, KL, Poole, EM, Tworoger, SS, Bandera, EV, and Chandran, U

Subjects
endocrine system diseases, female genital diseases and pregnancy complications
Abstract

Epithelial ovarian cancer (EOC) is a heterogeneous cancer with both genetic and environmental risk factors. Variants influencing the risk of developing the less-common EOC subtypes have not been fully investigated. We performed a genome-wide association study (GWAS) of EOC according to subtype by pooling genomic DNA from 545 cases and 398 controls of European descent, and testing for allelic associations. We evaluated for replication 188 variants from the GWAS [56 variants for mucinous, 55 for endometrioid and clear cell, 53 for low-malignant potential (LMP) serous, and 24 for invasive serous EOC], selected using pre-defined criteria. Genotypes from 13,188 cases and 23,164 controls of European descent were used to perform unconditional logistic regression under the log-additive genetic model; odds ratios (OR) and 95 % confidence intervals are reported. Nine variants tagging six loci were associated with subtype-specific EOC risk at P < 0.05, and had an OR that agreed in direction of effect with the GWAS results. Several of these variants are in or near genes with a biological rationale for conferring EOC risk, including ZFP36L1 and RAD51B for mucinous EOC (rs17106154, OR = 1.17, P = 0.029, n = 1,483 cases), GRB10 for endometrioid and clear cell EOC (rs2190503, P = 0.014, n = 2,903 cases), and C22orf26/BPIL2 for LMP serous EOC (rs9609538, OR = 0.86, P = 0.0043, n = 892 cases). In analyses that included the 75 GWAS samples, the association between rs9609538 (OR = 0.84, P = 0.0007) and LMP serous EOC risk remained statistically significant at P < 0.0012 adjusted for multiple testing. Replication in additional samples will be important to verify these results for the less-common EOC subtypes. © 2013 Springer-Verlag Berlin Heidelberg.

Published
2014

43. Consortium analysis of gene and gene-folate interactions in purine and pyrimidine metabolism pathways with ovarian carcinoma risk

Author

Kelemen, LE, Terry, KL, Goodman, MT, Webb, PM, Bandera, EV, McGuire, V, Anne Rossing, M, Wang, Q, Dicks, E, Tyrer, JP, Song, H, Kupryjanczyk, J, Dansonka-Mieszkowska, A, Plisiecka-Halasa, J, Timorek, A, Menon, U, Gentry-Maharaj, A, Gayther, SA, Ramus, SJ, Narod, SA, Risch, HA, McLaughlin, JR, Siddiqui, N, Glasspool, R, Paul, J, Carty, K, Gronwald, J, Lubiński, J, Jakubowska, A, Cybulski, C, Kiemeney, LA, Massuger, LFAG, van Altena, AM, Aben, KKH, Olson, SH, Orlow, I, Cramer, DW, Levine, DA, Bisogna, M, Giles, GG, Southey, MC, Bruinsma, F, Kjær, SK, Høgdall, E, Jensen, A, Høgdall, CK, Lundvall, L, Engelholm, SA, Heitz, F, du Bois, A, Harter, P, Schwaab, I, Butzow, R, Nevanlinna, H, Pelttari, LM, Leminen, A, Thompson, PJ, Lurie, G, Wilkens, LR, Lambrechts, D, Van Nieuwenhuysen, E, Lambrechts, S, Vergote, I, Beesley, J, Fasching, PA, Beckmann, MW, Hein, A, Ekici, AB, Doherty, JA, Wu, AH, Pearce, CL, Pike, MC, Stram, D, Chang-Claude, J, Rudolph, A, Dörk, T, Dürst, M, Hillemanns, P, Runnebaum, IB, and Bogdanova, N

Subjects
Folate, Serine hydroxymethyltransferase 1 (soluble), Case-control, Polymorphism, Dihydropyrimidine dehydrogenase
Abstract

© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. Scope: We reevaluated previously reported associations between variants in pathways of onecarbon (1-C) (folate) transfer genes and ovarian carcinoma (OC) risk, and in related pathways of purine and pyrimidine metabolism, and assessed interactions with folate intake. Methods and results: Odds ratios (OR) for 446 genetic variants were estimated among 13 410 OC cases and 22 635 controls, and among 2281 cases and 3444 controls with folate information. Following multiple testing correction, the most significant main effect associations were for dihydropyrimidine dehydrogenase (DPYD) variants rs11587873 (OR = 0.92; p = 6 × 10-5) and rs828054 (OR = 1.06; p = 1 × 10-4). Thirteen variants in the pyrimidine metabolism genes, DPYD, DPYS, PPAT, and TYMS, also interacted significantly with folate in a multivariant analysis (corrected p = 9.9 × 10-6) but collectively explained only 0.2% of OC risk. Although no other associations were significant after multiple testing correction, variants in SHMT1 in 1-C transfer, previously reported with OC, suggested lower risk at higher folate (pinteraction= 0.03-0.006). Conclusion: Variation in pyrimidine metabolism genes, particularly DPYD, which was previously reported to be associated with OC, may influence risk; however, stratification by folate intake is unlikely to modify disease risk appreciably in these women. SHMT1 SNP-by-folate interactions are plausible but require further validation. Polymorphisms in selected genes in purine metabolism were not associated with OC.

Published
2014

44. Common Genetic Variation In Cellular Transport Genes and Epithelial Ovarian Cancer (EOC) Risk

Author

Agoulnik, IU, Chornokur, G, Lin, H-Y, Tyrer, JP, Lawrenson, K, Dennis, J, Amankwah, EK, Qu, X, Tsai, Y-Y, Jim, HSL, Chen, Z, Chen, AY, Permuth-Wey, J, Aben, KKH, Anton-Culver, H, Antonenkova, N, Bruinsma, F, Bandera, EV, Bean, YT, Beckmann, MW, Bisogna, M, Bjorge, L, Bogdanova, N, Brinton, LA, Brooks-Wilson, A, Bunker, CH, Butzow, R, Campbell, IG, Carty, K, Chang-Claude, J, Cook, LS, Cramer, DW, Cunningham, JM, Cybulski, C, Dansonka-Mieszkowska, A, du Bois, A, Despierre, E, Dicks, E, Doherty, JA, Dork, T, Durst, M, Easton, DF, Eccles, DM, Edwards, RP, Ekici, AB, Fasching, PA, Fridley, BL, Gao, Y-T, Gentry-Maharaj, A, Giles, GG, Glasspool, R, Goodman, MT, Gronwald, J, Harrington, P, Harter, P, Hein, A, Heitz, F, Hildebrandt, MAT, Hillemanns, P, Hogdall, CK, Hogdall, E, Hosono, S, Jakubowska, A, Jensen, A, Ji, B-T, Karlan, BY, Kelemen, LE, Kellar, M, Kiemeney, LA, Krakstad, C, Kjaer, SK, Kupryjanczyk, J, Lambrechts, D, Lambrechts, S, Le, ND, Lee, AW, Lele, S, Leminen, A, Lester, J, Levine, DA, Liang, D, Lim, BK, Lissowska, J, Lu, K, Lubinski, J, Lundvall, L, Massuger, LFAG, Matsuo, K, McGuire, V, McLaughlin, JR, McNeish, I, Menon, U, Milne, RL, Modugno, F, Moysich, KB, Ness, RB, Nevanlinna, H, Eilber, U, Odunsi, K, Olson, SH, Orlow, I, Orsulic, S, Weber, RP, Paul, J, Pearce, CL, Pejovic, T, Pelttari, LM, Pike, MC, Poole, EM, Risch, HA, Rosen, B, Rossing, MA, Rothstein, JH, Rudolph, A, Runnebaum, IB, Rzepecka, IK, Salvesen, HB, Schernhammer, E, Schwaab, I, Shu, X-O, Shvetsov, YB, Siddiqui, N, Sieh, W, Song, H, Southey, MC, Spiewankiewicz, B, Sucheston, L, Teo, S-H, Terry, KL, Thompson, PJ, Thomsen, L, Tangen, IL, Tworoger, SS, van Altena, AM, Vierkant, RA, Vergote, I, Walsh, CS, Wang-Gohrke, S, Wentzensen, N, Whittemore, AS, Wicklund, KG, Wilkens, LR, Wu, AH, Wu, X, Woo, Y-L, Yang, H, Zheng, W, Ziogas, A, Hasmad, HN, Berchuck, A, Iversen, ES, Schildkraut, JM, Ramus, SJ, Goode, EL, Monteiro, ANA, Gayther, SA, Narod, SA, Pharoah, PP, Sellers, TA, Phelan, CM, Agoulnik, IU, Chornokur, G, Lin, H-Y, Tyrer, JP, Lawrenson, K, Dennis, J, Amankwah, EK, Qu, X, Tsai, Y-Y, Jim, HSL, Chen, Z, Chen, AY, Permuth-Wey, J, Aben, KKH, Anton-Culver, H, Antonenkova, N, Bruinsma, F, Bandera, EV, Bean, YT, Beckmann, MW, Bisogna, M, Bjorge, L, Bogdanova, N, Brinton, LA, Brooks-Wilson, A, Bunker, CH, Butzow, R, Campbell, IG, Carty, K, Chang-Claude, J, Cook, LS, Cramer, DW, Cunningham, JM, Cybulski, C, Dansonka-Mieszkowska, A, du Bois, A, Despierre, E, Dicks, E, Doherty, JA, Dork, T, Durst, M, Easton, DF, Eccles, DM, Edwards, RP, Ekici, AB, Fasching, PA, Fridley, BL, Gao, Y-T, Gentry-Maharaj, A, Giles, GG, Glasspool, R, Goodman, MT, Gronwald, J, Harrington, P, Harter, P, Hein, A, Heitz, F, Hildebrandt, MAT, Hillemanns, P, Hogdall, CK, Hogdall, E, Hosono, S, Jakubowska, A, Jensen, A, Ji, B-T, Karlan, BY, Kelemen, LE, Kellar, M, Kiemeney, LA, Krakstad, C, Kjaer, SK, Kupryjanczyk, J, Lambrechts, D, Lambrechts, S, Le, ND, Lee, AW, Lele, S, Leminen, A, Lester, J, Levine, DA, Liang, D, Lim, BK, Lissowska, J, Lu, K, Lubinski, J, Lundvall, L, Massuger, LFAG, Matsuo, K, McGuire, V, McLaughlin, JR, McNeish, I, Menon, U, Milne, RL, Modugno, F, Moysich, KB, Ness, RB, Nevanlinna, H, Eilber, U, Odunsi, K, Olson, SH, Orlow, I, Orsulic, S, Weber, RP, Paul, J, Pearce, CL, Pejovic, T, Pelttari, LM, Pike, MC, Poole, EM, Risch, HA, Rosen, B, Rossing, MA, Rothstein, JH, Rudolph, A, Runnebaum, IB, Rzepecka, IK, Salvesen, HB, Schernhammer, E, Schwaab, I, Shu, X-O, Shvetsov, YB, Siddiqui, N, Sieh, W, Song, H, Southey, MC, Spiewankiewicz, B, Sucheston, L, Teo, S-H, Terry, KL, Thompson, PJ, Thomsen, L, Tangen, IL, Tworoger, SS, van Altena, AM, Vierkant, RA, Vergote, I, Walsh, CS, Wang-Gohrke, S, Wentzensen, N, Whittemore, AS, Wicklund, KG, Wilkens, LR, Wu, AH, Wu, X, Woo, Y-L, Yang, H, Zheng, W, Ziogas, A, Hasmad, HN, Berchuck, A, Iversen, ES, Schildkraut, JM, Ramus, SJ, Goode, EL, Monteiro, ANA, Gayther, SA, Narod, SA, Pharoah, PP, Sellers, TA, and Phelan, CM

Abstract

BACKGROUND: Defective cellular transport processes can lead to aberrant accumulation of trace elements, iron, small molecules and hormones in the cell, which in turn may promote the formation of reactive oxygen species, promoting DNA damage and aberrant expression of key regulatory cancer genes. As DNA damage and uncontrolled proliferation are hallmarks of cancer, including epithelial ovarian cancer (EOC), we hypothesized that inherited variation in the cellular transport genes contributes to EOC risk. METHODS: In total, DNA samples were obtained from 14,525 case subjects with invasive EOC and from 23,447 controls from 43 sites in the Ovarian Cancer Association Consortium (OCAC). Two hundred seventy nine SNPs, representing 131 genes, were genotyped using an Illumina Infinium iSelect BeadChip as part of the Collaborative Oncological Gene-environment Study (COGS). SNP analyses were conducted using unconditional logistic regression under a log-additive model, and the FDR q<0.2 was applied to adjust for multiple comparisons. RESULTS: The most significant evidence of an association for all invasive cancers combined and for the serous subtype was observed for SNP rs17216603 in the iron transporter gene HEPH (invasive: OR = 0.85, P = 0.00026; serous: OR = 0.81, P = 0.00020); this SNP was also associated with the borderline/low malignant potential (LMP) tumors (P = 0.021). Other genes significantly associated with EOC histological subtypes (p<0.05) included the UGT1A (endometrioid), SLC25A45 (mucinous), SLC39A11 (low malignant potential), and SERPINA7 (clear cell carcinoma). In addition, 1785 SNPs in six genes (HEPH, MGST1, SERPINA, SLC25A45, SLC39A11 and UGT1A) were imputed from the 1000 Genomes Project and examined for association with INV EOC in white-European subjects. The most significant imputed SNP was rs117729793 in SLC39A11 (per allele, OR = 2.55, 95% CI = 1.5-4.35, p = 5.66x10-4). CONCLUSION: These results, generated on a large cohort of women, revealed associatio

Published
2015

45. Common Genetic Variation in Circadian Rhythm Genes and Risk of Epithelial Ovarian Cancer (EOC).

Author

Jim, HSL, Lin, H-Y, Tyrer, JP, Lawrenson, K, Dennis, J, Chornokur, G, Chen, Z, Chen, AY, Permuth-Wey, J, Aben, KK, Anton-Culver, H, Antonenkova, N, Bruinsma, F, Bandera, EV, Bean, YT, Beckmann, MW, Bisogna, M, Bjorge, L, Bogdanova, N, Brinton, LA, Brooks-Wilson, A, Bunker, CH, Butzow, R, Campbell, IG, Carty, K, Chang-Claude, J, Cook, LS, Cramer, DW, Cunningham, JM, Cybulski, C, Dansonka-Mieszkowska, A, du Bois, A, Despierre, E, Sieh, W, Doherty, JA, Dörk, T, Dürst, M, Easton, DF, Eccles, DM, Edwards, RP, Ekici, AB, Fasching, PA, Fridley, BL, Gao, Y-T, Gentry-Maharaj, A, Giles, GG, Glasspool, R, Goodman, MT, Gronwald, J, Harter, P, Hasmad, HN, Hein, A, Heitz, F, Hildebrandt, MAT, Hillemanns, P, Hogdall, CK, Hogdall, E, Hosono, S, Iversen, ES, Jakubowska, A, Jensen, A, Ji, B-T, Karlan, BY, Kellar, M, Kiemeney, LA, Krakstad, C, Kjaer, SK, Kupryjanczyk, J, Vierkant, RA, Lambrechts, D, Lambrechts, S, Le, ND, Lee, AW, Lele, S, Leminen, A, Lester, J, Levine, DA, Liang, D, Lim, BK, Lissowska, J, Lu, K, Lubinski, J, Lundvall, L, Massuger, LFAG, Matsuo, K, McGuire, V, McLaughlin, JR, McNeish, I, Menon, U, Milne, RL, Modugno, F, Thomsen, L, Moysich, KB, Ness, RB, Nevanlinna, H, Eilber, U, Odunsi, K, Olson, SH, Orlow, I, Orsulic, S, Palmieri Weber, R, Paul, J, Pearce, CL, Pejovic, T, Pelttari, LM, Pike, MC, Poole, EM, Schernhammer, E, Risch, HA, Rosen, B, Rossing, MA, Rothstein, JH, Rudolph, A, Runnebaum, IB, Rzepecka, IK, Salvesen, HB, Schwaab, I, Shu, X-O, Shvetsov, YB, Siddiqui, N, Song, H, Southey, MC, Spiewankiewicz, B, Sucheston-Campbell, L, Teo, S-H, Terry, KL, Thompson, PJ, Tangen, IL, Tworoger, SS, van Altena, AM, Vergote, I, Walsh, CS, Wang-Gohrke, S, Wentzensen, N, Whittemore, AS, Wicklund, KG, Wilkens, LR, Wu, AH, Wu, X, Woo, Y-L, Yang, H, Zheng, W, Ziogas, A, Amankwah, E, Berchuck, A, Georgia Chenevix-Trench on behalf of the AOCS management group 95,96, Schildkraut, JM, Kelemen, LE, Ramus, SJ, Monteiro, ANA, Goode, EL, Narod, SA, Gayther, SA, Pharoah, PDP, Sellers, TA, Phelan, CM, Jim, HSL, Lin, H-Y, Tyrer, JP, Lawrenson, K, Dennis, J, Chornokur, G, Chen, Z, Chen, AY, Permuth-Wey, J, Aben, KK, Anton-Culver, H, Antonenkova, N, Bruinsma, F, Bandera, EV, Bean, YT, Beckmann, MW, Bisogna, M, Bjorge, L, Bogdanova, N, Brinton, LA, Brooks-Wilson, A, Bunker, CH, Butzow, R, Campbell, IG, Carty, K, Chang-Claude, J, Cook, LS, Cramer, DW, Cunningham, JM, Cybulski, C, Dansonka-Mieszkowska, A, du Bois, A, Despierre, E, Sieh, W, Doherty, JA, Dörk, T, Dürst, M, Easton, DF, Eccles, DM, Edwards, RP, Ekici, AB, Fasching, PA, Fridley, BL, Gao, Y-T, Gentry-Maharaj, A, Giles, GG, Glasspool, R, Goodman, MT, Gronwald, J, Harter, P, Hasmad, HN, Hein, A, Heitz, F, Hildebrandt, MAT, Hillemanns, P, Hogdall, CK, Hogdall, E, Hosono, S, Iversen, ES, Jakubowska, A, Jensen, A, Ji, B-T, Karlan, BY, Kellar, M, Kiemeney, LA, Krakstad, C, Kjaer, SK, Kupryjanczyk, J, Vierkant, RA, Lambrechts, D, Lambrechts, S, Le, ND, Lee, AW, Lele, S, Leminen, A, Lester, J, Levine, DA, Liang, D, Lim, BK, Lissowska, J, Lu, K, Lubinski, J, Lundvall, L, Massuger, LFAG, Matsuo, K, McGuire, V, McLaughlin, JR, McNeish, I, Menon, U, Milne, RL, Modugno, F, Thomsen, L, Moysich, KB, Ness, RB, Nevanlinna, H, Eilber, U, Odunsi, K, Olson, SH, Orlow, I, Orsulic, S, Palmieri Weber, R, Paul, J, Pearce, CL, Pejovic, T, Pelttari, LM, Pike, MC, Poole, EM, Schernhammer, E, Risch, HA, Rosen, B, Rossing, MA, Rothstein, JH, Rudolph, A, Runnebaum, IB, Rzepecka, IK, Salvesen, HB, Schwaab, I, Shu, X-O, Shvetsov, YB, Siddiqui, N, Song, H, Southey, MC, Spiewankiewicz, B, Sucheston-Campbell, L, Teo, S-H, Terry, KL, Thompson, PJ, Tangen, IL, Tworoger, SS, van Altena, AM, Vergote, I, Walsh, CS, Wang-Gohrke, S, Wentzensen, N, Whittemore, AS, Wicklund, KG, Wilkens, LR, Wu, AH, Wu, X, Woo, Y-L, Yang, H, Zheng, W, Ziogas, A, Amankwah, E, Berchuck, A, Georgia Chenevix-Trench on behalf of the AOCS management group 95,96, Schildkraut, JM, Kelemen, LE, Ramus, SJ, Monteiro, ANA, Goode, EL, Narod, SA, Gayther, SA, Pharoah, PDP, Sellers, TA, and Phelan, CM

Abstract

Disruption in circadian gene expression, whether due to genetic variation or environmental factors (e.g., light at night, shiftwork), is associated with increased incidence of breast, prostate, gastrointestinal and hematologic cancers and gliomas. Circadian genes are highly expressed in the ovaries where they regulate ovulation; circadian disruption is associated with several ovarian cancer risk factors (e.g., endometriosis). However, no studies have examined variation in germline circadian genes as predictors of ovarian cancer risk and invasiveness. The goal of the current study was to examine single nucleotide polymorphisms (SNPs) in circadian genes BMAL1, CRY2, CSNK1E, NPAS2, PER3, REV1 and TIMELESS and downstream transcription factors KLF10 and SENP3 as predictors of risk of epithelial ovarian cancer (EOC) and histopathologic subtypes. The study included a test set of 3,761 EOC cases and 2,722 controls and a validation set of 44,308 samples including 18,174 (10,316 serous) cases and 26,134 controls from 43 studies participating in the Ovarian Cancer Association Consortium (OCAC). Analysis of genotype data from 36 genotyped SNPs and 4600 imputed SNPs indicated that the most significant association was rs117104877 in BMAL1 (OR = 0.79, 95% CI = 0.68-0.90, p = 5.59 × 10-4]. Functional analysis revealed a significant down regulation of BMAL1 expression following cMYC overexpression and increasing transformation in ovarian surface epithelial (OSE) cells as well as alternative splicing of BMAL1 exons in ovarian and granulosa cells. These results suggest that variation in circadian genes, and specifically BMAL1, may be associated with risk of ovarian cancer, likely through disruption of hormonal pathways.

Published
2015

46. Identification of six new susceptibility loci for invasive epithelial ovarian cancer

Author

Kuchenbaecker, KB, Ramus, SJ, Tyrer, J, Lee, A, Shen, HC, Beesley, J, Lawrenson, K, McGuffog, L, Healey, S, Lee, JM, Spindler, TJ, Lin, YG, Pejovic, T, Bean, Y, Li, Q, Coetzee, S, Hazelett, D, Miron, A, Southey, M, Terry, MB, Goldgar, DE, Buys, SS, Janavicius, R, Dorfling, CM, van Rensburg, EJ, Neuhausen, SL, Ding, YC, Hansen, TVO, Jonson, L, Gerdes, A-M, Ejlertsen, B, Barrowdale, D, Dennis, J, Benitez, J, Osorio, A, Garcia, MJ, Komenaka, I, Weitzel, JN, Ganschow, P, Peterlongo, P, Bernard, L, Viel, A, Bonanni, B, Peissel, B, Manoukian, S, Radice, P, Papi, L, Ottini, L, Fostira, F, Konstantopoulou, I, Garber, J, Frost, D, Perkins, J, Platte, R, Ellis, S, Godwin, AK, Schmutzler, RK, Meindl, A, Engel, C, Sutter, C, Sinilnikova, OM, Damiola, F, Mazoyer, S, Stoppa-Lyonnet, D, Claes, K, De Leeneer, K, Kirk, J, Rodriguez, GC, Piedmonte, M, O'Malley, DM, de la Hoya, M, Caldes, T, Aittomaeki, K, Nevanlinna, H, Collee, JM, Rookus, MA, Oosterwijk, JC, Tihomirova, L, Tung, N, Hamann, U, Isaccs, C, Tischkowitz, M, Imyanitov, EN, Caligo, MA, Campbell, IG, Hogervorst, FBL, Olah, E, Diez, O, Blanco, I, Brunet, J, Lazaroso, C, Angel Pujana, M, Jakubowska, A, Gronwald, J, Lubinski, J, Sukiennicki, G, Barkardottir, RB, Plante, M, Simard, J, Soucy, P, Montagna, M, Tognazzo, S, Teixeira, MR, Pankratz, VS, Wang, X, Lindor, N, Szabo, CI, Kauff, N, Vijai, J, Aghajanian, CA, Pfeiler, G, Berger, A, Singer, CF, Tea, M-K, Phelan, CM, Greene, MH, Mai, PL, Rennert, G, Mulligan, AM, Tchatchou, S, Andrulis, IL, Glendon, G, Toland, AE, Jensen, UB, Kruse, TA, Thomassen, M, Bojesen, A, Zidan, J, Friedman, E, Laitman, Y, Soller, M, Liljegren, A, Arver, B, Einbeigi, Z, Stenmark-Askmalm, M, Olopade, OI, Nussbaum, RL, Rebbeck, TR, Nathanson, KL, Domchek, SM, Lu, KH, Karlan, BY, Walsh, C, Lester, J, Hein, A, Ekici, AB, Beckmann, MW, Fasching, PA, Lambrechts, D, Van Nieuwenhuysen, E, Vergote, I, Lambrechts, S, Dicks, E, Doherty, JA, Wicklund, KG, Rossing, MA, Rudolph, A, Chang-Claude, J, Wang-Gohrke, S, Eilber, U, Moysich, KB, Odunsi, K, Sucheston, L, Lele, S, Wilkens, LR, Goodman, MT, Thompson, PJ, Shvetsov, YB, Runnebaum, IB, Duerst, M, Hillemanns, P, Doerk, T, Antonenkova, N, Bogdanova, N, Leminen, A, Pelttari, LM, Butzow, R, Modugno, F, Kelley, JL, Edwards, RP, Ness, RB, du Bois, A, Heitz, F, Schwaab, I, Harter, P, Matsuo, K, Hosono, S, Orsulic, S, Jensen, A, Kjaer, SK, Hogdall, E, Hasmad, HN, Azmi, MAN, Teo, S-H, Woo, Y-L, Fridley, BL, Goode, EL, Cunningham, JM, Vierkant, RA, Bruinsma, F, Giles, GG, Liang, D, Hildebrandt, MAT, Wu, X, Levine, DA, Bisogna, M, Berchuck, A, Iversen, ES, Schildkraut, JM, Concannon, P, Weber, RP, Cramer, DW, Terry, KL, Poole, EM, Tworoger, SS, Bandera, EV, Orlow, I, Olson, SH, Krakstad, C, Salvesen, HB, Tangen, IL, Bjorge, L, van Altena, AM, Aben, KKH, Kiemeney, LA, Massuger, LFAG, Kellar, M, Brooks-Wilson, A, Kelemen, LE, Cook, LS, Le, ND, Cybulski, C, Yang, H, Lissowska, J, Brinton, LA, Wentzensen, N, Hogdall, C, Lundvall, L, Nedergaard, L, Baker, H, Song, H, Eccles, D, McNeish, I, Paul, J, Carty, K, Siddiqui, N, Glasspool, R, Whittemore, AS, Rothstein, JH, McGuire, V, Sieh, W, Ji, B-T, Zheng, W, Shu, X-O, Gao, Y-T, Rosen, B, Risch, HA, McLaughlin, JR, Narod, SA, Monteiro, AN, Chen, A, Lin, H-Y, Permuth-Wey, J, Sellers, TA, Tsai, Y-Y, Chen, Z, Ziogas, A, Anton-Culver, H, Gentry-Maharaj, A, Menon, U, Harrington, P, Lee, AW, Wu, AH, Pearce, CL, Coetzee, G, Pike, MC, Dansonka-Mieszkowska, A, Timorek, A, Rzepecka, IK, Kupryjanczyk, J, Freedman, M, Noushmehr, H, Easton, DF, Offit, K, Couch, FJ, Gayther, S, Pharoah, PP, Antoniou, AC, Chenevix-Trench, G, Kuchenbaecker, KB, Ramus, SJ, Tyrer, J, Lee, A, Shen, HC, Beesley, J, Lawrenson, K, McGuffog, L, Healey, S, Lee, JM, Spindler, TJ, Lin, YG, Pejovic, T, Bean, Y, Li, Q, Coetzee, S, Hazelett, D, Miron, A, Southey, M, Terry, MB, Goldgar, DE, Buys, SS, Janavicius, R, Dorfling, CM, van Rensburg, EJ, Neuhausen, SL, Ding, YC, Hansen, TVO, Jonson, L, Gerdes, A-M, Ejlertsen, B, Barrowdale, D, Dennis, J, Benitez, J, Osorio, A, Garcia, MJ, Komenaka, I, Weitzel, JN, Ganschow, P, Peterlongo, P, Bernard, L, Viel, A, Bonanni, B, Peissel, B, Manoukian, S, Radice, P, Papi, L, Ottini, L, Fostira, F, Konstantopoulou, I, Garber, J, Frost, D, Perkins, J, Platte, R, Ellis, S, Godwin, AK, Schmutzler, RK, Meindl, A, Engel, C, Sutter, C, Sinilnikova, OM, Damiola, F, Mazoyer, S, Stoppa-Lyonnet, D, Claes, K, De Leeneer, K, Kirk, J, Rodriguez, GC, Piedmonte, M, O'Malley, DM, de la Hoya, M, Caldes, T, Aittomaeki, K, Nevanlinna, H, Collee, JM, Rookus, MA, Oosterwijk, JC, Tihomirova, L, Tung, N, Hamann, U, Isaccs, C, Tischkowitz, M, Imyanitov, EN, Caligo, MA, Campbell, IG, Hogervorst, FBL, Olah, E, Diez, O, Blanco, I, Brunet, J, Lazaroso, C, Angel Pujana, M, Jakubowska, A, Gronwald, J, Lubinski, J, Sukiennicki, G, Barkardottir, RB, Plante, M, Simard, J, Soucy, P, Montagna, M, Tognazzo, S, Teixeira, MR, Pankratz, VS, Wang, X, Lindor, N, Szabo, CI, Kauff, N, Vijai, J, Aghajanian, CA, Pfeiler, G, Berger, A, Singer, CF, Tea, M-K, Phelan, CM, Greene, MH, Mai, PL, Rennert, G, Mulligan, AM, Tchatchou, S, Andrulis, IL, Glendon, G, Toland, AE, Jensen, UB, Kruse, TA, Thomassen, M, Bojesen, A, Zidan, J, Friedman, E, Laitman, Y, Soller, M, Liljegren, A, Arver, B, Einbeigi, Z, Stenmark-Askmalm, M, Olopade, OI, Nussbaum, RL, Rebbeck, TR, Nathanson, KL, Domchek, SM, Lu, KH, Karlan, BY, Walsh, C, Lester, J, Hein, A, Ekici, AB, Beckmann, MW, Fasching, PA, Lambrechts, D, Van Nieuwenhuysen, E, Vergote, I, Lambrechts, S, Dicks, E, Doherty, JA, Wicklund, KG, Rossing, MA, Rudolph, A, Chang-Claude, J, Wang-Gohrke, S, Eilber, U, Moysich, KB, Odunsi, K, Sucheston, L, Lele, S, Wilkens, LR, Goodman, MT, Thompson, PJ, Shvetsov, YB, Runnebaum, IB, Duerst, M, Hillemanns, P, Doerk, T, Antonenkova, N, Bogdanova, N, Leminen, A, Pelttari, LM, Butzow, R, Modugno, F, Kelley, JL, Edwards, RP, Ness, RB, du Bois, A, Heitz, F, Schwaab, I, Harter, P, Matsuo, K, Hosono, S, Orsulic, S, Jensen, A, Kjaer, SK, Hogdall, E, Hasmad, HN, Azmi, MAN, Teo, S-H, Woo, Y-L, Fridley, BL, Goode, EL, Cunningham, JM, Vierkant, RA, Bruinsma, F, Giles, GG, Liang, D, Hildebrandt, MAT, Wu, X, Levine, DA, Bisogna, M, Berchuck, A, Iversen, ES, Schildkraut, JM, Concannon, P, Weber, RP, Cramer, DW, Terry, KL, Poole, EM, Tworoger, SS, Bandera, EV, Orlow, I, Olson, SH, Krakstad, C, Salvesen, HB, Tangen, IL, Bjorge, L, van Altena, AM, Aben, KKH, Kiemeney, LA, Massuger, LFAG, Kellar, M, Brooks-Wilson, A, Kelemen, LE, Cook, LS, Le, ND, Cybulski, C, Yang, H, Lissowska, J, Brinton, LA, Wentzensen, N, Hogdall, C, Lundvall, L, Nedergaard, L, Baker, H, Song, H, Eccles, D, McNeish, I, Paul, J, Carty, K, Siddiqui, N, Glasspool, R, Whittemore, AS, Rothstein, JH, McGuire, V, Sieh, W, Ji, B-T, Zheng, W, Shu, X-O, Gao, Y-T, Rosen, B, Risch, HA, McLaughlin, JR, Narod, SA, Monteiro, AN, Chen, A, Lin, H-Y, Permuth-Wey, J, Sellers, TA, Tsai, Y-Y, Chen, Z, Ziogas, A, Anton-Culver, H, Gentry-Maharaj, A, Menon, U, Harrington, P, Lee, AW, Wu, AH, Pearce, CL, Coetzee, G, Pike, MC, Dansonka-Mieszkowska, A, Timorek, A, Rzepecka, IK, Kupryjanczyk, J, Freedman, M, Noushmehr, H, Easton, DF, Offit, K, Couch, FJ, Gayther, S, Pharoah, PP, Antoniou, AC, and Chenevix-Trench, G

Abstract

Genome-wide association studies (GWAS) have identified 12 epithelial ovarian cancer (EOC) susceptibility alleles. The pattern of association at these loci is consistent in BRCA1 and BRCA2 mutation carriers who are at high risk of EOC. After imputation to 1000 Genomes Project data, we assessed associations of 11 million genetic variants with EOC risk from 15,437 cases unselected for family history and 30,845 controls and from 15,252 BRCA1 mutation carriers and 8,211 BRCA2 mutation carriers (3,096 with ovarian cancer), and we combined the results in a meta-analysis. This new study design yielded increased statistical power, leading to the discovery of six new EOC susceptibility loci. Variants at 1p36 (nearest gene, WNT4), 4q26 (SYNPO2), 9q34.2 (ABO) and 17q11.2 (ATAD5) were associated with EOC risk, and at 1p34.3 (RSPO1) and 6p22.1 (GPX6) variants were specifically associated with the serous EOC subtype, all with P < 5 × 10(-8). Incorporating these variants into risk assessment tools will improve clinical risk predictions for BRCA1 and BRCA2 mutation carriers.

Published
2015

47. Identification and molecular characterization of a new ovarian cancer susceptibility locus at 17q21.31

Author

Permuth-Wey, J, Lawrenson, K, Shen, HC, Velkova, A, Tyrer, JP, Chen, Z, Lin, HY, Ann Chen, Y, Tsai, YY, Qu, X, Ramus, SJ, Karevan, R, Lee, J, Lee, N, Larson, MC, Aben, KK, Anton-Culver, H, Antonenkova, N, Antoniou, AC, Armasu, SM, Bacot, F, Baglietto, L, Bandera, EV, Barnholtz-Sloan, J, Beckmann, MW, Birrer, MJ, Bloom, G, Bogdanova, N, Brinton, LA, Brooks-Wilson, A, Brown, R, Butzow, R, Cai, Q, Campbell, I, Chang-Claude, J, Chanock, S, Chenevix-Trench, G, Cheng, JQ, Cicek, MS, Coetzee, GA, Cook, LS, Couch, FJ, Cramer, DW, Cunningham, JM, Dansonka-Mieszkowska, A, Despierre, E, Doherty, JA, Dörk, T, Du Bois, A, Dürst, M, Easton, DF, Eccles, D, Edwards, R, Ekici, AB, Fasching, PA, Fenstermacher, DA, Flanagan, JM, Garcia-Closas, M, Gentry-Maharaj, A, Giles, GG, Glasspool, RM, Gonzalez-Bosquet, J, Goodman, MT, Gore, M, Górski, B, Gronwald, J, Hall, P, Halle, MK, Harter, P, Heitz, F, Hillemanns, P, Hoatlin, M, Høgdall, CK, Høgdall, E, Hosono, S, Jakubowska, A, Jensen, A, Jim, H, Kalli, KR, Karlan, BY, Kaye, SB, Kelemen, LE, Kiemeney, LA, Kikkawa, F, and Konecny, GE

Subjects
endocrine system diseases, female genital diseases and pregnancy complications
Abstract

Epithelial ovarian cancer (EOC) has a heritable component that remains to be fully characterized. Most identified common susceptibility variants lie in non-protein-coding sequences. We hypothesized that variants in the 3′ untranslated region at putative microRNA (miRNA)-binding sites represent functional targets that influence EOC susceptibility. Here, we evaluate the association between 767 miRNA-related single-nucleotide polymorphisms (miRSNPs) and EOC risk in 18,174 EOC cases and 26,134 controls from 43 studies genotyped through the Collaborative Oncological Gene-environment Study. We identify several miRSNPs associated with invasive serous EOC risk (odds ratio=1.12, P=10-8) mapping to an inversion polymorphism at 17q21.31. Additional genotyping of non-miRSNPs at 17q21.31 reveals stronger signals outside the inversion (P=10-10). Variation at 17q21.31 is associated with neurological diseases, and our collaboration is the first to report an association with EOC susceptibility. An integrated molecular analysis in this region provides evidence for ARHGAP27 and PLEKHM1 as candidate EOC susceptibility genes. © 2013 Macmillan Publishers Limited. All rights reserved.

Published
2013

48. GWAS meta-analysis and replication identifies three new susceptibility loci for ovarian cancer

Author

Pharoah, PDP, Tsai, YY, Ramus, SJ, Phelan, CM, Goode, EL, Lawrenson, K, Buckley, M, Fridley, BL, Tyrer, JP, Shen, H, Weber, R, Karevan, R, Larson, MC, Song, H, Tessier, DC, Bacot, F, Vincent, D, Cunningham, JM, Dennis, J, Dicks, E, Aben, KK, Anton-Culver, H, Antonenkova, N, Armasu, SM, Baglietto, L, Bandera, EV, Beckmann, MW, Birrer, MJ, Bloom, G, Bogdanova, N, Brenton, JD, Brinton, LA, Brooks-Wilson, A, Brown, R, Butzow, R, Campbell, I, Carney, ME, Carvalho, RS, Chang-Claude, J, Chen, YA, Chen, Z, Chow, WH, Cicek, MS, Coetzee, G, Cook, LS, Cramer, DW, Cybulski, C, Dansonka-Mieszkowska, A, Despierre, E, Doherty, JA, Dörk, T, Du Bois, A, Dürst, M, Eccles, D, Edwards, R, Ekici, AB, Fasching, PA, Fenstermacher, D, Flanagan, J, Gao, YT, Garcia-Closas, M, Gentry-Maharaj, A, Giles, G, Gjyshi, A, Gore, M, Gronwald, J, Guo, Q, Halle, MK, Harter, P, Hein, A, Heitz, F, Hillemanns, P, Hoatlin, M, Høgdall, E, Høgdall, CK, Hosono, S, Jakubowska, A, Jensen, A, Kalli, KR, and Karlan, BY

Subjects
endocrine system diseases
Abstract

Genome-wide association studies (GWAS) have identified four susceptibility loci for epithelial ovarian cancer (EOC), with another two suggestive loci reaching near genome-wide significance. We pooled data from a GWAS conducted in North America with another GWAS from the UK. We selected the top 24,551 SNPs for inclusion on the iCOGS custom genotyping array. We performed follow-up genotyping in 18,174 individuals with EOC (cases) and 26,134 controls from 43 studies from the Ovarian Cancer Association Consortium. We validated the two loci at 3q25 and 17q21 that were previously found to have associations close to genome-wide significance and identified three loci newly associated with risk: two loci associated with all EOC subtypes at 8q21 (rs11782652, P = 5.5 × 10-9) and 10p12 (rs1243180, P = 1.8 × 10-8) and another locus specific to the serous subtype at 17q12 (rs757210, P = 8.1 × 10-10). An integrated molecular analysis of genes and regulatory regions at these loci provided evidence for functional mechanisms underlying susceptibility and implicated CHMP4C in the pathogenesis of ovarian cancer.

Published
2013

49. Common variants at 19p13 are associated with susceptibility to ovarian cancer

Author

Bolton, KL, Tyrer, J, Song, H, Ramus, SJ, Notaridou, M, Jones, C, Sher, T, Gentry-Maharaj, A, Wozniak, E, Tsai, YY, Weidhaas, J, Paik, D, Van Den Berg, DJ, Stram, DO, Pearce, CL, Wu, AH, Brewster, W, Anton-Culver, H, Ziogas, A, Narod, SA, Levine, DA, Kaye, SB, Brown, R, Paul, J, Flanagan, J, Sieh, W, McGuire, V, Whittemore, AS, Campbell, I, Gore, ME, Lissowska, J, Yang, HP, Medrek, K, Gronwald, J, Lubinski, J, Jakubowska, A, Le, ND, Cook, LS, Kelemen, LE, Brook-Wilson, A, Massuger, LFAG, Kiemeney, LA, Aben, KKH, Van Altena, AM, Houlston, R, Tomlinson, I, Palmieri, RT, Moorman, PG, Schildkraut, J, Iversen, ES, Phelan, C, Vierkant, RA, Cunningham, JM, Goode, EL, Fridley, BL, Kruger-Kjaer, S, Blaeker, J, Hogdall, E, Hogdall, C, Gross, J, Karlan, BY, Ness, RB, Edwards, RP, Odunsi, K, Moyisch, KB, Baker, JA, Modugno, F, Heikkinenen, T, Butzow, R, Nevanlinna, H, Leminen, A, Bogdanova, N, Antonenkova, N, Doerk, T, Hillemanns, P, Dürst, M, Runnebaum, I, Thompson, PJ, Carney, ME, Goodman, MT, Lurie, G, Wang-Gohrke, S, Hein, R, Chang-Claude, J, Rossing, MA, Cushing-Haugen, KL, Doherty, J, Chen, C, Rafnar, T, Besenbacher, S, Sulem, P, Stefansson, K, Birrer, MJ, Terry, KL, Hernandez, D, Cramer, DW, and Vergote, I

Subjects
endocrine system diseases, female genital diseases and pregnancy complications
Abstract

Epithelial ovarian cancer (EOC) is the leading cause of death from gynecological malignancy in the developed world, accounting for 4% of the deaths from cancer in women. We performed a three-phase genome-wide association study of EOC survival in 8,951 individuals with EOC (cases) with available survival time data and a parallel association analysis of EOC susceptibility. Two SNPs at 19p13.11, rs8170 and rs2363956, showed evidence of association with survival (overall P = 5×10-4and P = 6×10-4, respectively), but they did not replicate in phase 3. However, the same two SNPs demonstrated genome-wide significance for risk of serous EOC (P = 3×10-9and P = 4×10-11, respectively). Expression analysis of candidate genes at this locus in ovarian tumors supported a role for the BRCA1-interacting gene C19orf62, also known as MERIT40, which contains rs8170, in EOC development. © 2010 Nature America, Inc. All rights reserved.

Published
2010

50. Integrated genomic analyses of ovarian carcinoma

Author

Bell, D, Berchuck, A, Birrer, M, Chien, J, Cramer, DW, Dao, F, Dhir, R, DiSaia, P, Gabra, H, Glenn, P, Godwin, AK, Triche, T, Berman, BP, Van den Berg, DJ, Buckley, J, Baylin, SB, Zhang, J, Spellman, PT, Purdom, E, Iacocca, M, Shelton, T, Voet, D, Neuvial, P, Bengtsson, H, Jakkula, LR, Durinck, S, Han, J, Dorton, S, Marr, H, Zhang, H, Choi, YG, Wang, V, Wilkinson, J, Nguyen, H, Wang, NJ, Imielinski, M, Ngai, J, Conboy, JG, Parvin, B, Feiler, HS, Speed, TP, Gray, JW, Wu, CJ, Bloom, T, Levine, DA, Li, L, Socci, ND, Liang, Y, Taylor, BS, Kalloger, S, Schultz, N, Borsu, L, Lash, AE, Brennan, C, Ardlie, K, Viale, A, Shukla, S, Grimm, D, Sander, C, Ladanyi, M, Hoadley, KA, Meng, S, Du, Y, Karlan, BY, Shi, Y, Fennell, T, Cibulskis, K, Lawrence, MS, Meyerson, M, Hatfield, M, Mills, GB, Sivachenko, A, Jing, R, Park, RW, Liu, Y, Park, PJ, Ramos, AH, Noble, M, Chin, L, Carter, H, Kim, D, Morris, S, Winckler, W, Karchin, R, Morrison, C, Baldwin, J, Korkola, JE, Yena, P, Heiser, LM, Getz, G, Cho, RJ, Hu, Z, Gabriel, S, Mutch, D, Cerami, E, Rhodes, P, Olshen, A, Verhaak, RGW, Lander, ES, Reva, B, Antipin, Y, Shen, R, Olvera, N, Mankoo, P, Sheridan, R, Ciriello, G, Sherman, M, Chang, WK, Bernanke, JA, Hayes, DN, Carter, SL, Haussler, D, Orsulic, S, Benz, CC, Paulauskis, J, Stuart, JM, Zhang, N, Benz, SC, Sanborn, JZ, Vaske, CJ, Mermel, CH, Zhu, J, Szeto, C, Scott, GK, Yau, C, Rabeno, B, Ding, L, Park, K, Balu, S, Perou, CM, Saksena, G, Wilkerson, MD, Millis, S, Kahn, A, Turman, YJ, Fulton, RS, Onofrio, RC, Greene, JM, Sfeir, R, Jensen, MA, Chen, J, Whitmore, J, Alonso, S, Jordan, J, Chu, A, Rader, JS, Koboldt, DC, Zang, D, Gross, J, Barker, A, Compton, C, Eley, G, Ferguson, M, Fielding, P, Gerhard, DS, Myles, R, McLellan, MD, Schaefer, C, Helms, EB, Shaw, KRM, Sikic, BI, Vaught, J, Vockley, JB, Good, PJ, Guyer, MS, Ozenberger, B, Wylie, T, Peterson, J, Thomson, E, Smith-McCune, K, Sood, AK, Bowtell, D, Hubbard, D, Penny, R, Testa, JR, Chang, K, Walker, J, Dinh, HH, Drummond, JA, Fowler, G, Zhou, X, Gunaratne, P, Hawes, AC, Kovar, CL, Lewis, LR, Gupta, S, Morgan, MB, O'Laughlin, M, Newsham, IF, Santibanez, J, Reid, JG, Trevino, LR, Wu, J, Wu, Y-Q, Wang, M, Muzny, DM, Wheeler, DA, Gibbs, RA, Crenshaw, A, Sivachenko, AY, Topal, MD, Sougnez, C, Dooling, DJ, Fulton, L, Akbani, R, Abbott, R, Dees, ND, Zhang, Q, Kandoth, C, Wendl, M, Schierding, W, Shen, D, Harris, CC, Baggerly, KA, Schmidt, H, Wilson, RK, Kalicki, J, Delehaunty, KD, Fronick, CC, Demeter, R, Cook, L, Wallis, JW, Lin, L, Magrini, VJ, Yung, WK, Hodges, JS, Protopopov, A, Eldred, JM, Smith, SM, Pohl, CS, Vandin, F, Raphael, BJ, Weinstock, GM, Mardis, R, Kim, TM, Hartmann, L, Perna, I, Xiao, Y, Ren, G, Sathiamoorthy, N, Petrelli, N, Lee, E, Kucherlapati, R, Absher, DM, Huang, M, Waite, L, Sherlock, G, Brooks, JD, Li, JZ, Weinstein, JN, Xu, J, Myers, RM, Laird, PW, Cope, L, Herman, JG, Shen, H, Huntsman, DG, Weisenberger, DJ, Noushmehr, H, Pan, F, Massachusetts Institute of Technology. Department of Biology, Lander, Eric S., and Meyerson, Matthew L.

Subjects
endocrine system diseases, Serous carcinoma, Messenger, Gene Dosage, Cancer Genome Atlas Research Network, GYNECOLOGIC-ONCOLOGY-GROUP, GRADE SEROUS CARCINOMA, 0302 clinical medicine, Ovarian carcinoma, Aged, Carcinoma, DNA Methylation, Female, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Humans, MicroRNAs, Middle Aged, Mutation, Ovarian Neoplasms, RNA, Messenger, Genomics, Multidisciplinary, Genetics, HYBRID SELECTION, 0303 health sciences, female genital diseases and pregnancy complications, 3. Good health, Multidisciplinary Sciences, Serous fluid, BRCA MUTATION CARRIERS, 030220 oncology & carcinogenesis, DNA methylation, PARP inhibitor, Science & Technology - Other Topics, General Science & Technology, Biology, Article, 03 medical and health sciences, CLEAR-CELL CARCINOMA, MD Multidisciplinary, microRNA, HIGH-THROUGHPUT ANNOTATION, medicine, DRIVER MUTATIONS, Gene, 030304 developmental biology, Neoplastic, Science & Technology, MUTANT-CELLS, SOMATIC MUTATIONS, medicine.disease, CANCER STATISTICS, Gene Expression Regulation, Cancer research, RNA, Ovarian cancer
Abstract

A catalogue of molecular aberrations that cause ovarian cancer is critical for developing and deploying therapies that will improve patients’ lives. The Cancer Genome Atlas project has analysed messenger RNA expression, microRNA expression, promoter methylation and DNA copy number in 489 high-grade serous ovarian adenocarcinomas and the DNA sequences of exons from coding genes in 316 of these tumours. Here we report that high-grade serous ovarian cancer is characterized by TP53 mutations in almost all tumours (96%); low prevalence but statistically recurrent somatic mutations in nine further genes including NF1, BRCA1, BRCA2, RB1 and CDK12; 113 significant focal DNA copy number aberrations; and promoter methylation events involving 168 genes. Analyses delineated four ovarian cancer transcriptional subtypes, three microRNA subtypes, four promoter methylation subtypes and a transcriptional signature associated with survival duration, and shed new light on the impact that tumours with BRCA1/2 (BRCA1 or BRCA2) and CCNE1 aberrations have on survival. Pathway analyses suggested that homologous recombination is defective in about half of the tumours analysed, and that NOTCH and FOXM1 signalling are involved in serous ovarian cancer pathophysiology., National Institutes of Health (U.S.) (Grant U54HG003067), National Institutes of Health (U.S.) (Grant U54HG003273), National Institutes of Health (U.S.) (Grant U54HG003079), National Institutes of Health (U.S.) (Grant U24CA126543), National Institutes of Health (U.S.) (Grant U24CA126544), National Institutes of Health (U.S.) (Grant U24CA126546), National Institutes of Health (U.S.) (Grant U24CA126551), National Institutes of Health (U.S.) (Grant U24CA126554), National Institutes of Health (U.S.) (Grant U24CA126561), National Institutes of Health (U.S.) (Grant U24CA126563), National Institutes of Health (U.S.) (Grant U24CA143882), National Institutes of Health (U.S.) (Grant U24CA143731), National Institutes of Health (U.S.) (Grant U24CA143835), National Institutes of Health (U.S.) (Grant U24CA143845), National Institutes of Health (U.S.) (Grant U24CA143858), National Institutes of Health (U.S.) (Grant U24CA144025), National Institutes of Health (U.S.) (Grant U24CA143866), National Institutes of Health (U.S.) (Grant U24CA143867), National Institutes of Health (U.S.) (Grant U24CA143848), National Institutes of Health (U.S.) (Grant U24CA143843), National Institutes of Health (U.S.) (Grant R21CA135877)

Published
2010

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