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1. Benign breast disease and the risk of breast cancer

Author: Hartmann, LC, Sellers, TA, Frost, MH, Lingle, WL, Degnim, AC, Ghosh, K, Vierkant, RA, Maloney, SD, Pankratz, VS, Hillman, DW, Suman, VJ, Johnson, J, Blake, C, Tlsty, T, Vachon, CM, Melton, LJ, and Visscher, DW
Subjects: Clinical Research, Cancer, Breast Cancer, Patient Safety, Obstetrics & Reproductive Medicine, Paediatrics and Reproductive Medicine
Published: 2016

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. 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

4. 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

5. Methylation Signature Implicated in Immuno-Suppressive Activities in Tubo-Ovarian High-Grade Serous Carcinoma

Author: Wang, C, Block, MS, Cunningham, JM, Sherman, ME, McCauley, BM, Armasu, SM, Vierkant, RA, Traficante, N, Talhouk, A, Doherty, JA, Pejovic, N, Kobel, M, Jorgensen, BD, Garsed, DW, Fereday, S, Ramus, SJ, Ariyaratne, D, Anglesio, MS, Widschwendter, M, Pejovic, T, Bosquet, JG, Bowtell, DD, Winham, SJ, Goode, EL, Wang, C, Block, MS, Cunningham, JM, Sherman, ME, McCauley, BM, Armasu, SM, Vierkant, RA, Traficante, N, Talhouk, A, Doherty, JA, Pejovic, N, Kobel, M, Jorgensen, BD, Garsed, DW, Fereday, S, Ramus, SJ, Ariyaratne, D, Anglesio, MS, Widschwendter, M, Pejovic, T, Bosquet, JG, Bowtell, DD, Winham, SJ, and Goode, EL
Abstract: BACKGROUND: Better understanding of prognostic factors in tubo-ovarian high-grade serous carcinoma (HGSC) is critical, as diagnosis confers an aggressive disease course. Variation in tumor DNA methylation shows promise predicting outcome, yet prior studies were largely platform-specific and unable to evaluate multiple molecular features. METHODS: We analyzed genome-wide DNA methylation in 1,040 frozen HGSC, including 325 previously reported upon, seeking a multi-platform quantitative methylation signature that we evaluated in relation to clinical features, tumor characteristics, time to recurrence/death, extent of CD8+ tumor-infiltrating lymphocytes (TIL), gene expression molecular subtypes, and gene expression of the ATP-binding cassette transporter TAP1. RESULTS: Methylation signature was associated with shorter time to recurrence, independent of clinical factors (N = 715 new set, hazard ratio (HR), 1.65; 95% confidence interval (CI), 1.10-2.46; P = 0.015; N = 325 published set HR, 2.87; 95% CI, 2.17-3.81; P = 2.2 × 10-13) and remained prognostic after adjustment for gene expression molecular subtype and TAP1 expression (N = 599; HR, 2.22; 95% CI, 1.66-2.95; P = 4.1 × 10-8). Methylation signature was inversely related to CD8+ TIL levels (P = 2.4 × 10-7) and TAP1 expression (P = 0.0011) and was associated with gene expression molecular subtype (P = 5.9 × 10-4) in covariate-adjusted analysis. CONCLUSIONS: Multi-center analysis identified a novel quantitative tumor methylation signature of HGSC applicable to numerous commercially available platforms indicative of shorter time to recurrence/death, adjusting for other factors. Along with immune cell composition analysis, these results suggest a role for DNA methylation in the immunosuppressive microenvironment. IMPACT: This work aids in identification of targetable epigenome processes and stratification of patients for whom tailored treatment may be most beneficial.
Published: 2023

6. Concurrent RB1 loss and BRCA-deficiency predicts enhanced immunological response and long-term survival in tubo-ovarian high-grade serous carcinoma.

Author: Saner, FAM, Takahashi, K, Budden, T, Pandey, A, Ariyaratne, D, Zwimpfer, TA, Meagher, NS, Fereday, S, Twomey, L, Pishas, KI, Hoang, T, Bolithon, A, Traficante, N, Alsop, K, Christie, EL, Kang, E-Y, Nelson, GS, Ghatage, P, Lee, C-H, Riggan, MJ, Alsop, J, Beckmann, MW, Boros, J, Brand, AH, Brooks-Wilson, A, Carney, ME, Coulson, P, Courtney-Brooks, M, Cushing-Haugen, KL, Cybulski, C, El-Bahrawy, MA, Elishaev, E, Erber, R, Gayther, SA, Gentry-Maharaj, A, Blake Gilks, C, Harnett, PR, Harris, HR, Hartmann, A, Hein, A, Hendley, J, AOCS Group, Hernandez, BY, Jakubowska, A, Jimenez-Linan, M, Jones, ME, Kaufmann, SH, Kennedy, CJ, Kluz, T, Koziak, JM, Kristjansdottir, B, Le, ND, Lener, M, Lester, J, Lubiński, J, Mateoiu, C, Orsulic, S, Ruebner, M, Schoemaker, MJ, Shah, M, Sharma, R, Sherman, ME, Shvetsov, YB, Singh, N, Rinda Soong, T, Steed, H, Sukumvanich, P, Talhouk, A, Taylor, SE, Vierkant, RA, Wang, C, Widschwendter, M, Wilkens, LR, Winham, SJ, Anglesio, MS, Berchuck, A, Brenton, JD, Campbell, I, Cook, LS, Doherty, JA, Fasching, PA, Fortner, RT, Goodman, MT, Gronwald, J, Huntsman, DG, Karlan, BY, Kelemen, LE, Menon, U, Modugno, F, Pharoah, PDP, Schildkraut, JM, Sundfeldt, K, Swerdlow, AJ, Goode, EL, DeFazio, A, Köbel, M, Ramus, SJ, Bowtell, DDL, Garsed, DW, Saner, FAM, Takahashi, K, Budden, T, Pandey, A, Ariyaratne, D, Zwimpfer, TA, Meagher, NS, Fereday, S, Twomey, L, Pishas, KI, Hoang, T, Bolithon, A, Traficante, N, Alsop, K, Christie, EL, Kang, E-Y, Nelson, GS, Ghatage, P, Lee, C-H, Riggan, MJ, Alsop, J, Beckmann, MW, Boros, J, Brand, AH, Brooks-Wilson, A, Carney, ME, Coulson, P, Courtney-Brooks, M, Cushing-Haugen, KL, Cybulski, C, El-Bahrawy, MA, Elishaev, E, Erber, R, Gayther, SA, Gentry-Maharaj, A, Blake Gilks, C, Harnett, PR, Harris, HR, Hartmann, A, Hein, A, Hendley, J, AOCS Group, Hernandez, BY, Jakubowska, A, Jimenez-Linan, M, Jones, ME, Kaufmann, SH, Kennedy, CJ, Kluz, T, Koziak, JM, Kristjansdottir, B, Le, ND, Lener, M, Lester, J, Lubiński, J, Mateoiu, C, Orsulic, S, Ruebner, M, Schoemaker, MJ, Shah, M, Sharma, R, Sherman, ME, Shvetsov, YB, Singh, N, Rinda Soong, T, Steed, H, Sukumvanich, P, Talhouk, A, Taylor, SE, Vierkant, RA, Wang, C, Widschwendter, M, Wilkens, LR, Winham, SJ, Anglesio, MS, Berchuck, A, Brenton, JD, Campbell, I, Cook, LS, Doherty, JA, Fasching, PA, Fortner, RT, Goodman, MT, Gronwald, J, Huntsman, DG, Karlan, BY, Kelemen, LE, Menon, U, Modugno, F, Pharoah, PDP, Schildkraut, JM, Sundfeldt, K, Swerdlow, AJ, Goode, EL, DeFazio, A, Köbel, M, Ramus, SJ, Bowtell, DDL, and Garsed, DW
Abstract: BACKGROUND: Somatic loss of the tumour suppressor RB1 is a common event in tubo-ovarian high-grade serous carcinoma (HGSC), which frequently co-occurs with alterations in homologous recombination DNA repair genes including BRCA1 and BRCA2 (BRCA). We examined whether tumour expression of RB1 was associated with survival across ovarian cancer histotypes (HGSC, endometrioid (ENOC), clear cell (CCOC), mucinous (MOC), low-grade serous carcinoma (LGSC)), and how co-occurrence of germline BRCA pathogenic variants and RB1 loss influences long-term survival in a large series of HGSC. PATIENTS AND METHODS: RB1 protein expression patterns were classified by immunohistochemistry in epithelial ovarian carcinomas of 7436 patients from 20 studies participating in the Ovarian Tumor Tissue Analysis consortium and assessed for associations with overall survival (OS), accounting for patient age at diagnosis and FIGO stage. We examined RB1 expression and germline BRCA status in a subset of 1134 HGSC, and related genotype to survival, tumour infiltrating CD8+ lymphocyte counts and transcriptomic subtypes. Using CRISPR-Cas9, we deleted RB1 in HGSC cell lines with and without BRCA1 mutations to model co-loss with treatment response. We also performed genomic analyses on 126 primary HGSC to explore the molecular characteristics of concurrent homologous recombination deficiency and RB1 loss. RESULTS: RB1 protein loss was most frequent in HGSC (16.4%) and was highly correlated with RB1 mRNA expression. RB1 loss was associated with longer OS in HGSC (hazard ratio [HR] 0.74, 95% confidence interval [CI] 0.66-0.83, P = 6.8 ×10-7), but with poorer prognosis in ENOC (HR 2.17, 95% CI 1.17-4.03, P = 0.0140). Germline BRCA mutations and RB1 loss co-occurred in HGSC (P < 0.0001). Patients with both RB1 loss and germline BRCA mutations had a superior OS (HR 0.38, 95% CI 0.25-0.58, P = 5.2 ×10-6) compared to patients with either alteration alone, and their median OS was three times longer than non-carr
Published: 2023

7. 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

8. Increased FOXJ1 protein expression is associated with improved overall survival in high-grade serous ovarian carcinoma: an Ovarian Tumor Tissue Analysis Consortium Study

Author: Weir, A, Kang, E-Y, Meagher, NS, Nelson, GS, Ghatage, P, Lee, C-H, Riggan, MJ, Gentry-Maharaj, A, Ryan, A, Singh, N, Widschwendter, M, Alsop, J, Anglesio, MS, Beckmann, MW, Berger, J, Bisinotto, C, Boros, J, Brand, AH, Brenton, JD, Brooks-Wilson, A, Carney, ME, Cunningham, JM, Cushing-Haugen, KL, Cybulski, C, Elishaev, E, Erber, R, Fereday, S, Fischer, A, Paz-Ares, L, Gayarre, J, Gilks, BC, Grube, M, Harnett, PR, Harris, HR, Hartmann, A, Hein, A, Hendley, J, Hernandez, BY, Heublein, S, Huang, Y, Huzarski, T, Jakubowska, A, Jimenez-Linan, M, Kennedy, CJ, Kommoss, FKF, Koziak, JM, Kraemer, B, Le, ND, Lesnock, J, Lester, J, Lubinski, J, Menkiszak, J, Ney, B, Olawaiye, A, Orsulic, S, Osorio, A, Robles-Diaz, L, Ruebner, M, Shah, M, Sharma, R, Shvetsov, YB, Steed, H, Talhouk, A, Taylor, SE, Traficante, N, Vierkant, RA, Wang, C, Wilkens, LR, Winham, SJ, Benitez, J, Berchuck, A, Bowtell, DD, Candido dos Reis, FJ, Cook, LS, DeFazio, A, Doherty, JA, Fasching, PA, Garcia, MJ, Goode, EL, Goodman, MT, Gronwald, J, Huntsman, DG, Karlan, BY, Kommoss, S, Modugno, F, Schildkraut, JM, Sinn, H-P, Staebler, A, Kelemen, LE, Ford, CE, Menon, U, Pharoah, PDP, Koebel, M, Ramus, SJ, Bowtell, D, Brand, A, Harnett, P, Weir, A, Kang, E-Y, Meagher, NS, Nelson, GS, Ghatage, P, Lee, C-H, Riggan, MJ, Gentry-Maharaj, A, Ryan, A, Singh, N, Widschwendter, M, Alsop, J, Anglesio, MS, Beckmann, MW, Berger, J, Bisinotto, C, Boros, J, Brand, AH, Brenton, JD, Brooks-Wilson, A, Carney, ME, Cunningham, JM, Cushing-Haugen, KL, Cybulski, C, Elishaev, E, Erber, R, Fereday, S, Fischer, A, Paz-Ares, L, Gayarre, J, Gilks, BC, Grube, M, Harnett, PR, Harris, HR, Hartmann, A, Hein, A, Hendley, J, Hernandez, BY, Heublein, S, Huang, Y, Huzarski, T, Jakubowska, A, Jimenez-Linan, M, Kennedy, CJ, Kommoss, FKF, Koziak, JM, Kraemer, B, Le, ND, Lesnock, J, Lester, J, Lubinski, J, Menkiszak, J, Ney, B, Olawaiye, A, Orsulic, S, Osorio, A, Robles-Diaz, L, Ruebner, M, Shah, M, Sharma, R, Shvetsov, YB, Steed, H, Talhouk, A, Taylor, SE, Traficante, N, Vierkant, RA, Wang, C, Wilkens, LR, Winham, SJ, Benitez, J, Berchuck, A, Bowtell, DD, Candido dos Reis, FJ, Cook, LS, DeFazio, A, Doherty, JA, Fasching, PA, Garcia, MJ, Goode, EL, Goodman, MT, Gronwald, J, Huntsman, DG, Karlan, BY, Kommoss, S, Modugno, F, Schildkraut, JM, Sinn, H-P, Staebler, A, Kelemen, LE, Ford, CE, Menon, U, Pharoah, PDP, Koebel, M, Ramus, SJ, Bowtell, D, Brand, A, and Harnett, P
Abstract: BACKGROUND: Recently, we showed a >60% difference in 5-year survival for patients with tubo-ovarian high-grade serous carcinoma (HGSC) when stratified by a 101-gene mRNA expression prognostic signature. Given the varied patient outcomes, this study aimed to translate prognostic mRNA markers into protein expression assays by immunohistochemistry and validate their survival association in HGSC. METHODS: Two prognostic genes, FOXJ1 and GMNN, were selected based on high-quality antibodies, correlation with protein expression and variation in immunohistochemical scores in a preliminary cohort (n = 134 and n = 80, respectively). Six thousand four hundred and thirty-four (FOXJ1) and 5470 (GMNN) formalin-fixed, paraffin-embedded ovarian neoplasms (4634 and 4185 HGSC, respectively) represented on tissue microarrays from the Ovarian Tumor Tissue Analysis consortium underwent immunohistochemical staining and scoring, then univariate and multivariate survival analysis. RESULTS: Consistent with mRNA, FOXJ1 protein expression exhibited a linear, increasing association with improved overall survival in HGSC patients. Women with >50% expression had the most favourable outcomes (HR = 0.78, 95% CI 0.67-0.91, p < 0.0001). GMNN protein expression was not significantly associated with overall HSGC patient survival. However, HGSCs with >35% GMNN expression showed a trend for better outcomes, though this was not significant. CONCLUSION: We provide foundational evidence for the prognostic value of FOXJ1 in HGSC, validating the prior mRNA-based prognostic association by immunohistochemistry.
Published: 2023

9. 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

10. Polygenic risk modeling for prediction of epithelial ovarian cancer risk (vol 30, pg 349, 2021)

Author: Dareng, EO, Tyrer, JP, Barnes, DR, Jones, MR, Yang, X, Aben, KKH, Adank, MA, Agata, S, Andrulis, IL, Anton-Culver, H, Antonenkova, NN, Aravantinos, G, Arun, BK, Augustinsson, A, Balmana, J, Bandera, EV, Barkardottir, RB, Barrowdale, D, Beckmann, MW, Beeghly-Fadiel, A, Benitez, J, Bermisheva, M, Bernardini, MQ, Bjorge, L, Black, A, Bogdanova, NV, Bonanni, B, Borg, A, Brenton, JD, Budzilowska, A, Butzow, R, Buys, SS, Cai, H, Caligo, MA, Campbell, I, Cannioto, R, Cassingham, H, Chang-Claude, J, Chanock, SJ, Chen, K, Chiew, Y-E, Chung, WK, Claes, KBM, Colonna, S, Cook, LS, Couch, FJ, Daly, MB, Dao, F, Davies, E, de la Hoya, M, de Putter, R, Dennis, J, DePersia, A, Devilee, P, Diez, O, Ding, YC, Doherty, JA, Domchek, SM, Dork, T, du Bois, A, Durst, M, Eccles, DM, Eliassen, HA, Engel, C, Evans, GD, Fasching, PA, Flanagan, JM, Fortner, RT, Machackova, E, Friedman, E, Ganz, PA, Garber, J, Gensini, F, Giles, GG, Glendon, G, Godwin, AK, Goodman, MT, Greene, MH, Gronwald, J, Hahnen, E, Haiman, CA, Hakansson, N, Hamann, U, Hansen, TVO, Harris, HR, Hartman, M, Heitz, F, Hildebrandt, MAT, Hogdall, E, Hogdall, CK, Hopper, JL, Huang, R-Y, Huff, C, Hulick, PJ, Huntsman, DG, Imyanitov, EN, Isaacs, C, Jakubowska, A, James, PA, Janavicius, R, Jensen, A, Johannsson, OT, John, EM, Jones, ME, Kang, D, Karlan, BY, Karnezis, A, Kelemen, LE, Khusnutdinova, E, Kiemeney, LA, Kim, B-G, Kjaer, SK, Komenaka, I, Kupryjanczyk, J, Kurian, AW, Kwong, A, Lambrechts, D, Larson, MC, Lazaro, C, Le, ND, Leslie, G, Lester, J, Lesueur, F, Levine, DA, Li, L, Li, J, Loud, JT, Lu, KH, Lubinski, J, Mai, PL, Manoukian, S, Marks, JR, Matsuno, RK, Matsuo, K, May, T, McGuffog, L, McLaughlin, JR, McNeish, IA, Mebirouk, N, Menon, U, Miller, A, Milne, RL, Minlikeeva, A, Modugno, F, Montagna, M, Moysich, KB, Munro, E, Nathanson, KL, Neuhausen, SL, Nevanlinna, H, Yie, JNY, Nielsen, HR, Nielsen, FC, Nikitina-Zake, L, Odunsi, K, Offit, K, Olah, E, Olbrecht, S, Olopade, OI, Olson, SH, Olsson, H, Osorio, A, Papi, L, Park, SK, Parsons, MT, Pathak, H, Pedersen, IS, Peixoto, A, Pejovic, T, Perez-Segura, P, Permuth, JB, Peshkin, B, Peterlongo, P, Piskorz, A, Prokofyeva, D, Radice, P, Rantala, J, Riggan, MJ, Risch, HA, Rodriguez-Antona, C, Ross, E, Rossing, MA, Runnebaum, I, Sandler, DP, Santamarina, M, Soucy, P, Schmutzler, RK, Setiawan, VW, Shan, K, Sieh, W, Simard, J, Singer, CF, Sokolenko, AP, Song, H, Southey, MC, Steed, H, Stoppa-Lyonnet, D, Sutphen, R, Swerdlow, AJ, Tan, YY, Teixeira, MR, Teo, SH, Terry, KL, Terry, MB, Thomassen, M, Thompson, PJ, Thomsen, LCV, Thull, DL, Tischkowitz, M, Titus, L, Toland, AE, Torres, D, Trabert, B, Travis, R, Tung, N, Tworoger, SS, Valen, E, van Altena, AM, van der Hout, AH, Van Nieuwenhuysen, E, van Rensburg, EJ, Vega, A, Edwards, DV, Vierkant, RA, Wang, F, Wappenschmidt, B, Webb, PM, Weinberg, CR, Weitzel, JN, Wentzensen, N, White, E, Whittemore, AS, Winham, SJ, Wolk, A, Woo, Y-L, Wu, AH, Yan, L, Yannoukakos, D, Zavaglia, KM, Zheng, W, Ziogas, A, Zorn, KK, Kleibl, Z, Easton, D, Lawrenson, K, DeFazio, A, Sellers, TA, Ramus, SJ, Pearce, CL, Monteiro, AN, Cunningham, JM, Goode, EL, Schildkraut, JM, Berchuck, A, Chenevix-Trench, G, Gayther, SA, Antoniou, AC, Pharoah, PDP, Dareng, EO, Tyrer, JP, Barnes, DR, Jones, MR, Yang, X, Aben, KKH, Adank, MA, Agata, S, Andrulis, IL, Anton-Culver, H, Antonenkova, NN, Aravantinos, G, Arun, BK, Augustinsson, A, Balmana, J, Bandera, EV, Barkardottir, RB, Barrowdale, D, Beckmann, MW, Beeghly-Fadiel, A, Benitez, J, Bermisheva, M, Bernardini, MQ, Bjorge, L, Black, A, Bogdanova, NV, Bonanni, B, Borg, A, Brenton, JD, Budzilowska, A, Butzow, R, Buys, SS, Cai, H, Caligo, MA, Campbell, I, Cannioto, R, Cassingham, H, Chang-Claude, J, Chanock, SJ, Chen, K, Chiew, Y-E, Chung, WK, Claes, KBM, Colonna, S, Cook, LS, Couch, FJ, Daly, MB, Dao, F, Davies, E, de la Hoya, M, de Putter, R, Dennis, J, DePersia, A, Devilee, P, Diez, O, Ding, YC, Doherty, JA, Domchek, SM, Dork, T, du Bois, A, Durst, M, Eccles, DM, Eliassen, HA, Engel, C, Evans, GD, Fasching, PA, Flanagan, JM, Fortner, RT, Machackova, E, Friedman, E, Ganz, PA, Garber, J, Gensini, F, Giles, GG, Glendon, G, Godwin, AK, Goodman, MT, Greene, MH, Gronwald, J, Hahnen, E, Haiman, CA, Hakansson, N, Hamann, U, Hansen, TVO, Harris, HR, Hartman, M, Heitz, F, Hildebrandt, MAT, Hogdall, E, Hogdall, CK, Hopper, JL, Huang, R-Y, Huff, C, Hulick, PJ, Huntsman, DG, Imyanitov, EN, Isaacs, C, Jakubowska, A, James, PA, Janavicius, R, Jensen, A, Johannsson, OT, John, EM, Jones, ME, Kang, D, Karlan, BY, Karnezis, A, Kelemen, LE, Khusnutdinova, E, Kiemeney, LA, Kim, B-G, Kjaer, SK, Komenaka, I, Kupryjanczyk, J, Kurian, AW, Kwong, A, Lambrechts, D, Larson, MC, Lazaro, C, Le, ND, Leslie, G, Lester, J, Lesueur, F, Levine, DA, Li, L, Li, J, Loud, JT, Lu, KH, Lubinski, J, Mai, PL, Manoukian, S, Marks, JR, Matsuno, RK, Matsuo, K, May, T, McGuffog, L, McLaughlin, JR, McNeish, IA, Mebirouk, N, Menon, U, Miller, A, Milne, RL, Minlikeeva, A, Modugno, F, Montagna, M, Moysich, KB, Munro, E, Nathanson, KL, Neuhausen, SL, Nevanlinna, H, Yie, JNY, Nielsen, HR, Nielsen, FC, Nikitina-Zake, L, Odunsi, K, Offit, K, Olah, E, Olbrecht, S, Olopade, OI, Olson, SH, Olsson, H, Osorio, A, Papi, L, Park, SK, Parsons, MT, Pathak, H, Pedersen, IS, Peixoto, A, Pejovic, T, Perez-Segura, P, Permuth, JB, Peshkin, B, Peterlongo, P, Piskorz, A, Prokofyeva, D, Radice, P, Rantala, J, Riggan, MJ, Risch, HA, Rodriguez-Antona, C, Ross, E, Rossing, MA, Runnebaum, I, Sandler, DP, Santamarina, M, Soucy, P, Schmutzler, RK, Setiawan, VW, Shan, K, Sieh, W, Simard, J, Singer, CF, Sokolenko, AP, Song, H, Southey, MC, Steed, H, Stoppa-Lyonnet, D, Sutphen, R, Swerdlow, AJ, Tan, YY, Teixeira, MR, Teo, SH, Terry, KL, Terry, MB, Thomassen, M, Thompson, PJ, Thomsen, LCV, Thull, DL, Tischkowitz, M, Titus, L, Toland, AE, Torres, D, Trabert, B, Travis, R, Tung, N, Tworoger, SS, Valen, E, van Altena, AM, van der Hout, AH, Van Nieuwenhuysen, E, van Rensburg, EJ, Vega, A, Edwards, DV, Vierkant, RA, Wang, F, Wappenschmidt, B, Webb, PM, Weinberg, CR, Weitzel, JN, Wentzensen, N, White, E, Whittemore, AS, Winham, SJ, Wolk, A, Woo, Y-L, Wu, AH, Yan, L, Yannoukakos, D, Zavaglia, KM, Zheng, W, Ziogas, A, Zorn, KK, Kleibl, Z, Easton, D, Lawrenson, K, DeFazio, A, Sellers, TA, Ramus, SJ, Pearce, CL, Monteiro, AN, Cunningham, JM, Goode, EL, Schildkraut, JM, Berchuck, A, Chenevix-Trench, G, Gayther, SA, Antoniou, AC, and Pharoah, PDP
Published: 2022

11. Polygenic risk modeling for prediction of epithelial ovarian cancer risk

Author: Dareng, EO, Tyrer, JP, Barnes, DR, Jones, MR, Yang, X, Aben, KKH, Adank, MA, Agata, S, Andrulis, IL, Anton-Culver, H, Antonenkova, NN, Aravantinos, G, Arun, BK, Augustinsson, A, Balmana, J, Bandera, E, Barkardottir, RB, Barrowdale, D, Beckmann, MW, Beeghly-Fadiel, A, Benitez, J, Bermisheva, M, Bernardini, MQ, Bjorge, L, Black, A, Bogdanova, N, Bonanni, B, Borg, A, Brenton, JD, Budzilowska, A, Butzow, R, Buys, SS, Cai, H, Caligo, MA, Campbell, I, Cannioto, R, Cassingham, H, Chang-Claude, J, Chanock, SJ, Chen, K, Chiew, Y-E, Chung, WK, Claes, KBM, Colonna, S, Cook, LS, Couch, FJ, Daly, MB, Dao, F, Davies, E, de la Hoya, M, de Putter, R, Dennis, J, DePersia, A, Devilee, P, Diez, O, Ding, YC, Doherty, JA, Domchek, SM, Dork, T, du Bois, A, Durst, M, Eccles, DM, Eliassen, HA, Engel, C, Evans, GD, Fasching, PA, Flanagan, JM, Fortner, R, Machackova, E, Friedman, E, Ganz, PA, Garber, J, Gensini, F, Giles, GG, Glendon, G, Godwin, AK, Goodman, MT, Greene, MH, Gronwald, J, Group, OS, AOCSGroup, Hahnen, E, Haiman, CA, Hakansson, N, Hamann, U, Hansen, TVO, Harris, HR, Hartman, M, Heitz, F, Hildebrandt, MAT, Hogdall, E, Hogdall, CK, Hopper, JL, Huang, R-Y, Huff, C, Hulick, PJ, Huntsman, DG, Imyanitov, EN, Isaacs, C, Jakubowska, A, James, PA, Janavicius, R, Jensen, A, Johannsson, OT, John, EM, Jones, ME, Kang, D, Karlan, BY, Karnezis, A, Kelemen, LE, Khusnutdinova, E, Kiemeney, LA, Kim, B-G, Kjaer, SK, Komenaka, I, Kupryjanczyk, J, Kurian, AW, Kwong, A, Lambrechts, D, Larson, MC, Lazaro, C, Le, ND, Leslie, G, Lester, J, Lesueur, F, Levine, DA, Li, L, Li, J, Loud, JT, Lu, KH, Mai, PL, Manoukian, S, Marks, JR, KimMatsuno, R, Matsuo, K, May, T, McGuffog, L, McLaughlin, JR, McNeish, IA, Mebirouk, N, Menon, U, Miller, A, Milne, RL, Minlikeeva, A, Modugno, F, Montagna, M, Moysich, KB, Munro, E, Nathanson, KL, Neuhausen, SL, Nevanlinna, H, Yie, JNY, Nielsen, HR, Nielsen, FC, Nikitina-Zake, L, Odunsi, K, Offit, K, Olah, E, Olbrecht, S, Olopade, O, Olson, SH, Olsson, H, Osorio, A, Papi, L, Park, SK, Parsons, MT, Pathak, H, Pedersen, IS, Peixoto, A, Pejovic, T, Perez-Segura, P, Permuth, JB, Peshkin, B, Peterlongo, P, Piskorz, A, Prokofyeva, D, Radice, P, Rantala, J, Riggan, MJ, Risch, HA, Rodriguez-Antona, C, Ross, E, Rossing, MA, Runnebaum, I, Sandler, DP, Santamarina, M, Soucy, P, Schmutzler, RK, Setiawan, VW, Shan, K, Sieh, W, Simard, J, Singer, CF, Sokolenko, AP, Song, H, Southey, MC, Steed, H, Stoppa-Lyonnet, D, Sutphen, R, Swerdlow, AJ, Tan, YY, Teixeira, MR, Teo, SH, Terry, KL, BethTerry, M, Thomassen, M, Thompson, PJ, Thomsen, LCV, Thull, DL, Tischkowitz, M, Titus, L, Toland, AE, Torres, D, Trabert, B, Travis, R, Tung, N, Tworoger, SS, Valen, E, van Altena, AM, van der Hout, AH, Nieuwenhuysen, E, van Rensburg, EJ, Vega, A, Edwards, DV, Vierkant, RA, Wang, F, Wappenschmidt, B, Webb, PM, Weinberg, CR, Weitzel, JN, Wentzensen, N, White, E, Whittemore, AS, Winham, SJ, Wolk, A, Woo, Y-L, Wu, AH, Yan, L, Yannoukakos, D, Zavaglia, KM, Zheng, W, Ziogas, A, Zorn, KK, Kleibl, Z, Easton, D, Lawrenson, K, DeFazio, A, Sellers, TA, Ramus, SJ, Pearce, CL, Monteiro, AN, Cunningham, J, Goode, EL, Schildkraut, JM, Berchuck, A, Chenevix-Trench, G, Gayther, SA, Antoniou, AC, Pharoah, PDP, Dareng, EO, Tyrer, JP, Barnes, DR, Jones, MR, Yang, X, Aben, KKH, Adank, MA, Agata, S, Andrulis, IL, Anton-Culver, H, Antonenkova, NN, Aravantinos, G, Arun, BK, Augustinsson, A, Balmana, J, Bandera, E, Barkardottir, RB, Barrowdale, D, Beckmann, MW, Beeghly-Fadiel, A, Benitez, J, Bermisheva, M, Bernardini, MQ, Bjorge, L, Black, A, Bogdanova, N, Bonanni, B, Borg, A, Brenton, JD, Budzilowska, A, Butzow, R, Buys, SS, Cai, H, Caligo, MA, Campbell, I, Cannioto, R, Cassingham, H, Chang-Claude, J, Chanock, SJ, Chen, K, Chiew, Y-E, Chung, WK, Claes, KBM, Colonna, S, Cook, LS, Couch, FJ, Daly, MB, Dao, F, Davies, E, de la Hoya, M, de Putter, R, Dennis, J, DePersia, A, Devilee, P, Diez, O, Ding, YC, Doherty, JA, Domchek, SM, Dork, T, du Bois, A, Durst, M, Eccles, DM, Eliassen, HA, Engel, C, Evans, GD, Fasching, PA, Flanagan, JM, Fortner, R, Machackova, E, Friedman, E, Ganz, PA, Garber, J, Gensini, F, Giles, GG, Glendon, G, Godwin, AK, Goodman, MT, Greene, MH, Gronwald, J, Group, OS, AOCSGroup, Hahnen, E, Haiman, CA, Hakansson, N, Hamann, U, Hansen, TVO, Harris, HR, Hartman, M, Heitz, F, Hildebrandt, MAT, Hogdall, E, Hogdall, CK, Hopper, JL, Huang, R-Y, Huff, C, Hulick, PJ, Huntsman, DG, Imyanitov, EN, Isaacs, C, Jakubowska, A, James, PA, Janavicius, R, Jensen, A, Johannsson, OT, John, EM, Jones, ME, Kang, D, Karlan, BY, Karnezis, A, Kelemen, LE, Khusnutdinova, E, Kiemeney, LA, Kim, B-G, Kjaer, SK, Komenaka, I, Kupryjanczyk, J, Kurian, AW, Kwong, A, Lambrechts, D, Larson, MC, Lazaro, C, Le, ND, Leslie, G, Lester, J, Lesueur, F, Levine, DA, Li, L, Li, J, Loud, JT, Lu, KH, Mai, PL, Manoukian, S, Marks, JR, KimMatsuno, R, Matsuo, K, May, T, McGuffog, L, McLaughlin, JR, McNeish, IA, Mebirouk, N, Menon, U, Miller, A, Milne, RL, Minlikeeva, A, Modugno, F, Montagna, M, Moysich, KB, Munro, E, Nathanson, KL, Neuhausen, SL, Nevanlinna, H, Yie, JNY, Nielsen, HR, Nielsen, FC, Nikitina-Zake, L, Odunsi, K, Offit, K, Olah, E, Olbrecht, S, Olopade, O, Olson, SH, Olsson, H, Osorio, A, Papi, L, Park, SK, Parsons, MT, Pathak, H, Pedersen, IS, Peixoto, A, Pejovic, T, Perez-Segura, P, Permuth, JB, Peshkin, B, Peterlongo, P, Piskorz, A, Prokofyeva, D, Radice, P, Rantala, J, Riggan, MJ, Risch, HA, Rodriguez-Antona, C, Ross, E, Rossing, MA, Runnebaum, I, Sandler, DP, Santamarina, M, Soucy, P, Schmutzler, RK, Setiawan, VW, Shan, K, Sieh, W, Simard, J, Singer, CF, Sokolenko, AP, Song, H, Southey, MC, Steed, H, Stoppa-Lyonnet, D, Sutphen, R, Swerdlow, AJ, Tan, YY, Teixeira, MR, Teo, SH, Terry, KL, BethTerry, M, Thomassen, M, Thompson, PJ, Thomsen, LCV, Thull, DL, Tischkowitz, M, Titus, L, Toland, AE, Torres, D, Trabert, B, Travis, R, Tung, N, Tworoger, SS, Valen, E, van Altena, AM, van der Hout, AH, Nieuwenhuysen, E, van Rensburg, EJ, Vega, A, Edwards, DV, Vierkant, RA, Wang, F, Wappenschmidt, B, Webb, PM, Weinberg, CR, Weitzel, JN, Wentzensen, N, White, E, Whittemore, AS, Winham, SJ, Wolk, A, Woo, Y-L, Wu, AH, Yan, L, Yannoukakos, D, Zavaglia, KM, Zheng, W, Ziogas, A, Zorn, KK, Kleibl, Z, Easton, D, Lawrenson, K, DeFazio, A, Sellers, TA, Ramus, SJ, Pearce, CL, Monteiro, AN, Cunningham, J, Goode, EL, Schildkraut, JM, Berchuck, A, Chenevix-Trench, G, Gayther, SA, Antoniou, AC, and Pharoah, PDP
Abstract: Polygenic risk scores (PRS) for epithelial ovarian cancer (EOC) have the potential to improve risk stratification. Joint estimation of Single Nucleotide Polymorphism (SNP) effects in models could improve predictive performance over standard approaches of PRS construction. Here, we implemented computationally efficient, penalized, logistic regression models (lasso, elastic net, stepwise) to individual level genotype data and a Bayesian framework with continuous shrinkage, "select and shrink for summary statistics" (S4), to summary level data for epithelial non-mucinous ovarian cancer risk prediction. We developed the models in a dataset consisting of 23,564 non-mucinous EOC cases and 40,138 controls participating in the Ovarian Cancer Association Consortium (OCAC) and validated the best models in three populations of different ancestries: prospective data from 198,101 women of European ancestries; 7,669 women of East Asian ancestries; 1,072 women of African ancestries, and in 18,915 BRCA1 and 12,337 BRCA2 pathogenic variant carriers of European ancestries. In the external validation data, the model with the strongest association for non-mucinous EOC risk derived from the OCAC model development data was the S4 model (27,240 SNPs) with odds ratios (OR) of 1.38 (95% CI: 1.28-1.48, AUC: 0.588) per unit standard deviation, in women of European ancestries; 1.14 (95% CI: 1.08-1.19, AUC: 0.538) in women of East Asian ancestries; 1.38 (95% CI: 1.21-1.58, AUC: 0.593) in women of African ancestries; hazard ratios of 1.36 (95% CI: 1.29-1.43, AUC: 0.592) in BRCA1 pathogenic variant carriers and 1.49 (95% CI: 1.35-1.64, AUC: 0.624) in BRCA2 pathogenic variant carriers. Incorporation of the S4 PRS in risk prediction models for ovarian cancer may have clinical utility in ovarian cancer prevention programs.
Published: 2022

12. The genomic and immune landscape of long-term survivors of high-grade serous ovarian cancer

Author: Garsed, DW, Pandey, A, Fereday, S, Kennedy, CJ, Takahashi, K, Alsop, K, Hamilton, PT, Hendley, J, Chiew, Y-E, Traficante, N, Provan, P, Ariyaratne, D, Au-Yeung, G, Bateman, NW, Bowes, L, Brand, A, Christie, EL, Cunningham, JM, Friedlander, M, Grout, B, Harnett, P, Hung, J, McCauley, B, McNally, O, Piskorz, AM, Saner, FAM, Vierkant, RA, Wang, C, Winham, SJ, Pharoah, PDP, Brenton, JD, Conrads, TP, Maxwell, GL, Ramus, SJ, Pearce, CL, Pike, MC, Nelson, BH, Goode, EL, DeFazio, A, Bowtell, DDL, Garsed, DW, Pandey, A, Fereday, S, Kennedy, CJ, Takahashi, K, Alsop, K, Hamilton, PT, Hendley, J, Chiew, Y-E, Traficante, N, Provan, P, Ariyaratne, D, Au-Yeung, G, Bateman, NW, Bowes, L, Brand, A, Christie, EL, Cunningham, JM, Friedlander, M, Grout, B, Harnett, P, Hung, J, McCauley, B, McNally, O, Piskorz, AM, Saner, FAM, Vierkant, RA, Wang, C, Winham, SJ, Pharoah, PDP, Brenton, JD, Conrads, TP, Maxwell, GL, Ramus, SJ, Pearce, CL, Pike, MC, Nelson, BH, Goode, EL, DeFazio, A, and Bowtell, DDL
Abstract: Fewer than half of all patients with advanced-stage high-grade serous ovarian cancers (HGSCs) survive more than five years after diagnosis, but those who have an exceptionally long survival could provide insights into tumor biology and therapeutic approaches. We analyzed 60 patients with advanced-stage HGSC who survived more than 10 years after diagnosis using whole-genome sequencing, transcriptome and methylome profiling of their primary tumor samples, comparing this data to 66 short- or moderate-term survivors. Tumors of long-term survivors were more likely to have multiple alterations in genes associated with DNA repair and more frequent somatic variants resulting in an increased predicted neoantigen load. Patients clustered into survival groups based on genomic and immune cell signatures, including three subsets of patients with BRCA1 alterations with distinctly different outcomes. Specific combinations of germline and somatic gene alterations, tumor cell phenotypes and differential immune responses appear to contribute to long-term survival in HGSC.
Published: 2022

13. Association of p16 expression with prognosis varies across ovarian carcinoma histotypes: an Ovarian Tumor Tissue Analysis consortium study

Author: Rambau, PF, Vierkant, RA, Intermaggio, MP, Kelemen, LE, Goodman, MT, Herpel, E, Pharoah, PD, Kommoss, S, Jimenez-Linan, M, Karlan, BY, Gentry-Maharaj, A, Menon, U, Polo, SH, Candido Dos Reis, FJ, Doherty, JA, Gayther, SA, Sharma, R, Larson, MC, Harnett, PR, Hatfield, E, de Andrade, JM, Nelson, GS, Steed, H, Schildkraut, JM, Carney, ME, Høgdall, E, Whittemore, AS, Widschwendter, M, Kennedy, CJ, Wang, F, Wang, Q, Wang, C, Armasu, SM, Daley, F, Coulson, P, Jones, ME, Anglesio, MS, Chow, C, de Fazio, A, García-Closas, M, Brucker, SY, Cybulski, C, Harris, HR, Hartkopf, AD, Huzarski, T, Jensen, A, Lubiński, J, Oszurek, O, Benitez, J, Mina, F, Staebler, A, Taran, FA, Pasternak, J, Talhouk, A, Rossing, MA, Hendley, J, Edwards, RP, Fereday, S, Modugno, F, Ness, RB, Sieh, W, El-Bahrawy, MA, Winham, SJ, Lester, J, Kjaer, SK, Gronwald, J, Sinn, P, Fasching, PA, Chang-Claude, J, Moysich, KB, Bowtell, DD, Hernandez, BY, Luk, H, Behrens, S, Shah, M, Jung, A, Ghatage, P, Alsop, J, Alsop, K, García-Donas, J, Thompson, PJ, Swerdlow, AJ, Karpinskyj, C, Cazorla-Jiménez, A, García, MJ, Deen, S, Wilkens, LR, Palacios, J, Berchuck, A, Koziak, JM, Brenton, JD, Cook, LS, Goode, EL, Huntsman, DG, Ramus, SJ, Köbel, M, Rambau, PF, Vierkant, RA, Intermaggio, MP, Kelemen, LE, Goodman, MT, Herpel, E, Pharoah, PD, Kommoss, S, Jimenez-Linan, M, Karlan, BY, Gentry-Maharaj, A, Menon, U, Polo, SH, Candido Dos Reis, FJ, Doherty, JA, Gayther, SA, Sharma, R, Larson, MC, Harnett, PR, Hatfield, E, de Andrade, JM, Nelson, GS, Steed, H, Schildkraut, JM, Carney, ME, Høgdall, E, Whittemore, AS, Widschwendter, M, Kennedy, CJ, Wang, F, Wang, Q, Wang, C, Armasu, SM, Daley, F, Coulson, P, Jones, ME, Anglesio, MS, Chow, C, de Fazio, A, García-Closas, M, Brucker, SY, Cybulski, C, Harris, HR, Hartkopf, AD, Huzarski, T, Jensen, A, Lubiński, J, Oszurek, O, Benitez, J, Mina, F, Staebler, A, Taran, FA, Pasternak, J, Talhouk, A, Rossing, MA, Hendley, J, Edwards, RP, Fereday, S, Modugno, F, Ness, RB, Sieh, W, El-Bahrawy, MA, Winham, SJ, Lester, J, Kjaer, SK, Gronwald, J, Sinn, P, Fasching, PA, Chang-Claude, J, Moysich, KB, Bowtell, DD, Hernandez, BY, Luk, H, Behrens, S, Shah, M, Jung, A, Ghatage, P, Alsop, J, Alsop, K, García-Donas, J, Thompson, PJ, Swerdlow, AJ, Karpinskyj, C, Cazorla-Jiménez, A, García, MJ, Deen, S, Wilkens, LR, Palacios, J, Berchuck, A, Koziak, JM, Brenton, JD, Cook, LS, Goode, EL, Huntsman, DG, Ramus, SJ, and Köbel, M
Abstract: We aimed to validate the prognostic association of p16 expression in ovarian high-grade serous carcinomas (HGSC) and to explore it in other ovarian carcinoma histotypes. p16 protein expression was assessed by clinical-grade immunohistochemistry in 6525 ovarian carcinomas including 4334 HGSC using tissue microarrays from 24 studies participating in the Ovarian Tumor Tissue Analysis consortium. p16 expression patterns were interpreted as abnormal (either overexpression referred to as block expression or absence) or normal (heterogeneous). CDKN2A (which encodes p16) mRNA expression was also analyzed in a subset (n = 2280) mostly representing HGSC (n = 2010). Association of p16 expression with overall survival (OS) was determined within histotypes as was CDKN2A expression for HGSC only. p16 block expression was most frequent in HGSC (56%) but neither protein nor mRNA expression was associated with OS. However, relative to heterogeneous expression, block expression was associated with shorter OS in endometriosis-associated carcinomas, clear cell [hazard ratio (HR): 2.02, 95% confidence (CI) 1.47-2.77, p < 0.001] and endometrioid (HR: 1.88, 95% CI 1.30-2.75, p = 0.004), while absence was associated with shorter OS in low-grade serous carcinomas (HR: 2.95, 95% CI 1.61-5.38, p = 0.001). Absence was most frequent in mucinous carcinoma (50%), and was not associated with OS in this histotype. The prognostic value of p16 expression is histotype-specific and pattern dependent. We provide definitive evidence against an association of p16 expression with survival in ovarian HGSC as previously suggested. Block expression of p16 in clear cell and endometrioid carcinoma should be further validated as a prognostic marker, and absence in low-grade serous carcinoma justifies CDK4 inhibition.
Published: 2018

14. MyD88 and TLR4 Expression in Epithelial Ovarian Cancer

Author: Block, MS, Vierkant, RA, Rambau, PF, Winham, SJ, Wagner, P, Traficante, N, Toloczko, A, Tiezzi, DG, Taran, FA, Sinn, P, Sieh, W, Sharma, R, Rothstein, JH, Ramon y Cajal, T, Paz-Ares, L, Oszurek, O, Orsulic, S, Ness, RB, Nelson, G, Modugno, F, Menkiszak, J, McGuire, V, McCauley, BM, Mack, M, Lubinski, J, Longacre, TA, Li, Z, Lester, J, Kennedy, CJ, Kalli, KR, Jung, AY, Johnatty, SE, Jimenez-Linan, M, Jensen, A, Intermaggio, MP, Hung, J, Herpel, E, Hernandez, BY, Hartkopf, AD, Harnett, PR, Ghatage, P, Garcia-Bueno, JM, Gao, B, Fereday, S, Eilber, U, Edwards, RP, de Sousa, CB, de Andrade, JM, Chudecka-Glaz, A, Chenevix-Trench, G, Cazorla, A, Brucker, SY, Alsop, J, Whittemore, AS, Steed, H, Staebler, A, Moysich, KB, Menon, U, Koziak, JM, Kommoss, S, Kjaer, SK, Kelemen, LE, Karlan, BY, Huntsman, DG, Hogdall, E, Gronwald, J, Goodman, MT, Gilks, B, Jose Garcia, M, Fasching, PA, de Fazio, A, Deen, S, Chang-Claude, J, dos Reis, FJC, Campbell, IG, Brenton, JD, Bowtell, DD, Benitez, J, Pharoah, PDP, Kobel, M, Ramus, SJ, Goode, EL, Block, MS, Vierkant, RA, Rambau, PF, Winham, SJ, Wagner, P, Traficante, N, Toloczko, A, Tiezzi, DG, Taran, FA, Sinn, P, Sieh, W, Sharma, R, Rothstein, JH, Ramon y Cajal, T, Paz-Ares, L, Oszurek, O, Orsulic, S, Ness, RB, Nelson, G, Modugno, F, Menkiszak, J, McGuire, V, McCauley, BM, Mack, M, Lubinski, J, Longacre, TA, Li, Z, Lester, J, Kennedy, CJ, Kalli, KR, Jung, AY, Johnatty, SE, Jimenez-Linan, M, Jensen, A, Intermaggio, MP, Hung, J, Herpel, E, Hernandez, BY, Hartkopf, AD, Harnett, PR, Ghatage, P, Garcia-Bueno, JM, Gao, B, Fereday, S, Eilber, U, Edwards, RP, de Sousa, CB, de Andrade, JM, Chudecka-Glaz, A, Chenevix-Trench, G, Cazorla, A, Brucker, SY, Alsop, J, Whittemore, AS, Steed, H, Staebler, A, Moysich, KB, Menon, U, Koziak, JM, Kommoss, S, Kjaer, SK, Kelemen, LE, Karlan, BY, Huntsman, DG, Hogdall, E, Gronwald, J, Goodman, MT, Gilks, B, Jose Garcia, M, Fasching, PA, de Fazio, A, Deen, S, Chang-Claude, J, dos Reis, FJC, Campbell, IG, Brenton, JD, Bowtell, DD, Benitez, J, Pharoah, PDP, Kobel, M, Ramus, SJ, and Goode, EL
Abstract: OBJECTIVE: To evaluate myeloid differentiation primary response gene 88 (MyD88) and Toll-like receptor 4 (TLR4) expression in relation to clinical features of epithelial ovarian cancer, histologic subtypes, and overall survival. PATIENTS AND METHODS: We conducted centralized immunohistochemical staining, semi-quantitative scoring, and survival analysis in 5263 patients participating in the Ovarian Tumor Tissue Analysis consortium. Patients were diagnosed between January 1, 1978, and December 31, 2014, including 2865 high-grade serous ovarian carcinomas (HGSOCs), with more than 12,000 person-years of follow-up time. Tissue microarrays were stained for MyD88 and TLR4, and staining intensity was classified using a 2-tiered system for each marker (weak vs strong). RESULTS: Expression of MyD88 and TLR4 was similar in all histotypes except clear cell ovarian cancer, which showed reduced expression compared with other histotypes (P<.001 for both). In HGSOC, strong MyD88 expression was modestly associated with shortened overall survival (hazard ratio [HR], 1.13; 95% CI, 1.01-1.26; P=.04) but was also associated with advanced stage (P<.001). The expression of TLR4 was not associated with survival. In low-grade serous ovarian cancer (LGSOC), strong expression of both MyD88 and TLR4 was associated with favorable survival (HR [95% CI], 0.49 [0.29-0.84] and 0.44 [0.21-0.89], respectively; P=.009 and P=.02, respectively). CONCLUSION: Results are consistent with an association between strong MyD88 staining and advanced stage and poorer survival in HGSOC and demonstrate correlation between strong MyD88 and TLR4 staining and improved survival in LGSOC, highlighting the biological differences between the 2 serous histotypes.
Published: 2018

15. 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

16. 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

17. 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

18. 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, Doerk, T, Hillemanns, P, Preus, L, Knutson, KL, Wallace, PK, Hong, C-C, 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, Duerst, M, Easton, D, Eccles, D, Edwards, RP, Ekici, AB, Fasching, PA, Fridley, BL, Gao, Y-T, 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, B-T, 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, Lu, K, Lubinski, J, Lundvall, L, Massuger, LFAG, Matsuo, K, McGuire, V, McLaughlin, JR, McNeish, I, Menon, U, Moes-Sosnowska, J, Narod, SA, Nedergaard, L, Nevanlinna, H, Nickels, S, Olson, SH, Orlow, I, Weber, RP, Paul, J, Pejovic, T, Pelttari, LM, Perkins, B, Permuth-Wey, J, Pike, MC, Plisiecka-Halasa, J, Poole, EM, Risch, HA, Rossing, MA, Rothstein, JH, Rudolph, A, Runnebaum, IB, Rzepecka, IK, Salvesen, HB, Schernhammer, E, Schmitt, K, Schwaab, I, Shu, X-O, Shvetsov, YB, Siddiqui, N, Sieh, W, Song, H, Southey, MC, Tangen, IL, Teo, S-H, Thompson, PJ, Timorek, A, Tsai, Y-Y, Tworoger, SS, Tyrer, J, van Altena, AM, Vergote, I, Vierkant, RA, Walsh, C, Wang-Gohrke, S, Wentzensen, N, Whittemore, AS, Wicklund, KG, Wilkens, LR, Wu, AH, Wu, X, Woo, Y-L, Yang, H, Zheng, W, Ziogas, A, Gayther, SA, Ramus, SJ, Sellers, TA, Schildkraut, JM, Phelan, CM, Berchuck, A, Chenevix-Trench, G, Cunningham, JM, Pharoah, PP, Ness, RB, Odunsi, K, Goode, EL, Moysich, KB, Hampras, SS, Sucheston-Campbell, LE, Cannioto, R, Chang-Claude, J, Modugno, F, Doerk, T, Hillemanns, P, Preus, L, Knutson, KL, Wallace, PK, Hong, C-C, 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, Duerst, M, Easton, D, Eccles, D, Edwards, RP, Ekici, AB, Fasching, PA, Fridley, BL, Gao, Y-T, 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, B-T, 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, Lu, K, Lubinski, J, Lundvall, L, Massuger, LFAG, Matsuo, K, McGuire, V, McLaughlin, JR, McNeish, I, Menon, U, Moes-Sosnowska, J, Narod, SA, Nedergaard, L, Nevanlinna, H, Nickels, S, Olson, SH, Orlow, I, Weber, RP, Paul, J, Pejovic, T, Pelttari, LM, Perkins, B, Permuth-Wey, J, Pike, MC, Plisiecka-Halasa, J, Poole, EM, Risch, HA, Rossing, MA, Rothstein, JH, Rudolph, A, Runnebaum, IB, Rzepecka, IK, Salvesen, HB, Schernhammer, E, Schmitt, K, Schwaab, I, Shu, X-O, Shvetsov, YB, Siddiqui, N, Sieh, W, Song, H, Southey, MC, Tangen, IL, Teo, S-H, Thompson, PJ, Timorek, A, Tsai, Y-Y, Tworoger, SS, Tyrer, J, van Altena, AM, Vergote, I, Vierkant, RA, Walsh, C, Wang-Gohrke, S, Wentzensen, N, Whittemore, AS, Wicklund, KG, Wilkens, LR, Wu, AH, Wu, X, Woo, Y-L, Yang, H, Zheng, W, Ziogas, A, Gayther, SA, Ramus, SJ, Sellers, TA, Schildkraut, JM, Phelan, CM, Berchuck, A, Chenevix-Trench, G, Cunningham, JM, Pharoah, PP, Ness, RB, Odunsi, K, Goode, EL, and Moysich, KB
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

19. A targeted genetic association study of epithelial ovarian cancer susceptibility.

Author: Earp, M, Winham, SJ, Larson, N, Permuth, JB, Sicotte, H, Chien, J, Anton-Culver, H, Bandera, EV, Berchuck, A, Cook, LS, Cramer, D, Doherty, JA, Goodman, MT, Levine, DA, Monteiro, ANA, Ness, RB, Pearce, CL, Rossing, MA, Tworoger, SS, Wentzensen, N, Bisogna, M, Brinton, L, Brooks-Wilson, A, Carney, ME, Cunningham, JM, Edwards, RP, Fogarty, ZC, Iversen, ES, Kraft, P, Larson, MC, Le, ND, Lin, H-Y, Lissowska, J, Modugno, F, Moysich, KB, Olson, SH, Pike, MC, Poole, EM, Rider, DN, Terry, KL, Thompson, PJ, van den Berg, D, Vierkant, RA, Vitonis, AF, Wilkens, LR, Wu, AH, Yang, HP, Ziogas, A, Phelan, CM, Schildkraut, JM, Chen, YA, Sellers, TA, Fridley, BL, Goode, EL, Earp, M, Winham, SJ, Larson, N, Permuth, JB, Sicotte, H, Chien, J, Anton-Culver, H, Bandera, EV, Berchuck, A, Cook, LS, Cramer, D, Doherty, JA, Goodman, MT, Levine, DA, Monteiro, ANA, Ness, RB, Pearce, CL, Rossing, MA, Tworoger, SS, Wentzensen, N, Bisogna, M, Brinton, L, Brooks-Wilson, A, Carney, ME, Cunningham, JM, Edwards, RP, Fogarty, ZC, Iversen, ES, Kraft, P, Larson, MC, Le, ND, Lin, H-Y, Lissowska, J, Modugno, F, Moysich, KB, Olson, SH, Pike, MC, Poole, EM, Rider, DN, Terry, KL, Thompson, PJ, van den Berg, D, Vierkant, RA, Vitonis, AF, Wilkens, LR, Wu, AH, Yang, HP, Ziogas, A, Phelan, CM, Schildkraut, JM, Chen, YA, Sellers, TA, Fridley, BL, and Goode, EL
Abstract: BACKGROUND: Genome-wide association studies have identified several common susceptibility alleles for epithelial ovarian cancer (EOC). To further understand EOC susceptibility, we examined previously ungenotyped candidate variants, including uncommon variants and those residing within known susceptibility loci. RESULTS: At nine of eleven previously published EOC susceptibility regions (2q31, 3q25, 5p15, 8q21, 8q24, 10p12, 17q12, 17q21.31, and 19p13), novel variants were identified that were more strongly associated with risk than previously reported variants. Beyond known susceptibility regions, no variants were found to be associated with EOC risk at genome-wide statistical significance (p <5x10(-8)), nor were any significant after Bonferroni correction for 17,000 variants (p< 3x10-6). METHODS: A customized genotyping array was used to assess over 17,000 variants in coding, non-coding, regulatory, and known susceptibility regions in 4,973 EOC cases and 5,640 controls from 13 independent studies. Susceptibility for EOC overall and for select histotypes was evaluated using logistic regression adjusted for age, study site, and population substructure. CONCLUSION: Given the novel variants identified within the 2q31, 3q25, 5p15, 8q21, 8q24, 10p12, 17q12, 17q21.31, and 19p13 regions, larger follow-up genotyping studies, using imputation where necessary, are needed for fine-mapping and confirmation of low frequency variants that fall below statistical significance.
Published: 2016

20. 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

21. Risk of ovarian cancer and the NF-kB pathway: Genetic association with IL1A and TNFSF10

Author: Charbonneau, B, Block, MS, Bamlet, WR, Vierkant, RA, Kalli, KR, Fogarty, Z, Rider, DN, Sellers, TA, Tworoger, SS, Poole, E, Risch, HA, Salvesen, HB, Kiemeney, LA, Baglietto, L, Giles, GG, Severi, G, Trabert, B, Wentzensen, N, Chenevix-Trench, G, Whittemore, AS, Sieh, W, Chang-Claude, J, Bandera, EV, Orlow, I, Terry, K, Goodman, MT, Thompson, PJ, Cook, LS, Rossing, MA, Ness, RB, Narod, SA, Kupryjanczyk, J, Lu, K, Butzow, R, Dork, T, Pejovic, T, Campbell, I, Le, ND, Bunker, CH, Bogdanova, N, Runnebaum, IB, Eccles, D, Paul, J, Wu, AH, Gayther, SA, Hogdall, E, Heitz, F, Kaye, SB, Karlan, BY, Anton-Culver, H, Gronwald, J, Hogdall, CK, Lambrechts, D, Fasching, PA, Menon, U, Schildkraut, J, Pearce, CL, Levine, DA, Kjaer, SK, Cramer, D, Flanagan, JM, Phelan, CM, Brown, R, Massuger, LFAG, Song, H, Doherty, JA, Krakstad, C, Liang, D, Odunsi, K, Berchuck, A, Jensen, A, Lubinski, J, Nevanlinna, H, and Bean, YT
Abstract: A missense single-nucleotide polymorphism (SNP) in the immune modulatory gene IL1A has been associated with ovarian cancer risk (rs17561). Although the exact mechanism through which this SNP alters risk of ovarian cancer is not clearly understood, rs17561 has also been associated with risk of endometriosis, an epidemiologic risk factor for ovarian cancer. Interleukin-1a (IL1A) is both regulated by and able to activate NF-kB, a transcription factor family that induces transcription of many proinflammatory genes and may be an important mediator in carcinogenesis. We therefore tagged SNPs in more than 200 genes in the NF-kB pathway for a total of 2,282 SNPs (including rs17561) for genotype analysis of 15,604 cases of ovarian cancer in patients of European descent, including 6,179 of high-grade serous (HGS), 2,100 endometrioid, 1,591 mucinous, 1,034 clear cell, and 1,016 low-grade serous, including 23,235 control cases spanning 40 studies in the Ovarian Cancer Association Consortium. In this large population, we confirmed the association between rs17561 and clear cell ovarian cancer [OR, 0.84; 95% confidence interval (CI), 0.76-0.93; P < 0.00075], which remained intact even after excluding participants in the prior study (OR, 0.85; 95% CI, 0.75-0.95; P < 0.006). Considering a multiple-testing-corrected significance threshold of P < 2.5 ± 10-5, only one other variant, the TNFSF10 SNP rs6785617, was associated significantly with a risk of ovarian cancer (low malignant potential tumors OR, 0.85; 95% CI, 0.79-0.91; P < 0.00002). Our results extend the evidence that borderline tumors may have a distinct genetic etiology. Further investigation of how these SNPs might modify ovarian cancer associations with other inflammation-related risk factors is warranted. © 2013 AACR.
Published: 2014

22. 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

23. Variation in NF-κB signaling pathways and survival in invasive epithelial ovarian cancer

Author: Block, MS, Charbonneau, B, Vierkant, RA, Fogarty, Z, Bamlet, WR, Pharoah, PDP, Chenevix-Trench, G, Rossing, MA, Cramer, D, Pearce, CL, Schildkraut, J, Menon, U, Kjaer, SK, Levine, DA, Gronwald, J, Culver, HA, Whittemore, AS, Karlan, BY, Lambrechts, D, Wentzensen, N, Kupryjanczyk, J, Chang-Claude, J, Bandera, EV, Hogdall, E, Heitz, F, Kaye, SB, Fasching, PA, Campbell, I, Goodman, MT, Pejovic, T, Bean, YT, Hays, LE, Lurie, G, Eccles, D, Hein, A, Beckmann, MW, Ekici, AB, Paul, J, Brown, R, Flanagan, JM, Harter, P, Du Bois, A, Schwaab, I, Hogdall, CK, Lundvall, L, Olson, SH, Orlow, I, Paddock, LE, Rudolph, A, Eilber, U, Dansonka-Mieszkowska, A, Rzepecka, IK, Ziolkowska-Seta, I, Brinton, LA, Yang, H, Garcia-Closas, M, Despierre, E, Lambrechts, S, Vergote, I, Walsh, CS, Lester, J, Sieh, W, McGuire, V, Rothstein, JH, Ziogas, A, Lubinski, J, Cybulski, C, Menkiszak, J, Jensen, A, Gayther, SA, Ramus, SJ, Gentry-Maharaj, A, Berchuck, A, Wu, AH, Pike, MC, Van Den Berg, D, Terry, KL, Vitonis, AF, Ramirez, SM, Rider, DN, Knutson, KL, and Sellers, TA
Subjects: endocrine system diseases, female genital diseases and pregnancy complications
Abstract: Survival in epithelial ovarian cancer (EOC) is influenced by the host immune response, yet the key genetic determinants of inflammation and immunity that affect prognosis are not known. The nuclear factor-kB (NF-kB) transcription factor family plays an important role in many immune and inflammatory responses, including the response to cancer. We studied common inherited variation in 210 genes in the NF-kB family in 10,084 patients with invasive EOC (5,248 high-grade serous, 1,452 endometrioid, 795 clear cell, and 661 mucinous) from the Ovarian Cancer Association Consortium. Associations between genotype and overall survival were assessed using Cox regression for all patients and by major histology, adjusting for known prognostic factors and correcting for multiple testing (threshold for statistical significance, P < 2.5 × 10-5). Results were statistically significant when assessed for patients of a single histology. Key associations were with caspase recruitment domain family, member 11 (CARD11) rs41324349 in patients with mucinous EOC [HR, 1.82; 95% confidence interval (CI), 1.41-2.35; P = 4.13 × 10-6] and tumor necrosis factor receptor superfamily, member 13B (TNFRSF13B) rs7501462 in patients with endometrioid EOC (HR, 0.68; 95% CI, 0.56-0.82; P = 2.33 × 10-5). Other associations of note included TNF receptor-associated factor 2 (TRAF2) rs17250239 in patients with high-grade serous EOC (HR, 0.84; 95% CI, 0.77-0.92; P = 6.49 ± 10-5) and phospholipase C, gamma 1 (PLCG1) rs11696662 in patients with clear cell EOC (HR, 0.43; 95% CI, 0.26-0.73; P = 4.56 × 10-4). These associations highlight the potential importance of genes associated with host inflammation and immunity in modulating clinical outcomes in distinct EOC histologies. © 2014 American Association for Cancer Research.
Published: 2014

24. Abstract P6-10-19: Clinicopathologic features of breast cancers that develop in women with previous benign breast disease

Author: Visscher, DW, primary, Frost, MH, additional, Hartmanan, LC, additional, Frank, RD, additional, Vierkant, RA, additional, McCullough, AE, additional, Winham, SJ, additional, Vachon, C, additional, Ghosh, K, additional, Brandt, KR, additional, Farrell, AM, additional, Tarabishy, Y, additional, Hieken, TJ, additional, Haddad, TC, additional, Kraft, RA, additional, Radisky, DC, additional, and Degnim, AC, additional
Published: 2016
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25. Abstract P6-09-05: No evidence of association between mammographic breast density and risk of breast cancer in women with atypical hyperplasia

Author: Vierkant, RA, primary, Degnim, AC, additional, Hartmann, LC, additional, Frank, RD, additional, Radisky, DC, additional, Visscher, DW, additional, Frost, MH, additional, Winham, SJ, additional, Ghosh, K, additional, and Vachon, CM, additional
Published: 2016
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26. 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

27. 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

28. 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

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

Author: Kelemen, LE, Lawrenson, K, Tyrer, J, Li, Q, Lee, JM, Seo, J-H, 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, Doerk, T, du Bois, A, Duerst, M, Eccles, D, Easton, DT, Edwards, RP, Eilber, U, Ekici, AB, Engelholm, SA, Fasching, PA, Fridley, BL, Gao, Y-T, 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, B-T, Karlan, BY, Kellar, M, Kelley, JL, 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, Lissowska, J, Lu, K, Lubinski, J, Lundvall, L, Massuger, LFAG, Matsuo, K, McGuire, V, McLaughlin, JR, McNeish, I, Menon, U, Modugno, F, Moes-Sosnowska, J, Moysich, KB, Narod, SA, Nedergaard, L, Ness, RB, Nevanlinna, H, Adenan, NAM, Odunsi, K, Olson, SH, Orlow, I, Orsulic, S, Weber, RP, Paul, J, Pearce, CL, Pejovic, T, Pelttari, LM, Permuth-Wey, J, Pike, MC, Poole, EM, Ramus, SJ, Risch, HA, Rosen, B, Rossing, MA, Rothstein, JH, Rudolph, A, Runnebaum, IB, Rzepecka, IK, Salvesen, HB, Schildkraut, JM, Schwaab, I, Shu, X-O, Shvetsov, YB, Siddiqui, N, Sieh, W, Song, H, Southey, MC, Sucheston, L, Tangen, IL, Teo, S-H, Terry, KL, Thompson, PJ, Tworoger, SS, van Altena, AM, Van Nieuwenhuysen, E, Vergote, I, Vierkant, RA, Wang-Gohrke, S, Walsh, C, Wentzensen, N, Whittemore, AS, Wicklund, KG, Wilkens, LR, Sawicki, W, Woo, Y-L, Wu, X, Wu, AH, Yang, H, Zheng, W, Ziogas, A, Sellers, TA, Freedman, ML, Chenevix-Trench, G, Pharoah, PDP, Gayther, SA, Berchuck, A, Kelemen, LE, Lawrenson, K, Tyrer, J, Li, Q, Lee, JM, Seo, J-H, 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, Doerk, T, du Bois, A, Duerst, M, Eccles, D, Easton, DT, Edwards, RP, Eilber, U, Ekici, AB, Engelholm, SA, Fasching, PA, Fridley, BL, Gao, Y-T, 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, B-T, Karlan, BY, Kellar, M, Kelley, JL, 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, Lissowska, J, Lu, K, Lubinski, J, Lundvall, L, Massuger, LFAG, Matsuo, K, McGuire, V, McLaughlin, JR, McNeish, I, Menon, U, Modugno, F, Moes-Sosnowska, J, Moysich, KB, Narod, SA, Nedergaard, L, Ness, RB, Nevanlinna, H, Adenan, NAM, Odunsi, K, Olson, SH, Orlow, I, Orsulic, S, Weber, RP, Paul, J, Pearce, CL, Pejovic, T, Pelttari, LM, Permuth-Wey, J, Pike, MC, Poole, EM, Ramus, SJ, Risch, HA, Rosen, B, Rossing, MA, Rothstein, JH, Rudolph, A, Runnebaum, IB, Rzepecka, IK, Salvesen, HB, Schildkraut, JM, Schwaab, I, Shu, X-O, Shvetsov, YB, Siddiqui, N, Sieh, W, Song, H, Southey, MC, Sucheston, L, Tangen, IL, Teo, S-H, Terry, KL, Thompson, PJ, Tworoger, SS, van Altena, AM, Van Nieuwenhuysen, E, Vergote, I, Vierkant, RA, Wang-Gohrke, S, Walsh, C, Wentzensen, N, Whittemore, AS, Wicklund, KG, Wilkens, LR, Sawicki, W, Woo, Y-L, Wu, X, Wu, AH, Yang, H, Zheng, W, Ziogas, A, Sellers, TA, Freedman, ML, Chenevix-Trench, G, Pharoah, PDP, Gayther, SA, and Berchuck, A
Abstract: 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

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

Author: Lawrenson, K, Li, Q, Kar, S, Seo, J-H, 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, Doerk, T, Du Bois, A, Duerst, M, Eccles, D, Easton, DT, Edwards, RP, Eilber, U, Ekici, AB, Fasching, PA, Fridley, BL, Gao, Y-T, 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, B-T, Karlan, BY, Kjaer, SK, Kelemen, LE, Kellar, M, Kelley, JL, Kiemeney, LA, Krakstad, C, Kupryjanczyk, J, Lambrechts, D, Lambrechts, S, Le, ND, Lee, AW, Lele, S, Leminen, A, Lester, J, Levine, DA, Liang, D, Lissowska, J, Lu, K, Lubinski, J, Lundvall, L, Massuger, LFAG, Matsuo, K, McGuire, V, McLaughlin, JR, Nevanlinna, H, McNeish, I, Menon, U, Modugno, F, Moysich, KB, Narod, SA, Nedergaard, L, Ness, RB, Azmi, MAN, Odunsi, K, Olson, SH, Orlow, I, Orsulic, S, Weber, RP, Pearce, CL, Pejovic, T, Pelttari, LM, Permuth-Wey, J, Phelan, CM, Pike, MC, Poole, EM, Ramus, SJ, Risch, HA, Rosen, B, Rossing, MA, Rothstein, JH, Rudolph, A, Runnebaum, IB, Rzepecka, IK, Salvesen, HB, Schildkraut, JM, Schwaab, I, Sellers, TA, Shu, X-O, Shvetsov, YB, Siddiqui, N, Sieh, W, Song, H, Southey, MC, Sucheston, L, Tangen, IL, Teo, S-H, Terry, KL, Thompson, PJ, Timorek, A, Tsai, Y-Y, Tworoger, SS, Van Altena, AM, Van Nieuwenhuysen, E, Vergote, I, Vierkant, RA, Wang-Gohrke, S, Walsh, C, Wentzensen, N, Whittemore, AS, Wicklund, KG, Wilkens, LR, Woo, Y-L, Wu, X, Wu, AH, Yang, H, Zheng, W, Ziogas, A, Monteiro, A, Pharoah, PD, Gayther, SA, Freedman, ML, Grp, AOCS, Bowtell, D, Webb, PM, Defazio, A, Lawrenson, K, Li, Q, Kar, S, Seo, J-H, 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, Doerk, T, Du Bois, A, Duerst, M, Eccles, D, Easton, DT, Edwards, RP, Eilber, U, Ekici, AB, Fasching, PA, Fridley, BL, Gao, Y-T, 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, B-T, Karlan, BY, Kjaer, SK, Kelemen, LE, Kellar, M, Kelley, JL, Kiemeney, LA, Krakstad, C, Kupryjanczyk, J, Lambrechts, D, Lambrechts, S, Le, ND, Lee, AW, Lele, S, Leminen, A, Lester, J, Levine, DA, Liang, D, Lissowska, J, Lu, K, Lubinski, J, Lundvall, L, Massuger, LFAG, Matsuo, K, McGuire, V, McLaughlin, JR, Nevanlinna, H, McNeish, I, Menon, U, Modugno, F, Moysich, KB, Narod, SA, Nedergaard, L, Ness, RB, Azmi, MAN, Odunsi, K, Olson, SH, Orlow, I, Orsulic, S, Weber, RP, Pearce, CL, Pejovic, T, Pelttari, LM, Permuth-Wey, J, Phelan, CM, Pike, MC, Poole, EM, Ramus, SJ, Risch, HA, Rosen, B, Rossing, MA, Rothstein, JH, Rudolph, A, Runnebaum, IB, Rzepecka, IK, Salvesen, HB, Schildkraut, JM, Schwaab, I, Sellers, TA, Shu, X-O, Shvetsov, YB, Siddiqui, N, Sieh, W, Song, H, Southey, MC, Sucheston, L, Tangen, IL, Teo, S-H, Terry, KL, Thompson, PJ, Timorek, A, Tsai, Y-Y, Tworoger, SS, Van Altena, AM, Van Nieuwenhuysen, E, Vergote, I, Vierkant, RA, Wang-Gohrke, S, Walsh, C, Wentzensen, N, Whittemore, AS, Wicklund, KG, Wilkens, LR, Woo, Y-L, Wu, X, Wu, AH, Yang, H, Zheng, W, Ziogas, A, Monteiro, A, Pharoah, PD, Gayther, SA, Freedman, ML, Grp, AOCS, Bowtell, D, Webb, PM, and Defazio, A
Abstract: 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<1.4 × 10(-3), FDR<0.05) at 1p36 (CDC42), 1p34 (CDCA8) and 2q31 (HOXD9), we evaluate the functional role of each candidate by perturbing expression of each gene in HGSOC precursor cells. Overexpression of HOXD9 increases anchorage-independent growth, shortens population-doubling time and reduces contact inhibition. Chromosome conformation capture identifies an interaction between rs2857532 and the HOXD9 promoter, suggesting this SNP is a leading causal variant. Transcriptomic profiling after HOXD9 overexpression reveals enrichment of HGSOC risk variants within HOXD9 target genes (P=6 × 10(-10) for risk variants (P<10(-4)) within 10 kb of a HOXD9 target gene in ovarian cells), suggesting a broader role for this network in genetic susceptibility to HGSOC.
Published: 2015

31. 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

32. Evidence for a time-dependent association between FOLR1 expression and survival from ovarian carcinoma: implications for clinical testing. An Ovarian Tumour Tissue Analysis consortium study

Author: Koebel, M, Madore, J, Ramus, SJ, Clarke, BA, Pharoah, PDP, Deen, S, Bowtell, DD, Odunsi, K, Menon, U, Morrison, C, Lele, S, Bshara, W, Sucheston, L, Beckmann, MW, Hein, A, Thiel, FC, Hartmann, A, Wachter, DL, Anglesio, MS, Hogdall, E, Jensen, A, Hogdall, C, Kalli, KR, Fridley, BL, Keeney, GL, Fogarty, ZC, Vierkant, RA, Liu, S, Cho, S, Nelson, G, Ghatage, P, Gentry-Maharaj, A, Gayther, SA, Benjamin, E, Widschwendter, M, Intermaggio, MP, Rosen, B, Bernardini, MQ, Mackay, H, Oza, A, Shaw, P, Jimenez-Linan, M, Driver, KE, Alsop, J, Mack, M, Koziak, JM, Steed, H, Ewanowich, C, DeFazio, A, Chenevix-Trench, G, Fereday, S, Gao, B, Johnatty, SE, George, J, Galletta, L, Goode, EL, Kjaer, SK, Huntsman, DG, Fasching, PA, Moysich, KB, Brenton, JD, Kelemen, LE, Koebel, M, Madore, J, Ramus, SJ, Clarke, BA, Pharoah, PDP, Deen, S, Bowtell, DD, Odunsi, K, Menon, U, Morrison, C, Lele, S, Bshara, W, Sucheston, L, Beckmann, MW, Hein, A, Thiel, FC, Hartmann, A, Wachter, DL, Anglesio, MS, Hogdall, E, Jensen, A, Hogdall, C, Kalli, KR, Fridley, BL, Keeney, GL, Fogarty, ZC, Vierkant, RA, Liu, S, Cho, S, Nelson, G, Ghatage, P, Gentry-Maharaj, A, Gayther, SA, Benjamin, E, Widschwendter, M, Intermaggio, MP, Rosen, B, Bernardini, MQ, Mackay, H, Oza, A, Shaw, P, Jimenez-Linan, M, Driver, KE, Alsop, J, Mack, M, Koziak, JM, Steed, H, Ewanowich, C, DeFazio, A, Chenevix-Trench, G, Fereday, S, Gao, B, Johnatty, SE, George, J, Galletta, L, Goode, EL, Kjaer, SK, Huntsman, DG, Fasching, PA, Moysich, KB, Brenton, JD, and Kelemen, LE
Abstract: BACKGROUND: Folate receptor 1 (FOLR1) is expressed in the majority of ovarian carcinomas (OvCa), making it an attractive target for therapy. However, clinical trials testing anti-FOLR1 therapies in OvCa show mixed results and require better understanding of the prognostic relevance of FOLR1 expression. We conducted a large study evaluating FOLR1 expression with survival in different histological types of OvCa. METHODS: Tissue microarrays composed of tumour samples from 2801 patients in the Ovarian Tumour Tissue Analysis (OTTA) consortium were assessed for FOLR1 expression by centralised immunohistochemistry. We estimated associations for overall (OS) and progression-free (PFS) survival using adjusted Cox regression models. High-grade serous ovarian carcinomas (HGSC) from The Cancer Genome Atlas (TCGA) were evaluated independently for association between FOLR1 mRNA upregulation and survival. RESULTS: FOLR1 expression ranged from 76% in HGSC to 11% in mucinous carcinomas in OTTA. For HGSC, the association between FOLR1 expression and OS changed significantly during the years following diagnosis in OTTA (Pinteraction=0.01, N=1422) and TCGA (Pinteraction=0.01, N=485). In OTTA, particularly for FIGO stage I/II tumours, patients with FOLR1-positive HGSC showed increased OS during the first 2 years only (hazard ratio=0.44, 95% confidence interval=0.20-0.96) and patients with FOLR1-positive clear cell carcinomas (CCC) showed decreased PFS independent of follow-up time (HR=1.89, 95% CI=1.10-3.25, N=259). In TCGA, FOLR1 mRNA upregulation in HGSC was also associated with increased OS during the first 2 years following diagnosis irrespective of tumour stage (HR: 0.48, 95% CI: 0.25-0.94). CONCLUSIONS: FOLR1-positive HGSC tumours were associated with an increased OS in the first 2 years following diagnosis. Patients with FOLR1-negative, poor prognosis HGSC would be unlikely to benefit from anti-FOLR1 therapies. In contrast, a decreased PFS interval was observed for FOLR1-positive
Published: 2014

33. Genome-wide association study identifies multiple loci associated with both mammographic density and breast cancer risk

Author: Lindstroem, S, Thompson, DJ, Paterson, AD, Li, J, Gierach, GL, Scott, C, Stone, J, Douglas, JA, dos-Santos-Silva, I, Fernandez-Navarro, P, Verghase, J, Smith, P, Brown, J, Luben, R, Wareham, NJ, Loos, RJF, Heit, JA, Pankratz, VS, Norman, A, Goode, EL, Cunningham, JM, Deandrade, M, Vierkant, RA, Czene, K, Fasching, PA, Baglietto, L, Southey, MC, Giles, GG, Shah, KP, Chan, H-P, Helvie, MA, Beck, AH, Knoblauch, NW, Hazra, A, Hunter, DJ, Kraft, P, Pollan, M, Figueroa, JD, Couch, FJ, Hopper, JL, Hall, P, Easton, DF, Boyd, NF, Vachon, CM, Tamimi, RM, Lindstroem, S, Thompson, DJ, Paterson, AD, Li, J, Gierach, GL, Scott, C, Stone, J, Douglas, JA, dos-Santos-Silva, I, Fernandez-Navarro, P, Verghase, J, Smith, P, Brown, J, Luben, R, Wareham, NJ, Loos, RJF, Heit, JA, Pankratz, VS, Norman, A, Goode, EL, Cunningham, JM, Deandrade, M, Vierkant, RA, Czene, K, Fasching, PA, Baglietto, L, Southey, MC, Giles, GG, Shah, KP, Chan, H-P, Helvie, MA, Beck, AH, Knoblauch, NW, Hazra, A, Hunter, DJ, Kraft, P, Pollan, M, Figueroa, JD, Couch, FJ, Hopper, JL, Hall, P, Easton, DF, Boyd, NF, Vachon, CM, and Tamimi, RM
Abstract: Mammographic density reflects the amount of stromal and epithelial tissues in relation to adipose tissue in the breast and is a strong risk factor for breast cancer. Here we report the results from meta-analysis of genome-wide association studies (GWAS) of three mammographic density phenotypes: dense area, non-dense area and percent density in up to 7,916 women in stage 1 and an additional 10,379 women in stage 2. We identify genome-wide significant (P<5 × 10(-8)) loci for dense area (AREG, ESR1, ZNF365, LSP1/TNNT3, IGF1, TMEM184B and SGSM3/MKL1), non-dense area (8p11.23) and percent density (PRDM6, 8p11.23 and TMEM184B). Four of these regions are known breast cancer susceptibility loci, and four additional regions were found to be associated with breast cancer (P<0.05) in a large meta-analysis. These results provide further evidence of a shared genetic basis between mammographic density and breast cancer and illustrate the power of studying intermediate quantitative phenotypes to identify putative disease-susceptibility loci.
Published: 2014

34. ABCB1 (MDR1) polymorphisms and ovarian cancer progression and survival: A comprehensive analysis from the Ovarian Cancer Association Consortium and the Cancer Genome Atlas

Author: Johnatty, SE, Beesley, J, Gao, B, Chen, X, Lu, Y, Law, MH, Henderson, MJ, Russell, AJ, Hedditch, EL, Emmanuel, C, Fereday, S, Webb, PM, Goode, EL, Vierkant, RA, Fridley, BL, Cunningham, JM, Fasching, PA, Beckmann, MW, Ekici, AB, Hogdall, E, Kjaer, SK, Jensen, A, Hogdall, C, Brown, R, Paul, J, Lambrechts, S, Despierre, E, Vergote, I, Lester, J, Karlan, BY, Heitz, F, Du Bois, A, Harter, P, Schwaab, I, Bean, Y, Pejovic, T, Levine, DA, Goodman, MT, Camey, ME, Thompson, PJ, Lurie, G, Shildkraut, J, Berchuck, A, Terry, KL, Cramer, DW, Norris, MD, Haber, M, MacGregor, S, DeFazio, A, Chenevix-Trench, G, Johnatty, SE, Beesley, J, Gao, B, Chen, X, Lu, Y, Law, MH, Henderson, MJ, Russell, AJ, Hedditch, EL, Emmanuel, C, Fereday, S, Webb, PM, Goode, EL, Vierkant, RA, Fridley, BL, Cunningham, JM, Fasching, PA, Beckmann, MW, Ekici, AB, Hogdall, E, Kjaer, SK, Jensen, A, Hogdall, C, Brown, R, Paul, J, Lambrechts, S, Despierre, E, Vergote, I, Lester, J, Karlan, BY, Heitz, F, Du Bois, A, Harter, P, Schwaab, I, Bean, Y, Pejovic, T, Levine, DA, Goodman, MT, Camey, ME, Thompson, PJ, Lurie, G, Shildkraut, J, Berchuck, A, Terry, KL, Cramer, DW, Norris, MD, Haber, M, MacGregor, S, DeFazio, A, and Chenevix-Trench, G
Abstract: Objective. ABCB1 encodes the multi-drug efflux pump P-glycoprotein (P-gp) and has been implicated in multi-drug resistance.We comprehensively evaluated this gene and flanking regions for an associationwith clinical outcome in epithelial ovarian cancer (EOC). Methods. The best candidates from fine-mapping analysis of 21 ABCB1 SNPs tagging C1236T (rs1128503), G2677T/A (rs2032582), and C3435T (rs1045642) were analysed in 4616 European invasive EOC patients from thirteen Ovarian Cancer Association Consortium(OCAC) studies and The Cancer Genome Atlas (TCGA). Additionally we analysed 1,562 imputed SNPs around ABCB1 in patients receiving cytoreductive surgery and either 'standard' first-line paclitaxel-carboplatin chemotherapy (n = 1158) or any first-line chemotherapy regimen (n = 2867). We also evaluated ABCB1 expression in primary tumours from 143 EOC patients. Result. Fine-mapping revealed that rs1128503, rs2032582, and rs1045642were the best candidates in optimally debulked patients. However, we observed no significant association between any SNP and either progression-free survivaloroverall survival inanalysis ofdata from14 studies. There was a marginal association between rs1128503 and overall survival in patients with nil residual disease (HR 0.88, 95% CI 0.77-1.01; p = 0.07). In contrast, ABCB1 expression in the primary tumour may confer worse prognosis in patients with sub-optimally debulked tumours. Conclusion. Our study represents the largest analysis of ABCB1 SNPs and EOC progression and survival to date, but has not identified additional signals, or validated reported associations with progression-free survival for rs1128503, rs2032582, and rs1045642. However, we cannot rule out the possibility of a subtle effect of rs1128503, or other SNPs linked to it, on overall survival. © 2013 The Authors. Published by Elsevier Inc. All rights reserved.
Published: 2013

35. 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, H-Y, Chen, YA, Tsai, Y-Y, 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, Doerk, T, du Bois, A, Duerst, 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, Gorski, B, Gronwald, J, Hall, P, Halle, MK, Harter, P, Heitz, F, Hillemanns, P, Hoatlin, M, Hogdall, CK, Hogdall, E, Hosono, S, Jakubowska, A, Jensen, A, Jim, H, Kalli, KR, Karlan, BY, Kaye, SB, Kelemen, LE, Kiemeney, LA, Kikkawa, F, Konecny, GE, Krakstad, C, Kjaer, SK, Kupryjanczyk, J, Lambrechts, D, Lambrechts, S, Lancaster, JM, Le, ND, Leminen, A, Levine, DA, Liang, D, Lim, BK, Lin, J, Lissowska, J, Lu, KH, Lubinski, J, Lurie, G, Massuger, LFAG, Matsuo, K, McGuire, V, McLaughlin, JR, Menon, U, Modugno, F, Moysich, KB, Nakanishi, T, Narod, SA, Nedergaard, L, Ness, RB, Nevanlinna, H, Nickels, S, Noushmehr, H, Odunsi, K, Olson, SH, Orlow, I, Paul, J, Pearce, CL, Pejovic, T, Pelttari, LM, Pike, MC, Poole, EM, Raska, P, Renner, SP, Risch, HA, Rodriguez-Rodriguez, L, Rossing, MA, Rudolph, A, Runnebaum, IB, Rzepecka, IK, Salvesen, HB, Schwaab, I, Severi, G, Shridhar, V, Shu, X-O, Shvetsov, YB, Sieh, W, Song, H, Southey, MC, Spiewankiewicz, B, Stram, D, Sutphen, R, Teo, S-H, Terry, KL, Tessier, DC, Thompson, PJ, Tworoger, SS, van Altena, AM, Vergote, I, Vierkant, RA, Vincent, D, Vitonis, AF, Wang-Gohrke, S, Weber, RP, Wentzensen, N, Whittemore, AS, Wik, E, Wilkens, LR, Winterhoff, B, Woo, YL, Wu, AH, Xiang, Y-B, Yang, HP, Zheng, W, Ziogas, A, Zulkifli, F, Phelan, CM, Iversen, E, Schildkraut, JM, Berchuck, A, Fridley, BL, Goode, EL, Pharoah, PDP, Monteiro, ANA, Sellers, TA, Gayther, SA, Permuth-Wey, J, Lawrenson, K, Shen, HC, Velkova, A, Tyrer, JP, Chen, Z, Lin, H-Y, Chen, YA, Tsai, Y-Y, 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, Doerk, T, du Bois, A, Duerst, 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, Gorski, B, Gronwald, J, Hall, P, Halle, MK, Harter, P, Heitz, F, Hillemanns, P, Hoatlin, M, Hogdall, CK, Hogdall, E, Hosono, S, Jakubowska, A, Jensen, A, Jim, H, Kalli, KR, Karlan, BY, Kaye, SB, Kelemen, LE, Kiemeney, LA, Kikkawa, F, Konecny, GE, Krakstad, C, Kjaer, SK, Kupryjanczyk, J, Lambrechts, D, Lambrechts, S, Lancaster, JM, Le, ND, Leminen, A, Levine, DA, Liang, D, Lim, BK, Lin, J, Lissowska, J, Lu, KH, Lubinski, J, Lurie, G, Massuger, LFAG, Matsuo, K, McGuire, V, McLaughlin, JR, Menon, U, Modugno, F, Moysich, KB, Nakanishi, T, Narod, SA, Nedergaard, L, Ness, RB, Nevanlinna, H, Nickels, S, Noushmehr, H, Odunsi, K, Olson, SH, Orlow, I, Paul, J, Pearce, CL, Pejovic, T, Pelttari, LM, Pike, MC, Poole, EM, Raska, P, Renner, SP, Risch, HA, Rodriguez-Rodriguez, L, Rossing, MA, Rudolph, A, Runnebaum, IB, Rzepecka, IK, Salvesen, HB, Schwaab, I, Severi, G, Shridhar, V, Shu, X-O, Shvetsov, YB, Sieh, W, Song, H, Southey, MC, Spiewankiewicz, B, Stram, D, Sutphen, R, Teo, S-H, Terry, KL, Tessier, DC, Thompson, PJ, Tworoger, SS, van Altena, AM, Vergote, I, Vierkant, RA, Vincent, D, Vitonis, AF, Wang-Gohrke, S, Weber, RP, Wentzensen, N, Whittemore, AS, Wik, E, Wilkens, LR, Winterhoff, B, Woo, YL, Wu, AH, Xiang, Y-B, Yang, HP, Zheng, W, Ziogas, A, Zulkifli, F, Phelan, CM, Iversen, E, Schildkraut, JM, Berchuck, A, Fridley, BL, Goode, EL, Pharoah, PDP, Monteiro, ANA, Sellers, TA, and Gayther, SA
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.
Published: 2013

36. Hormone-receptor expression and ovarian cancer survival: an Ovarian Tumor Tissue Analysis consortium study

Author: Sieh, W, Koebel, M, Longacre, TA, Bowtell, DD, defazio, A, Goodman, MT, Hogdall, E, Deen, S, Wentzensen, N, Moysich, KB, Brenton, JD, Clarke, BA, Menon, U, Gilks, CB, Kim, A, Madore, J, Fereday, S, George, J, Galletta, L, Lurie, G, Wilkens, LR, Carney, ME, Thompson, PJ, Matsuno, RK, Kjaer, SK, Jensen, A, Hogdall, C, Kalli, KR, Fridley, BL, Keeney, GL, Vierkant, RA, Cunningham, JM, Brinton, LA, Yang, HP, Sherman, ME, Garcia-Closas, M, Lissowska, J, Odunsi, K, Morrison, C, Lele, S, Bshara, W, Sucheston, L, Jimenez-Linan, M, Driver, K, Alsop, J, Mack, M, McGuire, V, Rothstein, JH, Rosen, BP, Bernardini, MQ, Mackay, H, Oza, A, Wozniak, EL, Benjamin, E, Gentry-Maharaj, A, Gayther, SA, Tinker, AV, Prentice, LM, Chow, C, Anglesio, MS, Johnatty, SE, Chenevix-Trench, G, Whittemore, AS, Pharoah, PDP, Goode, EL, Huntsman, DG, Ramus, SJ, Sieh, W, Koebel, M, Longacre, TA, Bowtell, DD, defazio, A, Goodman, MT, Hogdall, E, Deen, S, Wentzensen, N, Moysich, KB, Brenton, JD, Clarke, BA, Menon, U, Gilks, CB, Kim, A, Madore, J, Fereday, S, George, J, Galletta, L, Lurie, G, Wilkens, LR, Carney, ME, Thompson, PJ, Matsuno, RK, Kjaer, SK, Jensen, A, Hogdall, C, Kalli, KR, Fridley, BL, Keeney, GL, Vierkant, RA, Cunningham, JM, Brinton, LA, Yang, HP, Sherman, ME, Garcia-Closas, M, Lissowska, J, Odunsi, K, Morrison, C, Lele, S, Bshara, W, Sucheston, L, Jimenez-Linan, M, Driver, K, Alsop, J, Mack, M, McGuire, V, Rothstein, JH, Rosen, BP, Bernardini, MQ, Mackay, H, Oza, A, Wozniak, EL, Benjamin, E, Gentry-Maharaj, A, Gayther, SA, Tinker, AV, Prentice, LM, Chow, C, Anglesio, MS, Johnatty, SE, Chenevix-Trench, G, Whittemore, AS, Pharoah, PDP, Goode, EL, Huntsman, DG, and Ramus, SJ
Abstract: BACKGROUND: Few biomarkers of ovarian cancer prognosis have been established, partly because subtype-specific associations might be obscured in studies combining all histopathological subtypes. We examined whether tumour expression of the progesterone receptor (PR) and oestrogen receptor (ER) was associated with subtype-specific survival. METHODS: 12 studies participating in the Ovarian Tumor Tissue Analysis consortium contributed tissue microarray sections and clinical data to our study. Participants included in our analysis had been diagnosed with invasive serous, mucinous, endometrioid, or clear-cell carcinomas of the ovary. For a patient to be eligible, tissue microarrays, clinical follow-up data, age at diagnosis, and tumour grade and stage had to be available. Clinical data were obtained from medical records, cancer registries, death certificates, pathology reports, and review of histological slides. PR and ER statuses were assessed by central immunohistochemistry analysis done by masked pathologists. PR and ER staining was defined as negative (<1% tumour cell nuclei), weak (1 to <50%), or strong (≥50%). Associations with disease-specific survival were assessed. FINDINGS: 2933 women with invasive epithelial ovarian cancer were included: 1742 with high-grade serous carcinoma, 110 with low-grade serous carcinoma, 207 with mucinous carcinoma, 484 with endometrioid carcinoma, and 390 with clear-cell carcinoma. PR expression was associated with improved disease-specific survival in endometrioid carcinoma (log-rank p<0·0001) and high-grade serous carcinoma (log-rank p=0·0006), and ER expression was associated with improved disease-specific survival in endometrioid carcinoma (log-rank p<0·0001). We recorded no significant associations for mucinous, clear-cell, or low-grade serous carcinoma. Positive hormone-receptor expression (weak or strong staining for PR or ER, or both) was associated with significantly improved disease-specific survival in endometrioid carcinoma
Published: 2013

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

Author: Pharoah, PDP, Tsai, Y-Y, 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, W-H, Cicek, MS, Coetzee, G, Cook, LS, Cramer, DW, Cybulski, C, Dansonka-Mieszkowska, A, Despierre, E, Doherty, JA, Doerk, T, du Bois, A, Duerst, M, Eccles, D, Edwards, R, Ekici, AB, Fasching, PA, Fenstermacher, D, Flanagan, J, Gao, Y-T, 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, Hogdall, E, Hogdall, CK, Hosono, S, Jakubowska, A, Jensen, A, Kalli, KR, Karlan, BY, Kelemen, LE, Kiemeney, LA, Kjaer, SK, Konecny, GE, Krakstad, C, Kupryjanczyk, J, Lambrechts, D, Lambrechts, S, Le, ND, Lee, N, Lee, J, Leminen, A, Lim, BK, Lissowska, J, Lubinski, J, Lundvall, L, Lurie, G, Massuger, LFAG, Matsuo, K, McGuire, V, McLaughlin, JR, Menon, U, Modugno, F, Moysich, KB, Nakanishi, T, Narod, SA, Ness, RB, Nevanlinna, H, Nickels, S, Noushmehr, H, Odunsi, K, Olson, S, Orlow, I, Paul, J, Pejovic, T, Pelttari, LM, Permuth-Wey, J, Pike, MC, Poole, EM, Qu, X, Risch, HA, Rodriguez-Rodriguez, L, Rossing, MA, Rudolph, A, Runnebaum, I, Rzepecka, IK, Salvesen, HB, Schwaab, I, Severi, G, Shridhar, V, Shu, X-O, Sieh, W, Southey, MC, Spellman, P, Tajima, K, Teo, S-H, Terry, KL, Thompson, PJ, Timorek, A, Tworoger, SS, van Altena, AM, van den Berg, D, Vergote, I, Vierkant, RA, Vitonis, AF, Wang-Gohrke, S, Wentzensen, N, Whittemore, AS, Wik, E, Winterhoff, B, Woo, YL, Wu, AH, Yang, HP, Zheng, W, Ziogas, A, Zulkifli, F, Goodman, MT, Hall, P, Easton, DF, Pearce, CL, Berchuck, A, Chenevix-Trench, G, Iversen, E, Monteiro, ANA, Gayther, SA, Schildkraut, JM, Sellers, TA, Pharoah, PDP, Tsai, Y-Y, 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, W-H, Cicek, MS, Coetzee, G, Cook, LS, Cramer, DW, Cybulski, C, Dansonka-Mieszkowska, A, Despierre, E, Doherty, JA, Doerk, T, du Bois, A, Duerst, M, Eccles, D, Edwards, R, Ekici, AB, Fasching, PA, Fenstermacher, D, Flanagan, J, Gao, Y-T, 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, Hogdall, E, Hogdall, CK, Hosono, S, Jakubowska, A, Jensen, A, Kalli, KR, Karlan, BY, Kelemen, LE, Kiemeney, LA, Kjaer, SK, Konecny, GE, Krakstad, C, Kupryjanczyk, J, Lambrechts, D, Lambrechts, S, Le, ND, Lee, N, Lee, J, Leminen, A, Lim, BK, Lissowska, J, Lubinski, J, Lundvall, L, Lurie, G, Massuger, LFAG, Matsuo, K, McGuire, V, McLaughlin, JR, Menon, U, Modugno, F, Moysich, KB, Nakanishi, T, Narod, SA, Ness, RB, Nevanlinna, H, Nickels, S, Noushmehr, H, Odunsi, K, Olson, S, Orlow, I, Paul, J, Pejovic, T, Pelttari, LM, Permuth-Wey, J, Pike, MC, Poole, EM, Qu, X, Risch, HA, Rodriguez-Rodriguez, L, Rossing, MA, Rudolph, A, Runnebaum, I, Rzepecka, IK, Salvesen, HB, Schwaab, I, Severi, G, Shridhar, V, Shu, X-O, Sieh, W, Southey, MC, Spellman, P, Tajima, K, Teo, S-H, Terry, KL, Thompson, PJ, Timorek, A, Tworoger, SS, van Altena, AM, van den Berg, D, Vergote, I, Vierkant, RA, Vitonis, AF, Wang-Gohrke, S, Wentzensen, N, Whittemore, AS, Wik, E, Winterhoff, B, Woo, YL, Wu, AH, Yang, HP, Zheng, W, Ziogas, A, Zulkifli, F, Goodman, MT, Hall, P, Easton, DF, Pearce, CL, Berchuck, A, Chenevix-Trench, G, Iversen, E, Monteiro, ANA, Gayther, SA, Schildkraut, JM, and Sellers, TA
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

38. Epigenetic analysis leads to identification of HNF1B as a subtype-specific susceptibility gene for ovarian cancer

Author: Shen, H, Fridley, BL, Song, H, Lawrenson, K, Cunningham, JM, Ramus, SJ, Cicek, MS, Tyrer, J, Stram, D, Larson, MC, Koebel, M, Ziogas, A, Zheng, W, Yang, HP, Wu, AH, Wozniak, EL, Woo, YL, Winterhoff, B, Wik, E, Whittemore, AS, Wentzensen, N, Weber, RP, Vitonis, AF, Vincent, D, Vierkant, RA, Vergote, I, Van Den Berg, D, Van Altena, AM, Tworoger, SS, Thompson, PJ, Tessier, DC, Terry, KL, Teo, S-H, Templeman, C, Stram, DO, Southey, MC, Sieh, W, Siddiqui, N, Shvetsov, YB, Shu, X-O, Shridhar, V, Wang-Gohrke, S, Severi, G, Schwaab, I, Salvesen, HB, Rzepecka, IK, Runnebaum, IB, Rossing, MA, Rodriguez-Rodriguez, L, Risch, HA, Renner, SP, Poole, EM, Pike, MC, Phelan, CM, Pelttari, LM, Pejovic, T, Paul, J, Orlow, I, Omar, SZ, Olson, SH, Odunsi, K, Nickels, S, Nevanlinna, H, Ness, RB, Narod, SA, Nakanishi, T, Moysich, KB, Monteiro, ANA, Moes-Sosnowska, J, Modugno, F, Menon, U, McLaughlin, JR, McGuire, V, Matsuo, K, Adenan, NAM, Massuger, LFAG, Lurie, G, Lundvall, L, Lubinski, J, Lissowska, J, Levine, DA, Leminen, A, Lee, AW, Le, ND, Lambrechts, S, Lambrechts, D, Kupryjanczyk, J, Krakstad, C, Konecny, GE, Kjaer, SK, Kiemeney, LA, Kelemen, LE, Keeney, GL, Karlan, BY, Karevan, R, Kalli, KR, Kajiyama, H, Ji, B-T, Jensen, A, Jakubowska, A, Iversen, E, Hosono, S, Hogdall, CK, Hogdall, E, Hoatlin, M, Hillemanns, P, Heitz, F, Hein, R, Harter, P, Halle, MK, Hall, P, Gronwald, J, Gore, M, Goodman, MT, Giles, GG, Gentry-Maharaj, A, Garcia-Closas, M, Flanagan, JM, Fasching, PA, Ekici, AB, Edwards, R, Eccles, D, Easton, DF, Duerst, M, du Bois, A, Doerk, T, Doherty, JA, Despierre, E, Dansonka-Mieszkowska, A, Cybulski, C, Cramer, DW, Cook, LS, Chen, X, Charbonneau, B, Chang-Claude, J, Campbell, I, Butzow, R, Bunker, CH, Brueggmann, D, Brown, R, Brooks-Wilson, A, Brinton, LA, Bogdanova, N, Block, MS, Benjamin, E, Beesley, J, Beckmann, MW, Bandera, EV, Baglietto, L, Bacot, F, Armasu, SM, Antonenkova, N, Anton-Culver, H, Aben, KK, Liang, D, Wu, X, Lu, K, Hildebrandt, MAT, Schildkraut, JM, Sellers, TA, Huntsman, D, Berchuck, A, Chenevix-Trench, G, Gayther, SA, Pharoah, PDP, Laird, PW, Goode, EL, Pearce, CL, Shen, H, Fridley, BL, Song, H, Lawrenson, K, Cunningham, JM, Ramus, SJ, Cicek, MS, Tyrer, J, Stram, D, Larson, MC, Koebel, M, Ziogas, A, Zheng, W, Yang, HP, Wu, AH, Wozniak, EL, Woo, YL, Winterhoff, B, Wik, E, Whittemore, AS, Wentzensen, N, Weber, RP, Vitonis, AF, Vincent, D, Vierkant, RA, Vergote, I, Van Den Berg, D, Van Altena, AM, Tworoger, SS, Thompson, PJ, Tessier, DC, Terry, KL, Teo, S-H, Templeman, C, Stram, DO, Southey, MC, Sieh, W, Siddiqui, N, Shvetsov, YB, Shu, X-O, Shridhar, V, Wang-Gohrke, S, Severi, G, Schwaab, I, Salvesen, HB, Rzepecka, IK, Runnebaum, IB, Rossing, MA, Rodriguez-Rodriguez, L, Risch, HA, Renner, SP, Poole, EM, Pike, MC, Phelan, CM, Pelttari, LM, Pejovic, T, Paul, J, Orlow, I, Omar, SZ, Olson, SH, Odunsi, K, Nickels, S, Nevanlinna, H, Ness, RB, Narod, SA, Nakanishi, T, Moysich, KB, Monteiro, ANA, Moes-Sosnowska, J, Modugno, F, Menon, U, McLaughlin, JR, McGuire, V, Matsuo, K, Adenan, NAM, Massuger, LFAG, Lurie, G, Lundvall, L, Lubinski, J, Lissowska, J, Levine, DA, Leminen, A, Lee, AW, Le, ND, Lambrechts, S, Lambrechts, D, Kupryjanczyk, J, Krakstad, C, Konecny, GE, Kjaer, SK, Kiemeney, LA, Kelemen, LE, Keeney, GL, Karlan, BY, Karevan, R, Kalli, KR, Kajiyama, H, Ji, B-T, Jensen, A, Jakubowska, A, Iversen, E, Hosono, S, Hogdall, CK, Hogdall, E, Hoatlin, M, Hillemanns, P, Heitz, F, Hein, R, Harter, P, Halle, MK, Hall, P, Gronwald, J, Gore, M, Goodman, MT, Giles, GG, Gentry-Maharaj, A, Garcia-Closas, M, Flanagan, JM, Fasching, PA, Ekici, AB, Edwards, R, Eccles, D, Easton, DF, Duerst, M, du Bois, A, Doerk, T, Doherty, JA, Despierre, E, Dansonka-Mieszkowska, A, Cybulski, C, Cramer, DW, Cook, LS, Chen, X, Charbonneau, B, Chang-Claude, J, Campbell, I, Butzow, R, Bunker, CH, Brueggmann, D, Brown, R, Brooks-Wilson, A, Brinton, LA, Bogdanova, N, Block, MS, Benjamin, E, Beesley, J, Beckmann, MW, Bandera, EV, Baglietto, L, Bacot, F, Armasu, SM, Antonenkova, N, Anton-Culver, H, Aben, KK, Liang, D, Wu, X, Lu, K, Hildebrandt, MAT, Schildkraut, JM, Sellers, TA, Huntsman, D, Berchuck, A, Chenevix-Trench, G, Gayther, SA, Pharoah, PDP, Laird, PW, Goode, EL, and Pearce, CL
Abstract: HNF1B is overexpressed in clear cell epithelial ovarian cancer, and we observed epigenetic silencing in serous epithelial ovarian cancer, leading us to hypothesize that variation in this gene differentially associates with epithelial ovarian cancer risk according to histological subtype. Here we comprehensively map variation in HNF1B with respect to epithelial ovarian cancer risk and analyse DNA methylation and expression profiles across histological subtypes. Different single-nucleotide polymorphisms associate with invasive serous (rs7405776 odds ratio (OR)=1.13, P=3.1 × 10(-10)) and clear cell (rs11651755 OR=0.77, P=1.6 × 10(-8)) epithelial ovarian cancer. Risk alleles for the serous subtype associate with higher HNF1B-promoter methylation in these tumours. Unmethylated, expressed HNF1B, primarily present in clear cell tumours, coincides with a CpG island methylator phenotype affecting numerous other promoters throughout the genome. Different variants in HNF1B associate with risk of serous and clear cell epithelial ovarian cancer; DNA methylation and expression patterns are also notably distinct between these subtypes. These findings underscore distinct mechanisms driving different epithelial ovarian cancer histological subtypes.
Published: 2013

39. Analysis of Over 10,000 Cases Finds No Association between Previously Reported Candidate Polymorphisms and Ovarian Cancer Outcome

Author: White, KL, Vierkant, RA, Fogarty, ZC, Charbonneau, B, Block, MS, Pharoah, PDP, Chenevix-Trench, G, Rossing, MA, Cramer, DW, Pearce, CL, Schildkraut, JM, Menon, U, Kjaer, SK, Levine, DA, Gronwald, J, Culver, HA, Whittemore, AS, Karlan, BY, Lambrechts, D, Wentzensen, N, Kupryjanczyk, J, Chang-Claude, J, Bandera, EV, Hogdall, E, Heitz, F, Kaye, SB, Fasching, PA, Campbell, I, Goodman, MT, Pejovic, T, Bean, Y, Lurie, G, Eccles, D, Hein, A, Beckmann, MW, Ekici, AB, Paul, J, Brown, R, Flanagan, JM, Harter, P, Du Bois, A, Schwaab, I, Hogdall, CK, Lundvall, L, Olson, SH, Orlow, I, Paddock, LE, Rudolph, A, Eilber, U, Dansonka-Mieszkowska, A, Rzepecka, IK, Ziolkowska-Seta, I, Brinton, L, Yang, H, Garcia-Closas, M, Despierre, E, Lambrechts, S, Vergote, I, Walsh, C, Lester, J, Sieh, W, McGuire, V, Rothstein, JH, Ziogas, A, Lubinski, J, Cybulski, C, Menkiszak, J, Jensen, A, Gayther, SA, Ramus, SJ, Gentry-Maharaj, A, Berchuck, A, Wu, AH, Pike, MC, Van denBerg, D, Terry, KL, Vitonis, AF, Doherty, JA, Johnatty, SE, Defazio, A, Song, H, Tyrer, J, Sellers, TA, Phelan, CM, Kalli, KR, Cunningham, JM, Fridley, BL, Goode, EL, White, KL, Vierkant, RA, Fogarty, ZC, Charbonneau, B, Block, MS, Pharoah, PDP, Chenevix-Trench, G, Rossing, MA, Cramer, DW, Pearce, CL, Schildkraut, JM, Menon, U, Kjaer, SK, Levine, DA, Gronwald, J, Culver, HA, Whittemore, AS, Karlan, BY, Lambrechts, D, Wentzensen, N, Kupryjanczyk, J, Chang-Claude, J, Bandera, EV, Hogdall, E, Heitz, F, Kaye, SB, Fasching, PA, Campbell, I, Goodman, MT, Pejovic, T, Bean, Y, Lurie, G, Eccles, D, Hein, A, Beckmann, MW, Ekici, AB, Paul, J, Brown, R, Flanagan, JM, Harter, P, Du Bois, A, Schwaab, I, Hogdall, CK, Lundvall, L, Olson, SH, Orlow, I, Paddock, LE, Rudolph, A, Eilber, U, Dansonka-Mieszkowska, A, Rzepecka, IK, Ziolkowska-Seta, I, Brinton, L, Yang, H, Garcia-Closas, M, Despierre, E, Lambrechts, S, Vergote, I, Walsh, C, Lester, J, Sieh, W, McGuire, V, Rothstein, JH, Ziogas, A, Lubinski, J, Cybulski, C, Menkiszak, J, Jensen, A, Gayther, SA, Ramus, SJ, Gentry-Maharaj, A, Berchuck, A, Wu, AH, Pike, MC, Van denBerg, D, Terry, KL, Vitonis, AF, Doherty, JA, Johnatty, SE, Defazio, A, Song, H, Tyrer, J, Sellers, TA, Phelan, CM, Kalli, KR, Cunningham, JM, Fridley, BL, and Goode, EL
Abstract: BACKGROUND: Ovarian cancer is a leading cause of cancer-related death among women. In an effort to understand contributors to disease outcome, we evaluated single-nucleotide polymorphisms (SNP) previously associated with ovarian cancer recurrence or survival, specifically in angiogenesis, inflammation, mitosis, and drug disposition genes. METHODS: Twenty-seven SNPs in VHL, HGF, IL18, PRKACB, ABCB1, CYP2C8, ERCC2, and ERCC1 previously associated with ovarian cancer outcome were genotyped in 10,084 invasive cases from 28 studies from the Ovarian Cancer Association Consortium with over 37,000-observed person-years and 4,478 deaths. Cox proportional hazards models were used to examine the association between candidate SNPs and ovarian cancer recurrence or survival with and without adjustment for key covariates. RESULTS: We observed no association between genotype and ovarian cancer recurrence or survival for any of the SNPs examined. CONCLUSIONS: These results refute prior associations between these SNPs and ovarian cancer outcome and underscore the importance of maximally powered genetic association studies. IMPACT: These variants should not be used in prognostic models. Alternate approaches to uncovering inherited prognostic factors, if they exist, are needed.
Published: 2013

40. Polymorphisms in Stromal Genes and Susceptibility to Serous Epithelial Ovarian Cancer: A Report from the Ovarian Cancer Association Consortium

Author: Minna, JD, Amankwah, EK, Wang, Q, Schildkraut, JM, Tsai, Y-Y, Ramus, SJ, Fridley, BL, Beesley, J, Johnatty, SE, Webb, PM, Chenevix-Trench, G, Dale, LC, Lambrechts, D, Amant, F, Despierre, E, Vergote, I, Gayther, SA, Gentry-Maharaj, A, Menon, U, Chang-Claude, J, Wang-Gohrke, S, Anton-Culver, H, Ziogas, A, Doerk, T, Duerst, M, Antonenkova, N, Bogdanova, N, Brown, R, Flanagan, JM, Kaye, SB, Paul, J, Butzow, R, Nevanlinna, H, Campbell, I, Eccles, DM, Karlan, BY, Gross, J, Walsh, C, Pharoah, PDP, Song, H, Kjaer, SK, Hogdall, E, Hogdall, C, Lundvall, L, Nedergaard, L, Kiemeney, LALM, Massuger, LFAG, van Altena, AM, Vermeulen, SHHM, Le, ND, Brooks-Wilson, A, Cook, LS, Phelan, CM, Cunningham, JM, Vachon, CM, Vierkant, RA, Iversen, ES, Berchuck, A, Goode, EL, Sellers, TA, Kelemen, LE, Minna, JD, Amankwah, EK, Wang, Q, Schildkraut, JM, Tsai, Y-Y, Ramus, SJ, Fridley, BL, Beesley, J, Johnatty, SE, Webb, PM, Chenevix-Trench, G, Dale, LC, Lambrechts, D, Amant, F, Despierre, E, Vergote, I, Gayther, SA, Gentry-Maharaj, A, Menon, U, Chang-Claude, J, Wang-Gohrke, S, Anton-Culver, H, Ziogas, A, Doerk, T, Duerst, M, Antonenkova, N, Bogdanova, N, Brown, R, Flanagan, JM, Kaye, SB, Paul, J, Butzow, R, Nevanlinna, H, Campbell, I, Eccles, DM, Karlan, BY, Gross, J, Walsh, C, Pharoah, PDP, Song, H, Kjaer, SK, Hogdall, E, Hogdall, C, Lundvall, L, Nedergaard, L, Kiemeney, LALM, Massuger, LFAG, van Altena, AM, Vermeulen, SHHM, Le, ND, Brooks-Wilson, A, Cook, LS, Phelan, CM, Cunningham, JM, Vachon, CM, Vierkant, RA, Iversen, ES, Berchuck, A, Goode, EL, Sellers, TA, and Kelemen, LE
Abstract: Alterations in stromal tissue components can inhibit or promote epithelial tumorigenesis. Decorin (DCN) and lumican (LUM) show reduced stromal expression in serous epithelial ovarian cancer (sEOC). We hypothesized that common variants in these genes associate with risk. Associations with sEOC among Caucasians were estimated with odds ratios (OR) among 397 cases and 920 controls in two U.S.-based studies (discovery set), 436 cases and 1,098 controls in Australia (replication set 1) and a consortium of 15 studies comprising 1,668 cases and 4,249 controls (replication set 2). The discovery set and replication set 1 (833 cases and 2,013 controls) showed statistically homogeneous (P(heterogeneity)≥0.48) decreased risks of sEOC at four variants: DCN rs3138165, rs13312816 and rs516115, and LUM rs17018765 (OR = 0.6 to 0.9; P(trend) = 0.001 to 0.03). Results from replication set 2 were statistically homogeneous (P(heterogeneity)≥0.13) and associated with increased risks at DCN rs3138165 and rs13312816, and LUM rs17018765: all ORs = 1.2; P(trend)≤0.02. The ORs at the four variants were statistically heterogeneous across all 18 studies (P(heterogeneity)≤0.03), which precluded combining. In post-hoc analyses, interactions were observed between each variant and recruitment period (P(interaction)≤0.003), age at diagnosis (P(interaction) = 0.04), and year of diagnosis (P(interaction) = 0.05) in the five studies with available information (1,044 cases, 2,469 controls). We conclude that variants in DCN and LUM are not directly associated with sEOC, and that confirmation of possible effect modification of the variants by non-genetic factors is required.
Published: 2011

41. Functional Polymorphisms in the TERT Promoter Are Associated with Risk of Serous Epithelial Ovarian and Breast Cancers

Author: Zhang, L, Beesley, J, Pickett, HA, Johnatty, SE, Dunning, AM, Chen, X, Li, J, Michailidou, K, Lu, Y, Rider, DN, Palmieri, RT, Stutz, MD, Lambrechts, D, Despierre, E, Lambrechts, S, Vergote, I, Chang-Claude, J, Nickels, S, Vrieling, A, Flesch-Janys, D, Wang-Gohrke, S, Eilber, U, Bogdanova, N, Antonenkova, N, Runnebaum, IB, Doerk, T, Goodman, MT, Lurie, G, Wilkens, LR, Matsuno, RK, Kiemeney, LA, Aben, KKH, Marees, T, Massuger, LFAG, Fridley, BL, Vierkant, RA, Bandera, EV, Olson, SH, Orlow, I, Rodriguez-Rodriguez, L, Cook, LS, Le, ND, Brooks-Wilson, A, Kelemen, LE, Campbell, I, Gayther, SA, Ramus, SJ, Gentry-Maharaj, A, Menon, U, Ahmed, S, Baynes, C, Pharoah, PD, Muir, K, Lophatananon, A, Chaiwerawattana, A, Wiangnon, S, Macgregor, S, Easton, DF, Reddel, RR, Goode, EL, Chenevix-Trench, G, Zhang, L, Beesley, J, Pickett, HA, Johnatty, SE, Dunning, AM, Chen, X, Li, J, Michailidou, K, Lu, Y, Rider, DN, Palmieri, RT, Stutz, MD, Lambrechts, D, Despierre, E, Lambrechts, S, Vergote, I, Chang-Claude, J, Nickels, S, Vrieling, A, Flesch-Janys, D, Wang-Gohrke, S, Eilber, U, Bogdanova, N, Antonenkova, N, Runnebaum, IB, Doerk, T, Goodman, MT, Lurie, G, Wilkens, LR, Matsuno, RK, Kiemeney, LA, Aben, KKH, Marees, T, Massuger, LFAG, Fridley, BL, Vierkant, RA, Bandera, EV, Olson, SH, Orlow, I, Rodriguez-Rodriguez, L, Cook, LS, Le, ND, Brooks-Wilson, A, Kelemen, LE, Campbell, I, Gayther, SA, Ramus, SJ, Gentry-Maharaj, A, Menon, U, Ahmed, S, Baynes, C, Pharoah, PD, Muir, K, Lophatananon, A, Chaiwerawattana, A, Wiangnon, S, Macgregor, S, Easton, DF, Reddel, RR, Goode, EL, and Chenevix-Trench, G
Abstract: Genetic variation at the TERT-CLPTM1L locus at 5p15.33 is associated with susceptibility to several cancers, including epithelial ovarian cancer (EOC). We have carried out fine-mapping of this region in EOC which implicates an association with a single nucleotide polymorphism (SNP) within the TERT promoter. We demonstrate that the minor alleles at rs2736109, and at an additional TERT promoter SNP, rs2736108, are associated with decreased breast cancer risk, and that the combination of both SNPs substantially reduces TERT promoter activity.
Published: 2011

42. Evaluation of Candidate Stromal Epithelial Cross-Talk Genes Identifies Association between Risk of Serous Ovarian Cancer and TERT, a Cancer Susceptibility 'Hot-Spot'

Author: Dermitzakis, ET, 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, Dermitzakis, ET, 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, and Chenevix-Trench, G
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-allele<0.05 in the discovery stage were selected for replication in a subset of five OCAC studies (n=1,233 serous invasive cases; n=3,364 controls). The discovery stage associations in PODXL, ITGA6, and MMP3 were attenuated in the larger replication set (adj. Pper-allele>or=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

43. Abstract P4-12-03: Towards a risk prediction model for breast cancer that utilizes breast tissue risk features

Author: Pankratz, VS, primary, Degnim, AC, additional, Visscher, DW, additional, Frank, RD, additional, Vierkant, RA, additional, Ghosh, K, additional, Aziza, N, additional, Vachon, CM, additional, Frost, M, additional, Radisky, DC, additional, and Hartmann, LC, additional
Published: 2012
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44. Abstract P5-01-08: Complex fibroadenoma is not an independent risk marker for breast cancer

Author: Nassar, A, primary, Visscher, DW, additional, Degnim, AC, additional, Frank, RD, additional, Vierkant, RA, additional, Hartmann, LC, additional, Frost, MH, additional, and Ghosh, K, additional
Published: 2012
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45. Abstract P6-09-03: No Increased Breast Cancer Risk with Hormone Replacement Therapy (HRT) in Women with Benign Breast Disease

Author: McKian, KP, primary, Frost, MH, additional, Maloney, SD, additional, Vierkant, RA, additional, Visscher, DW, additional, and Hartmann, LC., additional
Published: 2010
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46. Benign breast disease and breast cancer risk in young women.

Author: Ghosh, K, primary, Pankratz, VS, additional, Reynolds, CA, additional, Vierkant, RA, additional, Anderson, SS, additional, Degnim, AC, additional, Visscher, DW, additional, Frost, MH, additional, Vachon, CM, additional, and Hartmann, LC, additional
Published: 2009
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47. A novel breast tissue feature strongly associated with risk of breast cancer.

Author: McKian, KP, primary, Reynolds, CA, additional, Anderson, S, additional, Vierkant, RA, additional, Visscher, DW, additional, Frost, MH, additional, Pankratz, VS, additional, Nassar, A, additional, and Hartmann, LC, additional
Published: 2009
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48. #2 Interaction of adolescent anthropometric characteristics and family history on breast cancer risk in a cohort study of 426 families

Author: Cerhan, JR, primary, Grabrick, DM, additional, Vierkant, RA, additional, Janney, CA, additional, Vachon, CM, additional, Olson, JE, additional, Kushi, LH, additional, and Sellers, TA, additional
Published: 2002
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49. #17 Pre-pregnancy exposure to cigarette smoking and subsequent risk of postmenopausal breast cancer

Author: Olson, JE, primary, Vachon, CM, additional, Vierkant, RA, additional, Sweeney, C, additional, Limburg, PJ, additional, Cerhan, JR, additional, and Sellers, TA, additional
Published: 2002
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50. ABO blood group and risk of epithelial ovarian cancer within the Ovarian Cancer Association Consortium.

Author: Poole EM, Gates MA, High BA, Chanock SJ, Cramer DW, Cunningham JM, Fridley BL, Gayther SA, Goode EL, Iversen ES, Lissowska J, Weber RT, Pharoah PD, Phelan CM, Ramus SJ, Schildkraut JM, Sutphen R, Tsai YY, Tyrer J, and Vierkant RA
Abstract: Purpose: Previous studies have examined the association between ABO blood group and ovarian cancer risk, with inconclusive results.Methods: In eight studies participating in the Ovarian Cancer Association Consortium, we determined ABO blood groups and diplotypes by genotyping 3 SNPs in the ABO locus. Odds ratios and 95 % confidence intervals were calculated in each study using logistic regression; individual study results were combined using random effects meta-analysis.Results: Compared to blood group O, the A blood group was associated with a modestly increased ovarian cancer risk: (OR: 1.09; 95 % CI: 1.01-1.18; p = 0.03). In diplotype analysis, the AO, but not the AA diplotype, was associated with increased risk (AO: OR: 1.11; 95 % CI: 1.01-1.22; p = 0.03; AA: OR: 1.03; 95 % CI: 0.87-1.21; p = 0.76). Neither AB nor the B blood groups were associated with risk. Results were similar across ovarian cancer histologic subtypes.Conclusion: Consistent with most previous reports, the A blood type was associated modestly with increased ovarian cancer risk in this large analysis of multiple studies of ovarian cancer. Future studies investigating potential biologic mechanisms are warranted. [ABSTRACT FROM AUTHOR]
Published: 2012
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