48 results on '"Whittemore, Alice S"'
Search Results
2. Alcohol and Tobacco Use in Relation to Mammographic Density in 23,456 Women.
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McBride, Russell B., Kezhen Fei, Rothstein, Joseph H., Alexeeff, Stacey E., Xiaoyu Song, Sakoda, Lori C., McGuire, Valerie, Achacoso, Ninah, Acton, Luana, Liang, Rhea Y., Lipson, Jafi A., Yaffe, Martin J., Rubin, Daniel L., Whittemore, Alice S., Habel, Laurel A., and Sieh, Weiva
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Background: Percent density (PD) is a strong risk factor for breast cancer that is potentially modifiable by lifestyle factors. PD is a composite of the dense (DA) and nondense (NDA) areas of a mammogram, representing predominantly fibroglandular or fatty tissues, respectively. Alcohol and tobacco use have been associated with increased breast cancer risk. However, their effects on mammographic density (MD) phenotypes are poorly understood. Methods: We examined associations of alcohol and tobacco use with PD, DA, and NDA in a population-based cohort of 23,456 women screened using full-field digital mammography machines manufactured by Hologic or General Electric. MD was measured using Cumulus. Machine-specific effects were estimated using linear regression, and combined using random effects meta-analysis. Results: Alcohol use was positively associated with PD (P
trend = 0.01), unassociated with DA (Ptrend = 0.23), and inversely associated with NDA (Ptrend = 0.02) adjusting for age, body mass index, reproductive factors, physical activity, and family history of breast cancer. In contrast, tobacco use was inversely associated with PD (Ptrend = 0.0008), unassociated with DA (Ptrend = 0.93), and positively associated with NDA (Ptrend <0.0001). These trends were stronger in normal and overweight women than in obese women. Conclusions: These findings suggest that associations of alcohol and tobacco use with PD result more from their associations with NDA than DA. Impact: PD and NDA may mediate the association of alcohol drinking, but not tobacco smoking, with increased breast cancer risk. Further studies are needed to elucidate the modifiable lifestyle factors that influence breast tissue composition, and the important role of the fatty tissues on breast health. [ABSTRACT FROM AUTHOR]- Published
- 2020
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3. Race/Ethnicity and Accuracy of Self-Reported Female First-Degree Family History of Breast and Other Cancers in the Northern California Breast Cancer Family Registry.
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John, Esther M., Canchola, Alison J., Sangaramoorthy, Meera, Koo, Jocelyn, Whittemore, Alice S., and West, Dee W.
- Abstract
Background: Few studies have evaluated accuracy of self-reported family history of breast and other cancers in racial/ethnic minorities. Methods: We assessed the accuracy of cancer family history reports by women with breast cancer (probands) from the Northern California Breast Cancer Family Registry compared with 2 reference standards: personal cancer history reports by female first-degree relatives and California Cancer Registry records. Results: Probands reported breast cancer in first-degree relatives with high accuracy, but accuracy was lower for other cancers. Sensitivity (percentage correctly identifying relatives with cancer) was 93% [95% confidence interval (CI), 89.5-95.4] when compared with the relatives' self-report of breast cancer as the reference standard and varied little by proband race/ethnicity and other demographic factors, except for marginally lower sensitivity for Hispanic white probands (87.3%; 95% CI, 78.0-93.1; P = 0.07) than non-Hispanic white probands (95.1%; 95% CI, 88.9-98.0). Accuracy was also high when compared with cancer registry records as the reference standard, with a sensitivity of 95.5% (95% CI, 93.4-96.9) for breast cancer, but lower sensitivity for Hispanic white probands (91.2%; 95% CI, 84.4-95.2; P = 0.05) and probands with low English language proficiency (80%; 95% CI, 52.8-93.5; P < 0.01). Conclusions: Non-Hispanic white, African American, and Asian American probands reported first-degree breast cancer family history with high accuracy, although sensitivity was lower for Hispanic white probands and those with low English language proficiency. [ABSTRACT FROM AUTHOR]
- Published
- 2019
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4. Germline Variation and Breast Cancer Incidence: A Gene-Based Association Study and Whole-Genome Prediction of Early-Onset Breast Cancer.
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Bryan, Molly Scannell, Argos, Maria, Andrulis, Irene L., Hopper, John L., Chang-Claude, Jenny, Malone, Kathleen E., John, Esther M., Gammon, Marilie D., Daly, Mary B., Terry, Mary Beth, Buys, Saundra S., Huo, Dezheng, Olopade, Olofunmilayo I., Genkinger, Jeanine M., Whittemore, Alice S., Jasmine, Farzana, Kibriya, Muhammad G., Chen, Lin S., and Ahsan, Habibul
- Abstract
Background: Although germline genetics influences breast cancer incidence, published research only explains approximately half of the expected association. Moreover, the accuracy of prediction models remains low. For women who develop breast cancer early, the genetic architecture is less established. Methods: To identify loci associated with early-onset breast cancer, gene-based tests were carried out using exome array data from 3,479 women with breast cancer diagnosed before age 50 and 973 age-matched controls. Replication was undertaken in a population that developed breast cancer at all ages of onset. Results: Three gene regions were associated with breast cancer incidence: FGFR2 (P = 1.23 × 10
-5 ; replication P < 1.00 × 10-6 ), NEK10 (P = 3.57 × 10-4 ; replication P < 1.00 × 10-6 ), and SIVA1 (P = 5.49 × 10-4 ; replication P < 1.00 × 10-6 ). Of the 151 gene regions reported in previous literature, 19 (12.5%) showed evidence of association (P < 0.05) with the risk of early-onset breast cancer in the early-onset population. To predict incidence, whole-genome prediction was implemented on a subset of 3,076 participants who were additionally genotyped on a genome wide array. The whole-genome prediction outperformed a polygenic risk score [AUC, 0.636; 95% confidence interval (CI), 0.614-0.659 compared with 0.601; 95% CI, 0.578-0.623], and when combined with known epidemiologic risk factors, the AUC rose to 0.662 (95% CI, 0.640-0.684). Conclusions: This research supports a role for variation within FGFR2 and NEK10 in breast cancer incidence, and suggests SIVA1 as a novel risk locus. Impact: This analysis supports a shared genetic etiology between women with early- and late-onset breast cancer, and suggests whole-genome data can improve risk assessment. [ABSTRACT FROM AUTHOR]- Published
- 2018
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5. Age at Menarche and Late Adolescent Adiposity Associated with Mammographic Density on Processed Digital Mammograms in 24,840 Women.
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Alexeeff, Stacey E., Odo, Nnaemeka U., Lipson, Jafi A., Achacoso, Ninah, Rothstein, Joseph H., Yaffe, Martin J., Liang, Rhea Y., Acton, Luana, McGuire, Valerie, Whittemore, Alice S., Rubin, Daniel L., Sieh, Weiva, and Habel, Laurel A.
- Abstract
Background: High mammographic density is strongly associated with increased breast cancer risk. Some, but not all, risk factors for breast cancer are also associated with higher mammographic density. Methods: The study cohort (N = 24,840) was drawn from the Research Program in Genes, Environment and Health of Kaiser Permanente Northern California and included non-Hispanic white females ages 40 to 74 years with a full-field digital mammogram (FFDM). Percent density (PD) and dense area (DA) were measured by a radiological technologist using Cumulus. The association of age at menarche and late adolescent body mass index (BMI) with PD and DA were modeled using linear regression adjusted for confounders. Results: Age at menarche and late adolescent BMI were negatively correlated. Age at menarche was positively associated with PD (P value for trend <0.0001) and DA (P value for trend <0.0001) in fully adjusted models. Compared with the reference category of ages 12 to 13 years at menarche, menarche at age >16 years was associated with an increase in PD of 1.47% (95% CI, 0.69-2.25) and an increase in DA of 1.59 cm2 (95% CI, 0.48-2.70). Late adolescent BMI was inversely associated with PD (P < 0.0001) and DA (P < 0.0001) in fully adjusted models. Conclusions: Age at menarche and late adolescent BMI are both associated with Cumulus measures of mammographic density on processed FFDM images. Impact: Age at menarche and late adolescent BMI may act through different pathways. The long-term effects of age at menarche on cancer risk may be mediated through factors besides mammographic density. [ABSTRACT FROM AUTHOR]
- Published
- 2017
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6. Parity and Oral Contraceptive Use in Relation to Ovarian Cancer Risk in Older Women.
- Author
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McGuire, Valerie, Hartge, Patricia, Liao, Linda M., Sinha, Rashmi, Bernstein, Leslie, Canchola, Alison J., Anderson, Garnet L., Stefanick, Marcia L., and Whittemore, Alice S.
- Abstract
Background: Several studies have suggested that the ovarian cancer risk reductions associated with parity and oral contraceptive use are weaker in postmenopausal than premenopausal women, yet little is known about the persistence of these reductions as women age. This question gains importance with the increasing numbers of older women in the population. Methods: We addressed the question using data from three large U.S. cohort studies involving 310,290 white women aged 50+ years at recruitment, of whom 1,815 developed subsequent incident invasive epithelial ovarian cancer. We used Cox regression, stratified by cohort, to examine age-related trends in the HRs per full-term pregnancy and per year of oral contraceptive use. Results: The parity-associated risk reductions waned with age (P
trend < 0.001 in HR with increasing age), particularly among women aged 75 years or more, for whom we observed no association with parity. However, we observed no such attenuation in the oral contraceptive-associated risk reductions (P=0.79 for trend in HR with increasing age). Conclusion: These findings suggest that prior oral contraceptive use is important for ovarian cancer risk assessment among womenof all ages, while the benefits of parity wane aswomenage. Impact: This information, if duplicated in other studies, will be useful to preventive counseling and risk prediction, particularly for women at increased ovarian cancer risk due to a personal history of breast cancer or a family history of ovarian cancer. [ABSTRACT FROM AUTHOR]- Published
- 2016
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7. The Role of Genome Sequencing in Personalized Breast Cancer Prevention.
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Sieh, Weiva, Rothstein, Joseph H., McGuire, Valerie, and Whittemore, Alice S.
- Abstract
The article presents research on role of genome sequencing in breast cancer prevention. Topics of the research include use of allele frequencies and effect sizes of 86 known breast cancer variants to estimate population distribution of breast cancer risks, evaluation of the strategy of targeting preventive efforts for those at highest cancer risk and comparison of efficacy of the strategy with a best-case strategy.
- Published
- 2014
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8. Analysis of Over 10,000 Cases Finds No Association between Previously Reported Candidate Polymorphisms and Ovarian Cancer Outcome.
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White, Kristin L., Vierkant, Robert A., Fogarty, Zachary C., Charbonneau, Bridget, Block, Matthew S., Pharoah, Paul D. P., Chenevix-Trench, Georgia, Rossing, Mary Anne, Cramer, Daniel W., Pearce, Celeste Leigh, Schildkraut, Joellen M., Menon, Usha, Kjaer, Susanne Kruger, Levine, Douglas A., Gronwald, Jacek, Culver, Hoda Anton, Whittemore, Alice S., Karlan, Beth Y., Lambrechts, Diether, and Wentzensen, Nicolas
- Abstract
The article presents the study which examined the relationship between ovarian cancer outcome and 27 single-nucleotide polymorphisms (SNP) in several genes including the taxol efflux and metabolism genes ABCB1 and CYP2C8 and DNA repair genes ERCC2 and ERCC1. In the study, data were taken from the studies of the Ovarian Cancer Association Consortium (OCAC). Based on the results, there is no relation between the genotype and ovarian cancer recurrence or survival for the SNPs.
- Published
- 2013
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9. Prostate Cancer Susceptibility Polymorphism rs2660753 Is Not Associated with Invasive Ovarian Cancer.
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Amankwah, Ernest K., Kelemen, Linda E., Qinggang Wang, Honglin Song, Chenevix-Trench, Georgia, Beesley, Jonathan, Webb, Penelope M., Pearce, Celeste L., Wu, Anna H., Pike, Malcolm C., Stram, Daniel O., Chang-Claude, Jenny, Wang-Gohrke, Shan, Ness, Roberta B., Goode, Ellen L., Cunningham, Julie M., Fridley, Brooke L., Vierkant, Robert A., Tworoger, Shelley S., and Whittemore, Alice S.
- Abstract
The article discusses a study which examined the association between rs2660753, a prostate cancer susceptibility polymorphism, and invasive epithelial ovarian cancer (EOC). Several white patients with non-Hispanic ancestry served as subjects in this study. Results of the study that there was no association between rs2660753 and invasive EOC. According to the study, there is a need to replicate potentially promising genetic risk associations.
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- 2011
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10. An Admixture Scan in 1,484 African American Women with Breast Cancer.
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Fejerman, Laura, Haiman, Christopher A., Reich, David, Tandon, Arti, Deo, Rahul C., John, Esther M., Ingles, Sue A., Ambrosone, Christine B., Bovbjerg, Dana Howard, Jandorf, Lina H., Davis, Warren, Ciupak, Gregory, Whittemore, Alice S., Press, Michael F., Ursin, Giske, Bernstein, Leslie, Huntsman, Scott, Henderson, Brian E., Ziv, Elad, and Freedman, Matthew L.
- Abstract
The article presents a study on African American women in the U.S. with breast cancer having tumors that do not show the estrogen receptor (ER) and progesterone receptor (PR) compared with the European American women. A genome admixture scan was done to look for risk alleles for breast cancer. Also investigated was the global genetic ancestry in connection with disease phenotypes and found little evidence that contributes to breast cancer risk or hormone receptor status.
- Published
- 2009
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11. Performance of Prediction Models for BRCA Mutation Carriage in Three Racial/Ethnic Groups: Findings from the Northern California Breast Cancer Family Registry.
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Kurian, Allison W., Gong, Gail D., John, Esther M., Miron, Alexander, Felberg, Anna, Phipps, Amanda I., West, Dee W., and Whittemore, Alice S.
- Abstract
The article presents a study that evaluates the BRCAPRO and BOADICEA models in a population-based series of African American, Hispanic, and non-Hispanic Whites breast cancer patients tested for BRCA1 and BRCA2 gene mutations. It suggests that both models were well-calibrated within each racial/ethnic group, with some exceptions.
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- 2009
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12. Candidate Gene Analysis Using Imputed Genotypes: Cell Cycle Single-Nucleotide Polymorphisms and Ovarian Cancer Risk.
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Goode, Ellen L., Fridley, Brooke L., Vierkant, Robert A., Cunningham, Julie M., Phelan, Catherine M., Anderson, Stephanie, Rider, David N., White, Kristin L., Pankratz, V. Shane, Honglin Song, Hogdall, Estrid, Kjaer, Susanne K., Whittemore, Alice S., DiCioccio, Richard, Ramus, Susan J., Gayther, Simon A., Schildkraut, Joellen M., Pharaoh, Paul P. D., and Sellers, Thomas A.
- Abstract
The article presents a combined analysis of five independent studies of invasive epithelial ovarian cancer in order to maximize information gleaned from existing genotype data. In this study, it notes that up to 2,120 cases and 3,382 controls were genotyped in the course of two collaborations at a variety of single-nucleotide polymorphisms (SNPs) in 11 cell cycle genes and one gene region. Discussions on the results of the study as well as the method used are offered.
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- 2009
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13. Association Between Single-Nucleotide Polymorphisms in Hormone Metabolism and DNA Repair Genes and Epithelial Ovarian Cancer: Results from Two Australian Studies and an Additional Validation Set.
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Beesley, Jonathan, Jordan, Susan J., Spurdle, Amanda B., Song, Honglin, Ramus, Susan J., Kjaer, Suzanne Kruger, Hogdall, Estrid, DiCioccio, Richard A., McGuire, Valerie, Whittemore, Alice S., Gayther, Simon A., Pharoah, Paul D. P., Webb, Penelope M., and Chenevix-Trench, Georgia
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The article focuses on a study which examined the association between single-nucleotide polymorphisms (SNP) in hormone metabolism and DNA repair genes and epithelial ovarian cancer. The study used clinical and epidemiologic data and DNA samples for genotyping from women who participated in two separate Australian studies of epithelial ovarian cancer. It found that the only SNP to be associated with ovarian cancer risk in the two studies was SRD5A2 V89L, which showed a significant trend of increasing risk per rare allele.
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- 2007
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14. Prostate Cancer Risk in Relation to Insulin-like Growth Factor (IGF)-I and IGF-Binding Protein-3: A Prospective Multiethnic Study.
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Borugian, Marilyn J., Spinelli, John J., Zheng Sun, Kolonel, Laurence N., Oakley-Girvan, Ingrid, Pollak, Michael D., Whittemore, Alice S., Wu, Anna H., and Gallagher, Richard P.
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The article details a study which determined whether prediagnostic levels of insulin-like growth factor (IGF)-I and IGF-binding protein-3 (IGFBP-3) are associated with prostate cancer risk. Participants of the study were black, white and Asian men who were divided into case and control groups. It concluded that there is no association between prediagnostic IGF-I or IGFBP-3 and prostate cancer risk.
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- 2008
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15. A GWAS of Cutaneous Squamous Cell Carcinoma--Letter.
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Whittemore, Alice S., Wei Wang, Jorgenson, Eric, and Asgari, Maryam M.
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- 2016
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16. Prediagnostic C-Peptide and Risk of Prostate Cancer.
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Borugian, Marilyn J., Spinelli, John J., Zheng Sun, Kolonel, Laurence N., Oakley-Girvan, Ingrid, Pollak, Michael D., Whittemore, Alice S., Wu, Anna H., and Gallagher, Richard P.
- Abstract
The article presents a study which investigated the association of prediagnostic C-peptide and risk of developing prostate cancer in a U.S. and Canadian cohort. The materials and methods used are described. The study showed no association between C-peptide and risk of cancer. The findings are consistent with an earlier study where cancer was not linked with insulin levels.
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- 2007
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17. Risk of Ovarian Cancer and the NF-κB Pathway: Genetic Association with IL1A and TNFSF10.
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Charbonneau, Bridget, Block, Matthew S., Bamlet, William R., Vierkant, Robert A., Kalli, Kimberly R., Fogarty, Zachary, Rider, David N., Sellers, Thomas A., Tworoger, Shelley S., Poole, Elizabeth, Risch, Harvey A., Salvesen, Helga B., Kiemeney, Lambertus A., Baglietto, Laura, Giles, Graham G., Severi, Gianluca, Trabert, Britton, Wentzensen, Nicolas, Chenevix-Trench, Georgia, and Whittemore, Alice S.
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SINGLE nucleotide polymorphisms , *NF-kappa B , *INTERLEUKIN-1 , *OVARIAN cancer , *CANCER genetics , *CONFIDENCE intervals - Abstract
A missense single-nucleotide polymorphism (SNP) in the immune modulatory gene has been associated IL1A 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-1α (IL1A) is both regulated by and able to activate NF-κB, a transcription factor family that induces transcription of many proinflammatory genes and may be an important mediator in carcinogenesis.We therefore tagged SNPs inmore than 200 genes in the NF-κB 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; = 0.00075], which remained intact even after excluding P participants in the prior study (OR, 0.85; 95% CI, 0.75-0.95; = 0.006). Considering a multiple-testing-corrected P significance threshold of < 2.5 x 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. [ABSTRACT FROM AUTHOR]
- Published
- 2014
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18. Cross-Cancer Genome-Wide Association Study of Endometrial Cancer and Epithelial Ovarian Cancer Identifies Genetic Risk Regions Associated with Risk of Both Cancers.
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Glubb DM, Thompson DJ, Aben KKH, Alsulimani A, Amant F, Annibali D, Attia J, Barricarte A, Beckmann MW, Berchuck A, Bermisheva M, Bernardini MQ, Bischof K, Bjorge L, Bodelon C, Brand AH, Brenton JD, Brinton LA, Bruinsma F, Buchanan DD, Burghaus S, Butzow R, Cai H, Carney ME, Chanock SJ, Chen C, Chen XQ, Chen Z, Cook LS, Cunningham JM, De Vivo I, deFazio A, Doherty JA, Dörk T, du Bois A, Dunning AM, Dürst M, Edwards T, Edwards RP, Ekici AB, Ewing A, Fasching PA, Ferguson S, Flanagan JM, Fostira F, Fountzilas G, Friedenreich CM, Gao B, Gaudet MM, Gawełko J, Gentry-Maharaj A, Giles GG, Glasspool R, Goodman MT, Gronwald J, Harris HR, Harter P, Hein A, Heitz F, Hildebrandt MAT, Hillemanns P, Høgdall E, Høgdall CK, Holliday EG, Huntsman DG, Huzarski T, Jakubowska A, Jensen A, Jones ME, Karlan BY, Karnezis A, Kelley JL, Khusnutdinova E, Killeen JL, Kjaer SK, Klapdor R, Köbel M, Konopka B, Konstantopoulou I, Kopperud RK, Koti M, Kraft P, Kupryjanczyk J, Lambrechts D, Larson MC, Le Marchand L, Lele S, Lester J, Li AJ, Liang D, Liebrich C, Lipworth L, Lissowska J, Lu L, Lu KH, Macciotta A, Mattiello A, May T, McAlpine JN, McGuire V, McNeish IA, Menon U, Modugno F, Moysich KB, Nevanlinna H, Odunsi K, Olsson H, Orsulic S, Osorio A, Palli D, Park-Simon TW, Pearce CL, Pejovic T, Permuth JB, Podgorska A, Ramus SJ, Rebbeck TR, Riggan MJ, Risch HA, Rothstein JH, Runnebaum IB, Scott RJ, Sellers TA, Senz J, Setiawan VW, Siddiqui N, Sieh W, Spiewankiewicz B, Sutphen R, Swerdlow AJ, Szafron LM, Teo SH, Thompson PJ, Thomsen LCV, Titus L, Tone A, Tumino R, Turman C, Vanderstichele A, Edwards DV, Vergote I, Vierkant RA, Wang Z, Wang-Gohrke S, Webb PM, White E, Whittemore AS, Winham SJ, Wu X, Wu AH, Yannoukakos D, Spurdle AB, and O'Mara TA
- Subjects
- Carcinoma, Ovarian Epithelial genetics, Female, Genome-Wide Association Study, Humans, Quantitative Trait Loci genetics, Risk Factors, Endometrial Neoplasms genetics, Ovarian Neoplasms genetics
- Abstract
Background: Accumulating evidence suggests a relationship between endometrial cancer and ovarian cancer. Independent genome-wide association studies (GWAS) for endometrial cancer and ovarian cancer have identified 16 and 27 risk regions, respectively, four of which overlap between the two cancers. We aimed to identify joint endometrial and ovarian cancer risk loci by performing a meta-analysis of GWAS summary statistics from these two cancers., Methods: Using LDScore regression, we explored the genetic correlation between endometrial cancer and ovarian cancer. To identify loci associated with the risk of both cancers, we implemented a pipeline of statistical genetic analyses (i.e., inverse-variance meta-analysis, colocalization, and M-values) and performed analyses stratified by subtype. Candidate target genes were then prioritized using functional genomic data., Results: Genetic correlation analysis revealed significant genetic correlation between the two cancers ( r
G = 0.43, P = 2.66 × 10-5 ). We found seven loci associated with risk for both cancers ( PBonferroni < 2.4 × 10-9 ). In addition, four novel subgenome-wide regions at 7p22.2, 7q22.1, 9p12, and 11q13.3 were identified ( P < 5 × 10-7 ). Promoter-associated HiChIP chromatin loops from immortalized endometrium and ovarian cell lines and expression quantitative trait loci data highlighted candidate target genes for further investigation., Conclusions: Using cross-cancer GWAS meta-analysis, we have identified several joint endometrial and ovarian cancer risk loci and candidate target genes for future functional analysis., Impact: Our research highlights the shared genetic relationship between endometrial cancer and ovarian cancer. Further studies in larger sample sets are required to confirm our findings., (©2020 American Association for Cancer Research.)- Published
- 2021
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19. Germline Variation and Breast Cancer Incidence: A Gene-Based Association Study and Whole-Genome Prediction of Early-Onset Breast Cancer.
- Author
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Scannell Bryan M, Argos M, Andrulis IL, Hopper JL, Chang-Claude J, Malone KE, John EM, Gammon MD, Daly MB, Terry MB, Buys SS, Huo D, Olopade OI, Genkinger JM, Whittemore AS, Jasmine F, Kibriya MG, Chen LS, and Ahsan H
- Subjects
- Female, Follow-Up Studies, Genotype, Humans, Incidence, Middle Aged, Prognosis, Exome Sequencing, Biomarkers, Tumor genetics, Breast Neoplasms epidemiology, Breast Neoplasms genetics, Genetic Predisposition to Disease, Genome-Wide Association Study methods, Polymorphism, Single Nucleotide
- Abstract
Background: Although germline genetics influences breast cancer incidence, published research only explains approximately half of the expected association. Moreover, the accuracy of prediction models remains low. For women who develop breast cancer early, the genetic architecture is less established. Methods: To identify loci associated with early-onset breast cancer, gene-based tests were carried out using exome array data from 3,479 women with breast cancer diagnosed before age 50 and 973 age-matched controls. Replication was undertaken in a population that developed breast cancer at all ages of onset. Results: Three gene regions were associated with breast cancer incidence: FGFR2 ( P = 1.23 × 10
-5 ; replication P < 1.00 × 10-6 ), NEK10 ( P = 3.57 × 10-4 ; replication P < 1.00 × 10-6 ), and SIVA1 ( P = 5.49 × 10-4 ; replication P < 1.00 × 10-6 ). Of the 151 gene regions reported in previous literature, 19 (12.5%) showed evidence of association ( P < 0.05) with the risk of early-onset breast cancer in the early-onset population. To predict incidence, whole-genome prediction was implemented on a subset of 3,076 participants who were additionally genotyped on a genome wide array. The whole-genome prediction outperformed a polygenic risk score [AUC, 0.636; 95% confidence interval (CI), 0.614-0.659 compared with 0.601; 95% CI, 0.578-0.623], and when combined with known epidemiologic risk factors, the AUC rose to 0.662 (95% CI, 0.640-0.684). Conclusions: This research supports a role for variation within FGFR2 and NEK10 in breast cancer incidence, and suggests SIVA1 as a novel risk locus. Impact: This analysis supports a shared genetic etiology between women with early- and late-onset breast cancer, and suggests whole-genome data can improve risk assessment. Cancer Epidemiol Biomarkers Prev; 27(9); 1057-64. ©2018 AACR ., (©2018 American Association for Cancer Research.)- Published
- 2018
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20. No Evidence That Genetic Variation in the Myeloid-Derived Suppressor Cell Pathway Influences Ovarian Cancer Survival.
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Sucheston-Campbell LE, Cannioto R, Clay AI, Etter JL, Eng KH, Liu S, Battaglia S, Hu Q, Szender JB, Minlikeeva A, Joseph JM, Mayor P, Abrams SI, Segal BH, Wallace PK, Soh KT, Zsiros E, Anton-Culver H, Bandera EV, Beckmann MW, Berchuck A, Bjorge L, Bruegl A, Campbell IG, Campbell SP, Chenevix-Trench G, Cramer DW, Dansonka-Mieszkowska A, Dao F, Diergaarde B, Doerk T, Doherty JA, du Bois A, Eccles D, Engelholm SA, Fasching PA, Gayther SA, Gentry-Maharaj A, Glasspool RM, Goodman MT, Gronwald J, Harter P, Hein A, Heitz F, Hillemmanns P, Høgdall C, Høgdall EV, Huzarski T, Jensen A, Johnatty SE, Jung A, Karlan BY, Klapdor R, Kluz T, Konopka B, Kjær SK, Kupryjanczyk J, Lambrechts D, Lester J, Lubiński J, Levine DA, Lundvall L, McGuire V, McNeish IA, Menon U, Modugno F, Ness RB, Orsulic S, Paul J, Pearce CL, Pejovic T, Pharoah P, Ramus SJ, Rothstein J, Rossing MA, Rübner M, Schildkraut JM, Schmalfeldt B, Schwaab I, Siddiqui N, Sieh W, Sobiczewski P, Song H, Terry KL, Van Nieuwenhuysen E, Vanderstichele A, Vergote I, Walsh CS, Webb PM, Wentzensen N, Whittemore AS, Wu AH, Ziogas A, Odunsi K, Chang-Claude J, Goode EL, and Moysich KB
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- Carcinoma, Ovarian Epithelial, Female, Genetic Association Studies, Humans, Neoplasms, Glandular and Epithelial immunology, Ovarian Neoplasms immunology, Genetic Variation, Myeloid-Derived Suppressor Cells immunology, Neoplasms, Glandular and Epithelial genetics, Neoplasms, Glandular and Epithelial mortality, Ovarian Neoplasms genetics, Ovarian Neoplasms mortality
- Abstract
Background: The precise mechanism by which the immune system is adversely affected in cancer patients remains poorly understood, but the accumulation of immunosuppressive/protumorigenic myeloid-derived suppressor cells (MDSCs) is thought to be a prominent mechanism contributing to immunologic tolerance of malignant cells in epithelial ovarian cancer (EOC). To this end, we hypothesized genetic variation in MDSC pathway genes would be associated with survival after EOC diagnoses. Methods: We measured the hazard of death due to EOC within 10 years of diagnosis, overall and by invasive subtype, attributable to SNPs in 24 genes relevant in the MDSC pathway in 10,751 women diagnosed with invasive EOC. Versatile Gene-based Association Study and the admixture likelihood method were used to test gene and pathway associations with survival. Results: We did not identify individual SNPs that were significantly associated with survival after correction for multiple testing ( P < 3.5 × 10
-5 ), nor did we identify significant associations between the MDSC pathway overall, or the 24 individual genes and EOC survival. Conclusions: In this well-powered analysis, we observed no evidence that inherited variations in MDSC-associated SNPs, individual genes, or the collective genetic pathway contributed to EOC survival outcomes. Impact: Common inherited variation in genes relevant to MDSCs was not associated with survival in women diagnosed with invasive EOC. Cancer Epidemiol Biomarkers Prev; 26(3); 420-4. ©2016 AACR ., (©2016 American Association for Cancer Research.)- Published
- 2017
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21. Cross-Cancer Genome-Wide Analysis of Lung, Ovary, Breast, Prostate, and Colorectal Cancer Reveals Novel Pleiotropic Associations.
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Fehringer G, Kraft P, Pharoah PD, Eeles RA, Chatterjee N, Schumacher FR, Schildkraut JM, Lindström S, Brennan P, Bickeböller H, Houlston RS, Landi MT, Caporaso N, Risch A, Amin Al Olama A, Berndt SI, Giovannucci EL, Grönberg H, Kote-Jarai Z, Ma J, Muir K, Stampfer MJ, Stevens VL, Wiklund F, Willett WC, Goode EL, Permuth JB, Risch HA, Reid BM, Bezieau S, Brenner H, Chan AT, Chang-Claude J, Hudson TJ, Kocarnik JK, Newcomb PA, Schoen RE, Slattery ML, White E, Adank MA, Ahsan H, Aittomäki K, Baglietto L, Blomquist C, Canzian F, Czene K, Dos-Santos-Silva I, Eliassen AH, Figueroa JD, Flesch-Janys D, Fletcher O, Garcia-Closas M, Gaudet MM, Johnson N, Hall P, Hazra A, Hein R, Hofman A, Hopper JL, Irwanto A, Johansson M, Kaaks R, Kibriya MG, Lichtner P, Liu J, Lund E, Makalic E, Meindl A, Müller-Myhsok B, Muranen TA, Nevanlinna H, Peeters PH, Peto J, Prentice RL, Rahman N, Sanchez MJ, Schmidt DF, Schmutzler RK, Southey MC, Tamimi R, Travis RC, Turnbull C, Uitterlinden AG, Wang Z, Whittemore AS, Yang XR, Zheng W, Buchanan DD, Casey G, Conti DV, Edlund CK, Gallinger S, Haile RW, Jenkins M, Le Marchand L, Li L, Lindor NM, Schmit SL, Thibodeau SN, Woods MO, Rafnar T, Gudmundsson J, Stacey SN, Stefansson K, Sulem P, Chen YA, Tyrer JP, Christiani DC, Wei Y, Shen H, Hu Z, Shu XO, Shiraishi K, Takahashi A, Bossé Y, Obeidat M, Nickle D, Timens W, Freedman ML, Li Q, Seminara D, Chanock SJ, Gong J, Peters U, Gruber SB, Amos CI, Sellers TA, Easton DF, Hunter DJ, Haiman CA, Henderson BE, and Hung RJ
- Subjects
- Female, Genome-Wide Association Study, Genotype, Humans, Male, Breast Neoplasms genetics, Colorectal Neoplasms genetics, Lung Neoplasms genetics, Ovarian Neoplasms genetics, Prostatic Neoplasms genetics
- Abstract
Identifying genetic variants with pleiotropic associations can uncover common pathways influencing multiple cancers. We took a two-stage approach to conduct genome-wide association studies for lung, ovary, breast, prostate, and colorectal cancer from the GAME-ON/GECCO Network (61,851 cases, 61,820 controls) to identify pleiotropic loci. Findings were replicated in independent association studies (55,789 cases, 330,490 controls). We identified a novel pleiotropic association at 1q22 involving breast and lung squamous cell carcinoma, with eQTL analysis showing an association with ADAM15/THBS3 gene expression in lung. We also identified a known breast cancer locus CASP8/ALS2CR12 associated with prostate cancer, a known cancer locus at CDKN2B-AS1 with different variants associated with lung adenocarcinoma and prostate cancer, and confirmed the associations of a breast BRCA2 locus with lung and serous ovarian cancer. This is the largest study to date examining pleiotropy across multiple cancer-associated loci, identifying common mechanisms of cancer development and progression. Cancer Res; 76(17); 5103-14. ©2016 AACR., Competing Interests: of Potential Conflicts of Interest: Dr. David Nickle is a full time employee at Merck & Co. No potential conflicts of interest were disclosed by other authors., (©2016 American Association for Cancer Research.)
- Published
- 2016
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22. Genome-Wide Meta-Analyses of Breast, Ovarian, and Prostate Cancer Association Studies Identify Multiple New Susceptibility Loci Shared by at Least Two Cancer Types.
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Kar SP, Beesley J, Amin Al Olama A, Michailidou K, Tyrer J, Kote-Jarai Z, Lawrenson K, Lindstrom S, Ramus SJ, Thompson DJ, Kibel AS, Dansonka-Mieszkowska A, Michael A, Dieffenbach AK, Gentry-Maharaj A, Whittemore AS, Wolk A, Monteiro A, Peixoto A, Kierzek A, Cox A, Rudolph A, Gonzalez-Neira A, Wu AH, Lindblom A, Swerdlow A, Ziogas A, Ekici AB, Burwinkel B, Karlan BY, Nordestgaard BG, Blomqvist C, Phelan C, McLean C, Pearce CL, Vachon C, Cybulski C, Slavov C, Stegmaier C, Maier C, Ambrosone CB, Høgdall CK, Teerlink CC, Kang D, Tessier DC, Schaid DJ, Stram DO, Cramer DW, Neal DE, Eccles D, Flesch-Janys D, Edwards DR, Wokozorczyk D, Levine DA, Yannoukakos D, Sawyer EJ, Bandera EV, Poole EM, Goode EL, Khusnutdinova E, Høgdall E, Song F, Bruinsma F, Heitz F, Modugno F, Hamdy FC, Wiklund F, Giles GG, Olsson H, Wildiers H, Ulmer HU, Pandha H, Risch HA, Darabi H, Salvesen HB, Nevanlinna H, Gronberg H, Brenner H, Brauch H, Anton-Culver H, Song H, Lim HY, McNeish I, Campbell I, Vergote I, Gronwald J, Lubiński J, Stanford JL, Benítez J, Doherty JA, Permuth JB, Chang-Claude J, Donovan JL, Dennis J, Schildkraut JM, Schleutker J, Hopper JL, Kupryjanczyk J, Park JY, Figueroa J, Clements JA, Knight JA, Peto J, Cunningham JM, Pow-Sang J, Batra J, Czene K, Lu KH, Herkommer K, Khaw KT, Matsuo K, Muir K, Offitt K, Chen K, Moysich KB, Aittomäki K, Odunsi K, Kiemeney LA, Massuger LF, Fitzgerald LM, Cook LS, Cannon-Albright L, Hooning MJ, Pike MC, Bolla MK, Luedeke M, Teixeira MR, Goodman MT, Schmidt MK, Riggan M, Aly M, Rossing MA, Beckmann MW, Moisse M, Sanderson M, Southey MC, Jones M, Lush M, Hildebrandt MA, Hou MF, Schoemaker MJ, Garcia-Closas M, Bogdanova N, Rahman N, Le ND, Orr N, Wentzensen N, Pashayan N, Peterlongo P, Guénel P, Brennan P, Paulo P, Webb PM, Broberg P, Fasching PA, Devilee P, Wang Q, Cai Q, Li Q, Kaneva R, Butzow R, Kopperud RK, Schmutzler RK, Stephenson RA, MacInnis RJ, Hoover RN, Winqvist R, Ness R, Milne RL, Travis RC, Benlloch S, Olson SH, McDonnell SK, Tworoger SS, Maia S, Berndt S, Lee SC, Teo SH, Thibodeau SN, Bojesen SE, Gapstur SM, Kjær SK, Pejovic T, Tammela TL, Dörk T, Brüning T, Wahlfors T, Key TJ, Edwards TL, Menon U, Hamann U, Mitev V, Kosma VM, Setiawan VW, Kristensen V, Arndt V, Vogel W, Zheng W, Sieh W, Blot WJ, Kluzniak W, Shu XO, Gao YT, Schumacher F, Freedman ML, Berchuck A, Dunning AM, Simard J, Haiman CA, Spurdle A, Sellers TA, Hunter DJ, Henderson BE, Kraft P, Chanock SJ, Couch FJ, Hall P, Gayther SA, Easton DF, Chenevix-Trench G, Eeles R, Pharoah PD, and Lambrechts D
- Subjects
- Breast Neoplasms metabolism, Case-Control Studies, Chromosome Mapping, Datasets as Topic, Enhancer Elements, Genetic, Female, Gene Regulatory Networks, Humans, Male, Meta-Analysis as Topic, Organ Specificity genetics, Polymorphism, Single Nucleotide, Prostatic Neoplasms metabolism, Quantitative Trait Loci, Signal Transduction, Breast Neoplasms genetics, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Ovarian Neoplasms genetics, Prostatic Neoplasms genetics
- Abstract
Unlabelled: Breast, ovarian, and prostate cancers are hormone-related and may have a shared genetic basis, but this has not been investigated systematically by genome-wide association (GWA) studies. Meta-analyses combining the largest GWA meta-analysis data sets for these cancers totaling 112,349 cases and 116,421 controls of European ancestry, all together and in pairs, identified at P < 10(-8) seven new cross-cancer loci: three associated with susceptibility to all three cancers (rs17041869/2q13/BCL2L11; rs7937840/11q12/INCENP; rs1469713/19p13/GATAD2A), two breast and ovarian cancer risk loci (rs200182588/9q31/SMC2; rs8037137/15q26/RCCD1), and two breast and prostate cancer risk loci (rs5013329/1p34/NSUN4; rs9375701/6q23/L3MBTL3). Index variants in five additional regions previously associated with only one cancer also showed clear association with a second cancer type. Cell-type-specific expression quantitative trait locus and enhancer-gene interaction annotations suggested target genes with potential cross-cancer roles at the new loci. Pathway analysis revealed significant enrichment of death receptor signaling genes near loci with P < 10(-5) in the three-cancer meta-analysis., Significance: We demonstrate that combining large-scale GWA meta-analysis findings across cancer types can identify completely new risk loci common to breast, ovarian, and prostate cancers. We show that the identification of such cross-cancer risk loci has the potential to shed new light on the shared biology underlying these hormone-related cancers. Cancer Discov; 6(9); 1052-67. ©2016 AACR.This article is highlighted in the In This Issue feature, p. 932., Competing Interests: The authors disclose no potential conflicts of interest., (©2016 American Association for Cancer Research.)
- Published
- 2016
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23. Assessment of Multifactor Gene-Environment Interactions and Ovarian Cancer Risk: Candidate Genes, Obesity, and Hormone-Related Risk Factors.
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Usset JL, Raghavan R, Tyrer JP, McGuire V, Sieh W, Webb P, Chang-Claude J, Rudolph A, Anton-Culver H, Berchuck A, Brinton L, Cunningham JM, DeFazio A, Doherty JA, Edwards RP, Gayther SA, Gentry-Maharaj A, Goodman MT, Høgdall E, Jensen A, Johnatty SE, Kiemeney LA, Kjaer SK, Larson MC, Lurie G, Massuger L, Menon U, Modugno F, Moysich KB, Ness RB, Pike MC, Ramus SJ, Rossing MA, Rothstein J, Song H, Thompson PJ, van den Berg DJ, Vierkant RA, Wang-Gohrke S, Wentzensen N, Whittemore AS, Wilkens LR, Wu AH, Yang H, Pearce CL, Schildkraut JM, Pharoah P, Goode EL, and Fridley BL
- Subjects
- Female, Gene-Environment Interaction, Humans, Middle Aged, Obesity, Ovarian Neoplasms genetics, Polymorphism, Single Nucleotide, Risk Factors, Ovarian Neoplasms epidemiology
- Abstract
Background: Many epithelial ovarian cancer (EOC) risk factors relate to hormone exposure and elevated estrogen levels are associated with obesity in postmenopausal women. Therefore, we hypothesized that gene-environment interactions related to hormone-related risk factors could differ between obese and non-obese women., Methods: We considered interactions between 11,441 SNPs within 80 candidate genes related to hormone biosynthesis and metabolism and insulin-like growth factors with six hormone-related factors (oral contraceptive use, parity, endometriosis, tubal ligation, hormone replacement therapy, and estrogen use) and assessed whether these interactions differed between obese and non-obese women. Interactions were assessed using logistic regression models and data from 14 case-control studies (6,247 cases; 10,379 controls). Histotype-specific analyses were also completed., Results: SNPs in the following candidate genes showed notable interaction: IGF1R (rs41497346, estrogen plus progesterone hormone therapy, histology = all, P = 4.9 × 10(-6)) and ESR1 (rs12661437, endometriosis, histology = all, P = 1.5 × 10(-5)). The most notable obesity-gene-hormone risk factor interaction was within INSR (rs113759408, parity, histology = endometrioid, P = 8.8 × 10(-6))., Conclusions: We have demonstrated the feasibility of assessing multifactor interactions in large genetic epidemiology studies. Follow-up studies are necessary to assess the robustness of our findings for ESR1, CYP11A1, IGF1R, CYP11B1, INSR, and IGFBP2 Future work is needed to develop powerful statistical methods able to detect these complex interactions., Impact: Assessment of multifactor interaction is feasible, and, here, suggests that the relationship between genetic variants within candidate genes and hormone-related risk factors may vary EOC susceptibility. Cancer Epidemiol Biomarkers Prev; 25(5); 780-90. ©2016 AACR., (©2016 American Association for Cancer Research.)
- Published
- 2016
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24. Network-Based Integration of GWAS and Gene Expression Identifies a HOX-Centric Network Associated with Serous Ovarian Cancer Risk.
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Kar SP, Tyrer JP, Li Q, Lawrenson K, Aben KK, Anton-Culver H, Antonenkova N, Chenevix-Trench G, Baker H, Bandera EV, Bean YT, Beckmann MW, Berchuck A, Bisogna M, Bjørge L, Bogdanova N, Brinton L, Brooks-Wilson A, Butzow R, Campbell I, Carty K, Chang-Claude J, Chen YA, Chen Z, Cook LS, Cramer D, Cunningham JM, Cybulski C, Dansonka-Mieszkowska A, Dennis J, Dicks E, Doherty JA, Dörk T, du Bois A, Dürst M, Eccles D, Easton DF, Edwards RP, Ekici AB, Fasching PA, Fridley BL, Gao YT, Gentry-Maharaj A, Giles GG, Glasspool R, Goode EL, Goodman MT, Grownwald J, Harrington P, Harter P, Hein A, Heitz F, Hildebrandt MA, Hillemanns P, Hogdall E, Hogdall CK, Hosono S, Iversen ES, Jakubowska A, Paul J, Jensen A, Ji BT, Karlan BY, Kjaer SK, Kelemen LE, Kellar M, Kelley J, 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 L, Matsuo K, McGuire V, McLaughlin JR, McNeish IA, Menon U, Modugno F, Moysich KB, Narod SA, Nedergaard L, Ness RB, Nevanlinna H, 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, Shu XO, Shvetsov YB, Siddiqui N, Sieh W, Song H, Southey MC, Sucheston-Campbell LE, Tangen IL, Teo SH, Terry KL, Thompson PJ, Timorek A, Tsai YY, 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 YL, Wu X, Wu A, Yang H, Zheng W, Ziogas A, Sellers TA, Monteiro AN, Freedman ML, Gayther SA, and Pharoah PD
- Subjects
- Cystadenocarcinoma, Serous epidemiology, Female, Genotype, Global Health, Humans, Morbidity trends, Nuclear Proteins, Ovarian Neoplasms epidemiology, Risk Factors, Transcription Factors biosynthesis, Transcription Factors genetics, Cystadenocarcinoma, Serous genetics, DNA, Neoplasm genetics, Gene Expression Regulation, Neoplastic, Genetic Predisposition to Disease, Genome-Wide Association Study, Ovarian Neoplasms genetics
- Abstract
Background: Genome-wide association studies (GWAS) have so far reported 12 loci associated with serous epithelial ovarian cancer (EOC) risk. We hypothesized that some of these loci function through nearby transcription factor (TF) genes and that putative target genes of these TFs as identified by coexpression may also be enriched for additional EOC risk associations., Methods: We selected TF genes within 1 Mb of the top signal at the 12 genome-wide significant risk loci. Mutual information, a form of correlation, was used to build networks of genes strongly coexpressed with each selected TF gene in the unified microarray dataset of 489 serous EOC tumors from The Cancer Genome Atlas. Genes represented in this dataset were subsequently ranked using a gene-level test based on results for germline SNPs from a serous EOC GWAS meta-analysis (2,196 cases/4,396 controls)., Results: Gene set enrichment analysis identified six networks centered on TF genes (HOXB2, HOXB5, HOXB6, HOXB7 at 17q21.32 and HOXD1, HOXD3 at 2q31) that were significantly enriched for genes from the risk-associated end of the ranked list (P < 0.05 and FDR < 0.05). These results were replicated (P < 0.05) using an independent association study (7,035 cases/21,693 controls). Genes underlying enrichment in the six networks were pooled into a combined network., Conclusion: We identified a HOX-centric network associated with serous EOC risk containing several genes with known or emerging roles in serous EOC development., Impact: Network analysis integrating large, context-specific datasets has the potential to offer mechanistic insights into cancer susceptibility and prioritize genes for experimental characterization., (©2015 American Association for Cancer Research.)
- Published
- 2015
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25. Variation in NF-κB signaling pathways and survival in invasive epithelial ovarian cancer.
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Block MS, Charbonneau B, Vierkant RA, Fogarty Z, Bamlet WR, Pharoah PD, 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, Lubiński 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, Sellers TA, Phelan CM, Doherty JA, Johnatty SE, deFazio A, Song H, Tyrer J, Kalli KR, Fridley BL, Cunningham JM, and Goode EL
- Subjects
- Adult, Aged, Carcinoma, Ovarian Epithelial, Female, Genotype, Humans, Middle Aged, Neoplasm Invasiveness, Neoplasms, Glandular and Epithelial pathology, Ovarian Neoplasms pathology, Polymorphism, Single Nucleotide, Proportional Hazards Models, NF-kappa B genetics, Neoplasms, Glandular and Epithelial genetics, Neoplasms, Glandular and Epithelial mortality, Ovarian Neoplasms genetics, Ovarian Neoplasms mortality, Signal Transduction genetics
- 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-κB (NF-κB) 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-κB 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
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26. A genome-wide association study of early-onset breast cancer identifies PFKM as a novel breast cancer gene and supports a common genetic spectrum for breast cancer at any age.
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Ahsan H, Halpern J, Kibriya MG, Pierce BL, Tong L, Gamazon E, McGuire V, Felberg A, Shi J, Jasmine F, Roy S, Brutus R, Argos M, Melkonian S, Chang-Claude J, Andrulis I, Hopper JL, John EM, Malone K, Ursin G, Gammon MD, Thomas DC, Seminara D, Casey G, Knight JA, Southey MC, Giles GG, Santella RM, Lee E, Conti D, Duggan D, Gallinger S, Haile R, Jenkins M, Lindor NM, Newcomb P, Michailidou K, Apicella C, Park DJ, Peto J, Fletcher O, dos Santos Silva I, Lathrop M, Hunter DJ, Chanock SJ, Meindl A, Schmutzler RK, Müller-Myhsok B, Lochmann M, Beckmann L, Hein R, Makalic E, Schmidt DF, Bui QM, Stone J, Flesch-Janys D, Dahmen N, Nevanlinna H, Aittomäki K, Blomqvist C, Hall P, Czene K, Irwanto A, Liu J, Rahman N, Turnbull C, Dunning AM, Pharoah P, Waisfisz Q, Meijers-Heijboer H, Uitterlinden AG, Rivadeneira F, Nicolae D, Easton DF, Cox NJ, and Whittemore AS
- Subjects
- Breast Neoplasms epidemiology, Case-Control Studies, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Middle Aged, Polymorphism, Single Nucleotide, Biomarkers, Tumor genetics, Breast Neoplasms enzymology, Breast Neoplasms genetics, Phosphofructokinase-1, Muscle Type genetics
- Abstract
Early-onset breast cancer (EOBC) causes substantial loss of life and productivity, creating a major burden among women worldwide. We analyzed 1,265,548 Hapmap3 single-nucleotide polymorphisms (SNP) among a discovery set of 3,523 EOBC incident cases and 2,702 population control women ages ≤ 51 years. The SNPs with smallest P values were examined in a replication set of 3,470 EOBC cases and 5,475 control women. We also tested EOBC association with 19,684 genes by annotating each gene with putative functional SNPs, and then combining their P values to obtain a gene-based P value. We examined the gene with smallest P value for replication in 1,145 breast cancer cases and 1,142 control women. The combined discovery and replication sets identified 72 new SNPs associated with EOBC (P < 4 × 10(-8)) located in six genomic regions previously reported to contain SNPs associated largely with later-onset breast cancer (LOBC). SNP rs2229882 and 10 other SNPs on chromosome 5q11.2 remained associated (P < 6 × 10(-4)) after adjustment for the strongest published SNPs in the region. Thirty-two of the 82 currently known LOBC SNPs were associated with EOBC (P < 0.05). Low power is likely responsible for the remaining 50 unassociated known LOBC SNPs. The gene-based analysis identified an association between breast cancer and the phosphofructokinase-muscle (PFKM) gene on chromosome 12q13.11 that met the genome-wide gene-based threshold of 2.5 × 10(-6). In conclusion, EOBC and LOBC seem to have similar genetic etiologies; the 5q11.2 region may contain multiple distinct breast cancer loci; and the PFKM gene region is worthy of further investigation. These findings should enhance our understanding of the etiology of breast cancer.
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- 2014
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27. Large-scale evaluation of common variation in regulatory T cell-related genes and ovarian cancer outcome.
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Charbonneau B, Moysich KB, Kalli KR, Oberg AL, Vierkant RA, Fogarty ZC, Block MS, Maurer MJ, Goergen KM, Fridley BL, Cunningham JM, Rider DN, Preston C, Hartmann LC, Lawrenson K, Wang C, Tyrer J, Song H, deFazio A, Johnatty SE, Doherty JA, Phelan CM, Sellers TA, Ramirez SM, Vitonis AF, Terry KL, Van Den Berg D, Pike MC, Wu AH, Berchuck A, Gentry-Maharaj A, Ramus SJ, Diergaarde B, Shen H, Jensen A, Menkiszak J, Cybulski C, Lubiłski J, Ziogas A, Rothstein JH, McGuire V, Sieh W, Lester J, Walsh C, Vergote I, Lambrechts S, Despierre E, Garcia-Closas M, Yang H, Brinton LA, Spiewankiewicz B, Rzepecka IK, Dansonka-Mieszkowska A, Seibold P, Rudolph A, Paddock LE, Orlow I, Lundvall L, Olson SH, Hogdall CK, Schwaab I, du Bois A, Harter P, Flanagan JM, Brown R, Paul J, Ekici AB, Beckmann MW, Hein A, Eccles D, Lurie G, Hays LE, Bean YT, Pejovic T, Goodman MT, Campbell I, Fasching PA, Konecny G, Kaye SB, Heitz F, Hogdall E, Bandera EV, Chang-Claude J, Kupryjanczyk J, Wentzensen N, Lambrechts D, Karlan BY, Whittemore AS, Culver HA, Gronwald J, Levine DA, Kjaer SK, Menon U, Schildkraut JM, Pearce CL, Cramer DW, Rossing MA, Chenevix-Trench G, Pharoah PD, Gayther SA, Ness RB, Odunsi K, Sucheston LE, Knutson KL, and Goode EL
- Subjects
- Female, Gene Expression, Germ-Line Mutation, Humans, Interleukin-2 Receptor alpha Subunit genetics, Neoplasm Grading, Neoplasm Invasiveness, Ovarian Neoplasms pathology, Patient Outcome Assessment, Polymorphism, Single Nucleotide, Prognosis, Gene Expression Profiling, Genetic Predisposition to Disease, Genetic Variation, Ovarian Neoplasms genetics, Ovarian Neoplasms mortality, T-Lymphocytes, Regulatory metabolism
- Abstract
The presence of regulatory T cells (Treg) in solid tumors is known to play a role in patient survival in ovarian cancer and other malignancies. We assessed inherited genetic variations via 749 tag single-nucleotide polymorphisms (SNP) in 25 Treg-associated genes (CD28, CTLA4, FOXP3, IDO1, IL10, IL10RA, IL15, 1L17RA, IL23A, IL23R, IL2RA, IL6, IL6R, IL8, LGALS1, LGALS9, MAP3K8, STAT5A, STAT5B, TGFB1, TGFB2, TGFB3, TGFBR1, TGRBR2, and TGFBR3) in relation to ovarian cancer survival. We analyzed genotype and overall survival in 10,084 women with invasive epithelial ovarian cancer, including 5,248 high-grade serous, 1,452 endometrioid, 795 clear cell, and 661 mucinous carcinoma cases of European descent across 28 studies from the Ovarian Cancer Association Consortium (OCAC). The strongest associations were found for endometrioid carcinoma and IL2RA SNPs rs11256497 [HR, 1.42; 95% confidence interval (CI), 1.22-1.64; P = 5.7 × 10(-6)], rs791587 (HR, 1.36; 95% CI, 1.17-1.57; P = 6.2 × 10(-5)), rs2476491 (HR, = 1.40; 95% CI, 1.19-1.64; P = 5.6 × 10(-5)), and rs10795763 (HR, 1.35; 95% CI, 1.17-1.57; P = 7.9 × 10(-5)), and for clear cell carcinoma and CTLA4 SNP rs231775 (HR, 0.67; 95% CI, 0.54-0.82; P = 9.3 × 10(-5)) after adjustment for age, study site, population stratification, stage, grade, and oral contraceptive use. The rs231775 allele associated with improved survival in our study also results in an amino acid change in CTLA4 and previously has been reported to be associated with autoimmune conditions. Thus, we found evidence that SNPs in genes related to Tregs seem to play a role in ovarian cancer survival, particularly in patients with clear cell and endometrioid epithelial ovarian cancer.
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- 2014
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28. Diagnostic chest X-rays and breast cancer risk before age 50 years for BRCA1 and BRCA2 mutation carriers.
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John EM, McGuire V, Thomas D, Haile R, Ozcelik H, Milne RL, Felberg A, West DW, Miron A, Knight JA, Terry MB, Daly M, Buys SS, Andrulis IL, Hopper JL, Southey MC, Giles GG, Apicella C, Thorne H, and Whittemore AS
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- Adult, Australia epidemiology, Breast Neoplasms diagnostic imaging, Canada epidemiology, Diagnostic Tests, Routine, Female, Genetic Predisposition to Disease, Humans, Middle Aged, Mutation, New Zealand epidemiology, Risk Assessment, Risk Factors, United States epidemiology, Breast Neoplasms epidemiology, Breast Neoplasms genetics, Genes, BRCA1, Genes, BRCA2, Radiography, Thoracic statistics & numerical data
- Abstract
Background: The effects of low-dose medical radiation on breast cancer risk are uncertain, and few studies have included genetically susceptible women, such as those who carry germline BRCA1 and BRCA2 mutations., Methods: We studied 454 BRCA1 and 273 BRCA2 mutation carriers ages younger than 50 years from three breast cancer family registries in the United States, Canada, and Australia/New Zealand. We estimated breast cancer risk associated with diagnostic chest X-rays by comparing mutation carriers with breast cancer (cases) with those without breast cancer (controls). Exposure to chest X-rays was self-reported. Mammograms were not considered in the analysis., Results: After adjusting for known risk factors for breast cancer, the ORs for a history of diagnostic chest X-rays, excluding those for tuberculosis or pneumonia, were 1.16 [95% confidence interval (CI), 0.64-2.11] for BRCA1 mutations carriers and 1.22 (95% CI, 0.62-2.42) for BRCA2 mutations carriers. The OR was statistically elevated for BRCA2 mutation carriers with three to five diagnostic chest X-rays (P = 0.01) but not for those with six or more chest X-rays. Few women reported chest fluoroscopy for tuberculosis or chest X-rays for pneumonia; the OR estimates were elevated, but not statistically significant, for BRCA1 mutation carriers., Conclusions: Our findings do not support a positive association between diagnostic chest X-rays and breast cancer risk before the ages of 50 years for BRCA1 or BRCA2 mutation carriers., Impact: Given the increasing use of diagnostic imaging involving higher ionizing radiation doses, further studies of genetically predisposed women are warranted., (©2013 AACR.)
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- 2013
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29. Genetic variation in TYMS in the one-carbon transfer pathway is associated with ovarian carcinoma types in the Ovarian Cancer Association Consortium.
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Kelemen LE, Goodman MT, McGuire V, Rossing MA, Webb PM, Köbel M, Anton-Culver H, Beesley J, Berchuck A, Brar S, Carney ME, Chang-Claude J, Chenevix-Trench G, Cramer DW, Cunningham JM, Dicioccio RA, Doherty JA, Easton DF, Fredericksen ZS, Fridley BL, Gates MA, Gayther SA, Gentry-Maharaj A, Høgdall E, Kjaer SK, Lurie G, Menon U, Moorman PG, Moysich K, Ness RB, Palmieri RT, Pearce CL, Pharoah PD, Ramus SJ, Song H, Stram DO, Tworoger SS, Van Den Berg D, Vierkant RA, Wang-Gohrke S, Whittemore AS, Wilkens LR, Wu AH, Schildkraut JM, Sellers TA, and Goode EL
- Subjects
- Adult, Aged, Biomarkers, Tumor genetics, Biomarkers, Tumor metabolism, Carbon-Nitrogen Ligases genetics, Case-Control Studies, DNA (Cytosine-5-)-Methyltransferases genetics, DNA Methyltransferase 3A, Dihydrouracil Dehydrogenase (NADP) genetics, Female, Folic Acid metabolism, Genetic Predisposition to Disease, Genetic Variation, Genotype, Humans, Methylenetetrahydrofolate Dehydrogenase (NADP) genetics, Middle Aged, Minor Histocompatibility Antigens, Ovarian Neoplasms metabolism, Ovarian Neoplasms pathology, Polymorphism, Single Nucleotide, Thymidylate Synthase biosynthesis, Thymidylate Synthase metabolism, Ovarian Neoplasms enzymology, Ovarian Neoplasms genetics, Thymidylate Synthase genetics
- Abstract
Background: We previously reported the risks of ovarian carcinoma for common polymorphisms in one-carbon transfer genes. We sought to replicate associations for DPYD rs1801265, DNMT3A rs13420827, MTHFD1 rs1950902, MTHFS rs17284990, and TYMS rs495139 with risk of ovarian carcinoma overall and to use the large sample of assembled cases to investigate associations by histologic type., Methods: Associations were evaluated in the Ovarian Cancer Association Consortium, including 16 studies of 5,593 epithelial ovarian carcinoma cases and 9,962 controls of white non-Hispanic origin. Odds ratios (OR) and 95% confidence intervals (CI) were adjusted for age and study site., Results: The five polymorphisms were not associated with ovarian carcinoma overall (P(trend) > 0.13); however, associations for the minor allele at TYMS rs495139 were observed for carcinomas of mucinous type (OR, 1.19; 95% CI, 1.03-1.39; P = 0.02), clear cell type (OR, 0.86; 95% CI, 0.75-0.99; P = 0.04), and endometrioid type (OR, 0.90; 95% CI, 0.81-0.99; P = 0.04; P(heterogeneity) = 0.001). Restriction to low-grade mucinous carcinomas further strengthened the association for the mucinous type (OR, 1.32; 95% CI, 1.07-1.62; P = 0.01). TYMS rs495139 was not associated with serous type (OR, 1.06; 95% CI, 1.00-1.13; P = 0.05)., Conclusions: TYMS rs495139 may be associated with a differential risk of ovarian carcinoma types, indicating the importance of accurate histopathologic classification., Impact: Biomarkers that distinguish ovarian carcinoma types are few, and TYMS rs495139 may provide a novel clue to type etiology.
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- 2010
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30. Polymorphism in the GALNT1 gene and epithelial ovarian cancer in non-Hispanic white women: the Ovarian Cancer Association Consortium.
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Phelan CM, Tsai YY, Goode EL, Vierkant RA, Fridley BL, Beesley J, Chen XQ, Webb PM, Chanock S, Cramer DW, Moysich K, Edwards RP, Chang-Claude J, Garcia-Closas M, Yang H, Wang-Gohrke S, Hein R, Green AC, Lissowska J, Carney ME, Lurie G, Wilkens LR, Ness RB, Pearce CL, Wu AH, Van Den Berg DJ, Stram DO, Terry KL, Whiteman DC, Whittemore AS, DiCioccio RA, McGuire V, Doherty JA, Rossing MA, Anton-Culver H, Ziogas A, Hogdall C, Hogdall E, Krüger Kjaer S, Blaakaer J, Quaye L, Ramus SJ, Jacobs I, Song H, Pharoah PD, Iversen ES, Marks JR, Pike MC, Gayther SA, Cunningham JM, Goodman MT, Schildkraut JM, Chenevix-Trench G, Berchuck A, and Sellers TA
- Subjects
- Case-Control Studies, Female, Humans, Middle Aged, Polymorphism, Single Nucleotide, White People, Polypeptide N-acetylgalactosaminyltransferase, Genetic Predisposition to Disease, N-Acetylgalactosaminyltransferases genetics, Neoplasms, Glandular and Epithelial genetics, Ovarian Neoplasms genetics
- Abstract
Aberrant glycosylation is a well-described hallmark of cancer. In a previous ovarian cancer case control study that examined polymorphisms in 26 glycosylation-associated genes, we found strong statistical evidence (P = 0.00017) that women who inherited two copies of a single-nucleotide polymorphism in the UDP-N-acetylgalactosamine:polypeptide N-acetylgalactosaminyltransferase, GALNT1, had decreased ovarian cancer risk. The current study attempted to replicate this observation. The GALNT1 single-nucleotide polymorphism rs17647532 was genotyped in 6,965 cases and 8,377 controls from 14 studies forming the Ovarian Cancer Association Consortium. The fixed effects estimate per rs17647532 allele was null (odds ratio, 0.99; 95% confidence interval, 0.92-1.07). When a recessive model was fit, the results were unchanged. Test for heterogeneity of the odds ratios revealed consistency across the 14 replication sites but significant differences compared with the original study population (P = 0.03). This study underscores the need for replication of putative findings in genetic association studies.
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- 2010
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31. ESR1/SYNE1 polymorphism and invasive epithelial ovarian cancer risk: an Ovarian Cancer Association Consortium study.
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Doherty JA, Rossing MA, Cushing-Haugen KL, Chen C, Van Den Berg DJ, Wu AH, Pike MC, Ness RB, Moysich K, Chenevix-Trench G, Beesley J, Webb PM, Chang-Claude J, Wang-Gohrke S, Goodman MT, Lurie G, Thompson PJ, Carney ME, Hogdall E, Kjaer SK, Hogdall C, Goode EL, Cunningham JM, Fridley BL, Vierkant RA, Berchuck A, Moorman PG, Schildkraut JM, Palmieri RT, Cramer DW, Terry KL, Yang HP, Garcia-Closas M, Chanock S, Lissowska J, Song H, Pharoah PD, Shah M, Perkins B, McGuire V, Whittemore AS, Di Cioccio RA, Gentry-Maharaj A, Menon U, Gayther SA, Ramus SJ, Ziogas A, Brewster W, Anton-Culver H, and Pearce CL
- Subjects
- Biomarkers, Tumor genetics, Cytoskeletal Proteins, Female, Genotype, Humans, Odds Ratio, Risk Factors, Estrogen Receptor alpha genetics, Genetic Predisposition to Disease, Nerve Tissue Proteins genetics, Nuclear Proteins genetics, Ovarian Neoplasms genetics, Ovarian Neoplasms pathology, Polymorphism, Single Nucleotide
- Abstract
We genotyped 13 single nucleotide polymorphisms (SNPs) in the estrogen receptor alpha gene (ESR1) region in three population-based case-control studies of epithelial ovarian cancer conducted in the United States, comprising a total of 1,128 and 1,866 non-Hispanic white invasive cases and controls, respectively. A SNP 19 kb downstream of ESR1 (rs2295190, G-to-T change) was associated with invasive ovarian cancer risk, with a per-T-allele odds ratio (OR) of 1.24 [95% confidence interval (CI), 1.06-1.44, P = 0.006]. rs2295190 is a nonsynonymous coding SNP in a neighboring gene called spectrin repeat containing, nuclear envelope 1 (SYNE1), which is involved in nuclear organization and structural integrity, function of the Golgi apparatus, and cytokinesis. An isoform encoded by SYNE1 has been reported to be downregulated in ovarian and other cancers. rs2295190 was genotyped in an additional 12 studies through the Ovarian Cancer Association Consortium, with 5,279 invasive epithelial cases and 7,450 controls. The per-T-allele OR for this 12-study set was 1.09 (95% CI, 1.02-1.17; P = 0.017). Results for the serous subtype in the 15 combined studies were similar to those overall (n = 3,545; OR, 1.09; 95% CI, 1.01-1.18; P = 0.025), and our findings were strongest for the mucinous subtype (n = 447; OR, 1.32; 95% CI, 1.11-1.58; P = 0.002). No association was observed for the endometrioid subtype. In an additional analysis of 1,459 borderline ovarian cancer cases and 7,370 controls, rs2295190 was not associated with risk. These data provide suggestive evidence that the rs2295190 T allele, or another allele in linkage disequilibrium with it, may be associated with increased risk of invasive ovarian cancer.
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- 2010
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32. Single nucleotide polymorphisms in the TP53 region and susceptibility to invasive epithelial ovarian cancer.
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Schildkraut JM, Goode EL, Clyde MA, Iversen ES, Moorman PG, Berchuck A, Marks JR, Lissowska J, Brinton L, Peplonska B, Cunningham JM, Vierkant RA, Rider DN, Chenevix-Trench G, Webb PM, Beesley J, Chen X, Phelan C, Sutphen R, Sellers TA, Pearce L, Wu AH, Van Den Berg D, Conti D, Elund CK, Anderson R, Goodman MT, Lurie G, Carney ME, Thompson PJ, Gayther SA, Ramus SJ, Jacobs I, Krüger Kjaer S, Hogdall E, Blaakaer J, Hogdall C, Easton DF, Song H, Pharoah PD, Whittemore AS, McGuire V, Quaye L, Anton-Culver H, Ziogas A, Terry KL, Cramer DW, Hankinson SE, Tworoger SS, Calingaert B, Chanock S, Sherman M, and Garcia-Closas M
- Subjects
- Adult, Aged, Alleles, Female, Genetic Predisposition to Disease, Humans, Linkage Disequilibrium, Middle Aged, Neoplasm Invasiveness, Ovarian Neoplasms pathology, Polymorphism, Single Nucleotide, Young Adult, Genes, p53, Ovarian Neoplasms genetics
- Abstract
The p53 protein is critical for multiple cellular functions including cell growth and DNA repair. We assessed whether polymorphisms in the region encoding TP53 were associated with risk of invasive ovarian cancer. The study population includes a total of 5,206 invasive ovarian cancer cases (2,829 of which were serous) and 8,790 controls from 13 case-control or nested case-control studies participating in the Ovarian Cancer Association Consortium (OCAC). Three of the studies performed independent discovery investigations involving genotyping of up to 23 single nucleotide polymorphisms (SNP) in the TP53 region. Significant findings from this discovery phase were followed up for replication in the other OCAC studies. Mixed effects logistic regression was used to generate posterior median per allele odds ratios (OR), 95% probability intervals (PI), and Bayes factors (BF) for genotype associations. Five SNPs showed significant associations with risk in one or more of the discovery investigations and were followed up by OCAC. Mixed effects analysis confirmed associations with serous invasive cancers for two correlated (r(2) = 0.62) SNPs: rs2287498 (median per allele OR, 1.30; 95% PI, 1.07-1.57) and rs12951053 (median per allele OR, 1.19; 95% PI, 1.01-1.38). Analyses of other histologic subtypes suggested similar associations with endometrioid but not with mucinous or clear cell cancers. This large study provides statistical evidence for a small increase in risk of ovarian cancer associated with common variants in the TP53 region.
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- 2009
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33. Polymorphism in the IL18 gene and epithelial ovarian cancer in non-Hispanic white women.
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Palmieri RT, Wilson MA, Iversen ES, Clyde MA, Calingaert B, Moorman PG, Poole C, Anderson AR, Anderson S, Anton-Culver H, Beesley J, Hogdall E, Brewster W, Carney ME, Chen X, Chenevix-Trench G, Chang-Claude J, Cunningham JM, Dicioccio RA, Doherty JA, Easton DF, Edlund CK, Gayther SA, Gentry-Maharaj A, Goode EL, Goodman MT, Kjaer SK, Hogdall CK, Hopkins MP, Jenison EL, Blaakaer J, Lurie G, McGuire V, Menon U, Moysich KB, Ness RB, Pearce CL, Pharoah PD, Pike MC, Ramus SJ, Rossing MA, Song H, Terada KY, Vandenberg D, Vierkant RA, Wang-Gohrke S, Webb PM, Whittemore AS, Wu AH, Ziogas A, Berchuck A, and Schildkraut JM
- Subjects
- Case-Control Studies, Chi-Square Distribution, Female, Genetic Predisposition to Disease, Genotype, Humans, Logistic Models, Middle Aged, North Carolina, White People genetics, Interleukin-18 genetics, Neoplasms, Glandular and Epithelial genetics, Ovarian Neoplasms genetics, Polymorphism, Single Nucleotide
- Abstract
Over 22,000 cases of ovarian cancer were diagnosed in 2007 in the United States, but only a fraction of them can be attributed to mutations in highly penetrant genes such as BRCA1. To determine whether low-penetrance genetic variants contribute to ovarian cancer risk, we genotyped 1,536 single nucleotide polymorphisms (SNP) in several candidate gene pathways in 848 epithelial ovarian cancer cases and 798 controls in the North Carolina Ovarian Cancer Study (NCO) using a customized Illumina array. The inflammation gene interleukin-18 (IL18) showed the strongest evidence for association with epithelial ovarian cancer in a gene-by-gene analysis (P = 0.002) with a <25% chance of being a false-positive finding (q value = 0.240). Using a multivariate model search algorithm over 11 IL18 tagging SNPs, we found that the association was best modeled by rs1834481. Further, this SNP uniquely tagged a significantly associated IL18 haplotype and there was an increased risk of epithelial ovarian cancer per rs1834481 allele (odds ratio, 1.24; 95% confidence interval, 1.06-1.45). In a replication stage, 12 independent studies from the Ovarian Cancer Association Consortium (OCAC) genotyped rs1834481 in an additional 5,877 cases and 7,791 controls. The fixed effects estimate per rs1834481 allele was null (odds ratio, 0.99; 95% confidence interval, 0.94-1.05) when data from the 12 OCAC studies were combined. The effect estimate remained unchanged with the addition of the initial North Carolina Ovarian Cancer Study data. This analysis shows the importance of consortia, like the OCAC, in either confirming or refuting the validity of putative findings in studies with smaller sample sizes. (Cancer Epidemiol Biomarkers Prev 2008;17(12):3567-72).
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- 2008
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34. Association study of prostate cancer susceptibility variants with risks of invasive ovarian, breast, and colorectal cancer.
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Song H, Koessler T, Ahmed S, Ramus SJ, Kjaer SK, Dicioccio RA, Wozniak E, Hogdall E, Whittemore AS, McGuire V, Ponder BA, Turnbull C, Hines S, Rahman N, Eeles RA, Easton DF, Gayther SA, Dunning AM, and Pharoah PD
- Subjects
- Adolescent, Adult, Aged, Breast Neoplasms pathology, Case-Control Studies, Colorectal Neoplasms pathology, Female, Humans, Male, Middle Aged, Ovarian Neoplasms pathology, Polymorphism, Single Nucleotide, Prostatic Neoplasms pathology, Risk Factors, United Kingdom, Breast Neoplasms genetics, Colorectal Neoplasms genetics, Genetic Predisposition to Disease, Neoplasm Invasiveness, Ovarian Neoplasms genetics, Prostatic Neoplasms genetics
- Abstract
Several prostate cancer susceptibility loci have recently been identified by genome-wide association studies. These loci are candidates for susceptibility to other epithelial cancers. The aim of this study was to test these tag single nucleotide polymorphisms (SNP) for association with invasive ovarian, colorectal, and breast cancer. Twelve prostate cancer-associated tag SNPs were genotyped in ovarian (2,087 cases/3,491 controls), colorectal (2,148 cases/2,265 controls) and breast (first set, 4,339 cases/4,552 controls; second set, 3,800 cases/3,995 controls) case-control studies. The primary test of association was a comparison of genotype frequencies between cases and controls, and a test for trend stratified by study where appropriate. Genotype-specific odds ratios (OR) were estimated by logistic regression. SNP rs2660753 (chromosome 3p12) showed evidence of association with ovarian cancer [per minor allele OR, 1.19; 95% confidence interval (95% CI), 1.04-1.37; P(trend) = 0.012]. This association was stronger for the serous histologic subtype (OR, 1.29; 95% CI, 1.09-1.53; P = 0.003). SNP rs7931342 (chromosome 11q13) showed some evidence of association with breast cancer (per minor allele OR, 0.95; 95% CI, 0.91-0.99; P(trend) = 0.028). This association was somewhat stronger for estrogen receptor-positive tumors (OR, 0.92; 95% CI, 0.87-0.98; P = 0.011). None of these tag SNPs were associated with risk of colorectal cancer. In conclusion, loci associated with risk of prostate cancer may also be associated with ovarian and breast cancer susceptibility. However, the effects are modest and warrant replication in larger studies.
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- 2008
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35. Tagging single nucleotide polymorphisms in cell cycle control genes and susceptibility to invasive epithelial ovarian cancer.
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Gayther SA, Song H, Ramus SJ, Kjaer SK, Whittemore AS, Quaye L, Tyrer J, Shadforth D, Hogdall E, Hogdall C, Blaeker J, DiCioccio R, McGuire V, Webb PM, Beesley J, Green AC, Whiteman DC, Goodman MT, Lurie G, Carney ME, Modugno F, Ness RB, Edwards RP, Moysich KB, Goode EL, Couch FJ, Cunningham JM, Sellers TA, Wu AH, Pike MC, Iversen ES, Marks JR, Garcia-Closas M, Brinton L, Lissowska J, Peplonska B, Easton DF, Jacobs I, Ponder BA, Schildkraut J, Pearce CL, Chenevix-Trench G, Berchuck A, and Pharoah PD
- Subjects
- Case-Control Studies, Cell Cycle genetics, Cell Cycle Proteins genetics, Cyclin-Dependent Kinases genetics, Cyclins genetics, Female, Genetic Predisposition to Disease, Humans, Ovarian Neoplasms pathology, Polymorphism, Single Nucleotide, Genes, cdc, Ovarian Neoplasms genetics
- Abstract
High-risk susceptibility genes explain <40% of the excess risk of familial ovarian cancer. Therefore, other ovarian cancer susceptibility genes are likely to exist. We have used a single nucleotide polymorphism (SNP)-tagging approach to evaluate common variants in 13 genes involved in cell cycle control-CCND1, CCND2, CCND3, CCNE1, CDK2, CDK4, CDK6, CDKN1A, CDKN1B, CDKN2A, CDKN2B, CDKN2C, and CDKN2D-and risk of invasive epithelial ovarian cancer. We used a two-stage, multicenter, case-control study. In stage 1, 88 SNPs that tag common variation in these genes were genotyped in three studies from the United Kingdom, United States, and Denmark ( approximately 1,500 cases and 2,500 controls). Genotype frequencies in cases and controls were compared using logistic regression. In stage 2, eight other studies from Australia, Poland, and the United States ( approximately 2,000 cases and approximately 3,200 controls) were genotyped for the five most significant SNPs from stage 1. No SNP was significant in the stage 2 data alone. Using the combined stages 1 and 2 data set, CDKN2A rs3731257 and CDKN1B rs2066827 were associated with disease risk (unadjusted P trend = 0.008 and 0.036, respectively), but these were not significant after adjusting for multiple testing. Carrying the minor allele of these SNPs was found to be associated with reduced risk [OR, 0.91 (0.85-0.98) for rs3731257; and OR, 0.93 (0.87-0.995) for rs2066827]. In conclusion, we have found evidence that a single tagged SNP in both the CDKN2A and CDKN1B genes may be associated with reduced ovarian cancer risk. This study highlights the need for multicenter collaborations for genetic association studies.
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- 2007
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36. Common variants in RB1 gene and risk of invasive ovarian cancer.
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Song H, Ramus SJ, Shadforth D, Quaye L, Kjaer SK, Dicioccio RA, Dunning AM, Hogdall E, Hogdall C, Whittemore AS, McGuire V, Lesueur F, Easton DF, Jacobs IJ, Ponder BA, Gayther SA, and Pharoah PD
- Subjects
- Case-Control Studies, Female, Genetic Predisposition to Disease, Humans, Neoplasm Invasiveness, Ovarian Neoplasms pathology, Polymorphism, Single Nucleotide, Ovarian Neoplasms genetics, Retinoblastoma Protein genetics
- Abstract
Somatic alteration of the RB1 gene is common in several types of cancer, and germ-line variants are implicated in others. We have used a single nucleotide polymorphism (SNP) tagging approach to evaluate the association between common variants (SNP) in RB1 and risks of invasive ovarian cancer. We genotyped 11 tagging SNPs in three ovarian case-control studies from the United Kingdom, United States, and Denmark, comprising >1500 cases and 4,800 controls. Two SNPs showed significant association with ovarian cancer risk: carriers of the minor allele of rs2854344 were at reduced risk compared with the common homozygotes [odds ratio (OR), 0.73; 95% confidence interval (95% CI), 0.61-0.89; P = 0.0009 dominant model]. Similarly, the minor allele of rs4151620 was found to be associated with reduced risk (rare versus common homozygote; OR, 0.19; 95% CI, 0.07-0.53; P = 0.00005 recessive model). After adjusting for multiple testing, the most significant association (rs4151620) was P = 0.001. A global test comparing common haplotype frequencies in cases and controls was of borderline significance (P(8df) = 0.04). There are no common coding SNPs in the RB1 gene. However, intron 17 of RB1 contains the open reading frame for the P2RY5 gene, and rs4151620 is perfectly correlated with rs2227311, which is located in the 5'-untranslated region of P2RY5 and is predicted to affect P2RY5 transcription. rs2854344 has been reported previously to be associated with breast cancer risk. The possible associations of rs2854344 and rs4151620 with ovarian cancer risk warrant confirmation in independent case-control studies before studies on their biological mode of action.
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- 2006
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37. BRCA1 and BRCA2 mutation carriers, oral contraceptive use, and breast cancer before age 50.
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Haile RW, Thomas DC, McGuire V, Felberg A, John EM, Milne RL, Hopper JL, Jenkins MA, Levine AJ, Daly MM, Buys SS, Senie RT, Andrulis IL, Knight JA, Godwin AK, Southey M, McCredie MR, Giles GG, Andrews L, Tucker K, Miron A, Apicella C, Tesoriero A, Bane A, Pike MC, and Whittemore AS
- Subjects
- Adult, Australia epidemiology, Breast Neoplasms epidemiology, Canada epidemiology, Carcinoma in Situ epidemiology, Carcinoma, Ductal, Breast epidemiology, Case-Control Studies, Female, Genetic Predisposition to Disease, Heterozygote, Humans, Logistic Models, Middle Aged, Receptors, Estrogen drug effects, Receptors, Progesterone drug effects, Risk Factors, Surveys and Questionnaires, Time Factors, United States epidemiology, Breast Neoplasms genetics, Carcinoma in Situ genetics, Carcinoma, Ductal, Breast genetics, Contraceptives, Oral pharmacology, Genes, BRCA1 drug effects, Genes, BRCA2 drug effects, Mutation drug effects
- Abstract
Background: Understanding the effect of oral contraceptives on risk of breast cancer in BRCA1 or BRCA2 mutation carriers is important because oral contraceptive use is a common, modifiable practice., Methods: We studied 497 BRCA1 and 307 BRCA2 mutation carriers, of whom 195 and 128, respectively, had been diagnosed with breast cancer. Case-control analyses were conducted using unconditional logistic regression with adjustments for family history and familial relationships and were restricted to subjects with a reference age under 50 years., Results: For BRCA1 mutation carriers, there was no significant association between risk of breast cancer and use of oral contraceptives for at least 1 year [odds ratio (OR), 0.77; 95% confidence interval (95% CI), 0.53-1.12] or duration of oral contraceptive use (P(trend) = 0.62). For BRCA2 mutation carriers, there was no association with use of oral contraceptives for at least 1 year (OR, 1.62; 95% CI, 0.90-2.92); however, there was an association of elevated risk with oral contraceptive use for at least 5 years (OR, 2.06; 95% CI, 1.08-3.94) and with duration of use (OR(trend) per year of use, 1.08; P = 0.008). Similar results were obtained when we considered only use of oral contraceptives that first started in 1975 or later., Conclusions: We found no evidence overall that use of oral contraceptives for at least 1 year is associated with breast cancer risk for BRCA1 and BRCA2 mutation carriers before age 50. For BRCA2 mutation carriers, use of oral contraceptives may be associated with an increased risk of breast cancer among women who use them for at least 5 years. Further studies reporting results separately for BRCA1 and BRCA2 mutation carriers are needed to resolve this important issue.
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- 2006
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38. No increased risk of breast cancer associated with alcohol consumption among carriers of BRCA1 and BRCA2 mutations ages <50 years.
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McGuire V, John EM, Felberg A, Haile RW, Boyd NF, Thomas DC, Jenkins MA, Milne RL, Daly MB, Ward J, Terry MB, Andrulis IL, Knight JA, Godwin AK, Giles GG, Southey M, West DW, Hopper JL, and Whittemore AS
- Subjects
- Breast Neoplasms chemically induced, Breast Neoplasms epidemiology, Female, Humans, Risk Factors, Alcohol Drinking adverse effects, Breast Neoplasms genetics, Genes, BRCA1, Genes, BRCA2, Germ-Line Mutation
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- 2006
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39. Breast and ovarian cancer in relatives of cancer patients, with and without BRCA mutations.
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Lee JS, John EM, McGuire V, Felberg A, Ostrow KL, DiCioccio RA, Li FP, Miron A, West DW, and Whittemore AS
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- Adult, Age of Onset, Aged, Breast Neoplasms epidemiology, Exons, Female, Genetic Predisposition to Disease, Germ-Line Mutation, Humans, Incidence, Middle Aged, Ovarian Neoplasms epidemiology, Risk, Breast Neoplasms genetics, Genes, BRCA1, Genes, BRCA2, Ovarian Neoplasms genetics
- Abstract
Background: First-degree relatives of patients with breast or ovarian cancer have increased risks for these cancers. Little is known about how their risks vary with the patient's cancer site, carrier status for predisposing genetic mutations, or age at cancer diagnosis., Methods: We evaluated breast and ovarian cancer incidence in 2,935 female first-degree relatives of non-Hispanic White female patients with incident invasive cancers of the breast (n = 669) or ovary (n = 339) who were recruited from a population-based cancer registry in northern California. Breast cancer patients were tested for BRCA1 and BRCA2 mutations. Ovarian cancer patients were tested for BRCA1 mutations. We estimated standardized incidence ratios (SIR) and 95% confidence intervals (95% CI) for breast and ovarian cancer among the relatives according to the patient's mutation status, cancer site, and age at cancer diagnosis., Results: In families of patients who were negative or untested for BRCA1 or BRCA2 mutations, risks were elevated only for the patient's cancer site. The breast cancer SIR was 1.5 (95% CI, 1.2-1.8) for relatives of breast cancer patients, compared with 1.1 (95% CI, 0.8-1.6) for relatives of ovarian cancer patients (P = 0.12 for difference by patient's cancer site). The ovarian cancer SIR was 0.9 (95% CI, 0.5-1.4) for relatives of breast cancer patients, compared with 1.9 (95% CI, 1.0-4.0) for relatives of ovarian cancer patients (P = 0.04 for difference by site). In families of BRCA1-positive patients, relatives' risks also correlated with the patient's cancer site. The breast cancer SIR was 10.6 (95% CI, 5.2-21.6) for relatives of breast cancer patients, compared with 3.3 (95% CI, 1.4-7.3) for relatives of ovarian cancer patients (two-sided P = 0.02 for difference by site). The ovarian cancer SIR was 7.9 (95% CI, 1.2-53.0) for relatives of breast cancer patients, compared with 11.3 (3.6-35.9) for relatives of ovarian cancer patients (two-sided P = 0.37 for difference by site). Relatives' risks were independent of patients' ages at diagnosis, with one exception: In families ascertained through a breast cancer patient without BRCA mutations, breast cancer risks were higher if the patient had been diagnosed before age 40 years., Conclusion: In families of patients with and without BRCA1 mutations, breast and ovarian cancer risks correlate with the patient's cancer site. Moreover, in families of breast cancer patients without BRCA mutations, breast cancer risk depends on the patient's age at diagnosis. These patterns support the presence of genes that modify risk specific to cancer site, in both carriers and noncarriers of BRCA1 and BRCA2 mutations.
- Published
- 2006
- Full Text
- View/download PDF
40. The CHEK2*1100delC allelic variant and risk of breast cancer: screening results from the Breast Cancer Family Registry.
- Author
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Bernstein JL, Teraoka SN, John EM, Andrulis IL, Knight JA, Lapinski R, Olson ER, Wolitzer AL, Seminara D, Whittemore AS, and Concannon P
- Subjects
- Adult, Aged, Alleles, Apoptosis genetics, California, Case-Control Studies, Checkpoint Kinase 2, Female, Genotype, Humans, Middle Aged, Ontario, Registries, Risk Factors, Breast Neoplasms genetics, Mutation, Protein Serine-Threonine Kinases genetics, Radiography, Thoracic adverse effects
- Abstract
CHEK2, a serine-threonine kinase, is activated in response to agents, such as ionizing radiation, which induce DNA double-strand breaks. Activation of CHEK2 can result in cell cycle checkpoint arrest or apoptosis. One specific variant, CHEK2*1100delC, has been associated with an increased risk of breast cancer. In this population-based study, we screened 2,311 female breast cancer cases and 496 general population controls enrolled in the Ontario and Northern California Breast Cancer Family Registries for this variant (all controls were Canadian). Overall, 30 cases and one control carried the 1100delC allele. In Ontario, the weighted mutation carrier frequency among cases and controls was 1.34% and 0.20%, respectively [odds ratio (OR), 6.65; 95% confidence interval (95% CI), 2.37-18.68]. In California, the weighted population mutation carrier frequency in cases was 0.40%. Across all cases, 1 of 524 non-Caucasians (0.19%) and 29 of 1,775 Caucasians (1.63%) were mutation carriers (OR, 0.12; 95% CI, 0.02-0.89). Among Caucasian cases >45 years age at diagnosis, carrier status was associated with history of benign breast disease (OR, 3.18; 95% CI, 1.30-7.80) and exposure to diagnostic ionizing radiation (excluding mammography; OR, 3.21; 95% CI, 1.13-9.14); compared with women without exposure to ionizing radiation, the association was strongest among women exposed >15 years before diagnosis (OR, 4.28; 95% CI, 1.50-12.20) and among those who received two or more chest X-rays (OR, 3.63; 95% CI, 1.25-10.52). These data supporting the biological relevance of CHEK2 in breast carcinogenesis suggest that further studies examining the joint roles of CHEK2*1100delC carrier status and radiation exposure may be warranted.
- Published
- 2006
- Full Text
- View/download PDF
41. Genetic association studies: time for a new paradigm?
- Author
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Whittemore AS
- Subjects
- Bayes Theorem, Humans, Models, Statistical, Risk Assessment, Editorial Policies, Genetic Predisposition to Disease, Neoplasms etiology
- Published
- 2005
- Full Text
- View/download PDF
42. Oral contraceptive use and risk of early-onset breast cancer in carriers and noncarriers of BRCA1 and BRCA2 mutations.
- Author
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Milne RL, Knight JA, John EM, Dite GS, Balbuena R, Ziogas A, Andrulis IL, West DW, Li FP, Southey MC, Giles GG, McCredie MR, Hopper JL, and Whittemore AS
- Subjects
- Adult, Case-Control Studies, Female, Germ-Line Mutation, Heterozygote, Humans, Risk Factors, White People, Breast Neoplasms epidemiology, Breast Neoplasms genetics, Contraceptives, Oral adverse effects, Genes, BRCA1, Genes, BRCA2
- Abstract
Background: Recent oral contraceptive use has been associated with a small increase in breast cancer risk and a substantial decrease in ovarian cancer risk. The effects on risks for women with germ line mutations in BRCA1 or BRCA2 are unclear., Methods: Subjects were population-based samples of Caucasian women that comprised 1,156 incident cases of invasive breast cancer diagnosed before age 40 (including 47 BRCA1 and 36 BRCA2 mutation carriers) and 815 controls from the San Francisco Bay area, California, Ontario, Canada, and Melbourne and Sydney, Australia. Relative risks by carrier status were estimated using unconditional logistic regression, comparing oral contraceptive use in case groups defined by mutation status with that in controls., Results: After adjustment for potential confounders, oral contraceptive use for at least 12 months was associated with decreased breast cancer risk for BRCA1 mutation carriers [odds ratio (OR), 0.22; 95% confidence interval (CI), 0.10-0.49; P < 0.001], but not for BRCA2 mutation carriers (OR, 1.02; 95% CI, 0.34-3.09) or noncarriers (OR, 0.93; 95% CI, 0.69-1.24). First use during or before 1975 was associated with increased risk for noncarriers (OR, 1.52 per year of use before 1976; 95% CI, 1.22-1.91; P < 0.001)., Conclusions: There was no evidence that use of current low-dose oral contraceptive formulations increases risk of early-onset breast cancer for mutation carriers, and there may be a reduced risk for BRCA1 mutation carriers. Because current formulations of oral contraceptives may reduce, or at least not exacerbate, ovarian cancer risk for mutation carriers, they should not be contraindicated for a woman with a germ line mutation in BRCA1 or BRCA2.
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- 2005
- Full Text
- View/download PDF
43. Prevalence of BRCA1 mutation carriers among U.S. non-Hispanic Whites.
- Author
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Whittemore AS, Gong G, John EM, McGuire V, Li FP, Ostrow KL, Dicioccio R, Felberg A, and West DW
- Subjects
- Adult, Aged, Breast Neoplasms genetics, California epidemiology, DNA Mutational Analysis, Female, Genetic Counseling, Humans, Jews, Middle Aged, Ovarian Neoplasms genetics, Prevalence, Resource Allocation, Genes, BRCA1, Germ-Line Mutation, SEER Program, White People
- Abstract
Data from several countries indicate that 1% to 2% of Ashkenazi Jews carry a pathogenic ancestral mutation of the tumor suppressor gene BRCA1. However, the prevalence of BRCA1 mutations among non-Ashkenazi Whites is uncertain. We estimated mutation carrier prevalence in U.S. non-Hispanic Whites, specific for Ashkenazi status, using data from two population-based series of San Francisco Bay Area patients with invasive cancers of the breast or ovary, and data on breast and ovarian cancer risks in Ashkenazi and non-Ashkenazi carriers. Assuming that 90% of the BRCA1 mutations were detected, we estimate a carrier prevalence of 0.24% (95% confidence interval, 0.15-0.39%) in non-Ashkenazi Whites, and 1.2% (95% confidence interval, 0.5-2.6%) in Ashkenazim. When combined with U.S. White census counts, these prevalence estimates suggest that approximately 550,513 U.S. Whites (506,206 non-Ashkenazim and 44,307 Ashkenazim) carry germ line BRCA1 mutations. These estimates may be useful in guiding resource allocation for genetic testing and genetic counseling and in planning preventive interventions.
- Published
- 2004
44. STK15 polymorphisms and association with risk of invasive ovarian cancer.
- Author
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Dicioccio RA, Song H, Waterfall C, Kimura MT, Nagase H, McGuire V, Hogdall E, Shah MN, Luben RN, Easton DF, Jacobs IJ, Ponder BA, Whittemore AS, Gayther SA, Pharoah PD, and Kruger-Kjaer S
- Subjects
- Adult, Aged, Aurora Kinase A, Aurora Kinases, Case-Control Studies, Denmark epidemiology, Female, Genotype, Haplotypes, Humans, Middle Aged, Ovarian Neoplasms epidemiology, Risk Factors, United Kingdom epidemiology, United States epidemiology, Genetic Predisposition to Disease, Ovarian Neoplasms etiology, Ovarian Neoplasms genetics, Polymorphism, Genetic, Protein Serine-Threonine Kinases genetics
- Abstract
STK15 is a putative oncogene that codes for a centrosome-associated, serine/threonine kinase, the normal function of which is to ensure accurate segregation of chromosomes during mitosis. Amplification of STK15 has been reported in ovarian tumors, suggesting a role in ovarian cancer pathology. STK15 is polymorphic with two single nucleotide substitutions (449t/a and 527g/a) in evolutionarily conserved regions causing amino acid changes (F31I and V57I). Two other nucleotide substitutions (287c/g and 1891g/c) of unknown significance are in 5' and 3' untranslated regions (UTR), respectively. To learn more about the involvement of STK15 in ovarian cancer, we genotyped and haplotyped these polymorphisms in three population-based ovarian cancer case-control studies from the United Kingdom, United States, and Denmark with 1,821 combined cases and 2,467 combined controls and calculated risks for developing ovarian cancer. Genotypes of individual polymorphisms in control groups of the United Kingdom, United States, and Denmark conformed to Hardy-Weinberg equilibrium. In combined cases and combined controls, rare allele frequencies were 0.23 and 0.21 for I31, 0.16 and 0.17 for I57, 0.08 and 0.07 for 5' UTR g, and 0.25 and 0.24 for 3' UTR c, respectively. Using FF common homozygotes of F31I as comparator, there was increased ovarian cancer risk to FI heterozygotes (odds ratio, 1.18; 95% confidence interval, 1.01-1.36), II homozygotes (odds ratio, 1.25; 95% confidence interval, 0.89-1.75), and I31 allele carriers (odds ratio, 1.17; 95% confidence interval, 1.02-1.35) in the combined group data. For either V57I, 5' UTR C/G, or 3' UTR G/C, all genotypic ovarian cancer risks were essentially in unity relative to their respective common homozygotes, VV, cc, or gg. Haplotype analysis of combined group data revealed seven haplotypes with frequencies between 0.02 and 0.5, with c-F-V-g the most common. None of the haplotype-specific risks significantly differed from unity relative to c-F-V-g. These results suggest a model of dominant inheritance of ovarian cancer risk by the I31 allele of F31I and that the I31 allele may be a common ovarian cancer susceptibility allele of low penetrance.
- Published
- 2004
45. Risk of early-onset prostate cancer in relation to germ line polymorphisms of the vitamin D receptor.
- Author
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Oakley-Girvan I, Feldman D, Eccleshall TR, Gallagher RP, Wu AH, Kolonel LN, Halpern J, Balise RR, West DW, Paffenbarger RS Jr, and Whittemore AS
- Subjects
- Adult, Black or African American genetics, Age Distribution, Age of Onset, Aged, Case-Control Studies, Confidence Intervals, Genetic Predisposition to Disease, Humans, Incidence, Male, Middle Aged, Odds Ratio, Prognosis, Reference Values, White People genetics, Germinoma ethnology, Germinoma genetics, Polymorphism, Genetic, Prostatic Neoplasms ethnology, Prostatic Neoplasms genetics, Receptors, Calcitriol genetics
- Abstract
Vitamin D inhibits prostate cancer cell growth, angiogenesis, and metastasis. These actions are mediated by the vitamin D receptor. We examined associations between prostate cancer risk and five polymorphisms in the VDR gene: four single nucleotide polymorphisms (FokI, BsmI, ApaI, and TaqI restriction sites) and the polyadenylic acid microsatellite. Specifically, we genotyped population-based samples of young African Americans (113 cases and 121 controls) and Whites (232 cases and 171 controls) and members of 98 predominantly White families with multiple cases of prostate cancer. Among Whites, there was no evidence for association between prostate cancer risk and alleles at any of the five polymorphic sites regardless of how the men were ascertained. Moreover, estimated five-locus haplotype frequencies were similar in White cases and controls. Among African Americans, prostate cancer risk was associated with homozygosity for the F allele at the FokI site (odds ratio 1.9, 95% confidence interval 1.0-3.3). In addition, estimated haplotype frequencies differed significantly (P < 0.01) between African American cases and controls. These findings need replication in other studies of African Americans. Homozygosity for the F allele at the FokI site is more prevalent in the African American population than in U.S. Whites. If the FokI association noted here were causal, this difference could account for some of the disease burden among African Americans and some of the excess risk in African Americans compared with Whites.
- Published
- 2004
46. BRCA1/2 mutation status influences somatic genetic progression in inherited and sporadic epithelial ovarian cancer cases.
- Author
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Ramus SJ, Pharoah PD, Harrington P, Pye C, Werness B, Bobrow L, Ayhan A, Wells D, Fishman A, Gore M, DiCioccio RA, Piver MS, Whittemore AS, Ponder BA, and Gayther SA
- Subjects
- Chromosome Aberrations, Female, Heterozygote, Humans, Nucleic Acid Hybridization, Genes, BRCA1, Genes, BRCA2, Germ-Line Mutation, Ovarian Neoplasms genetics
- Abstract
Metaphase comparative genomic hybridization was used to analyze the spectrum of genetic alterations in 141 epithelial ovarian cancers from BRCA1 and BRCA2 mutation carriers, individuals with familial non-BRCA1/2 epithelial ovarian cancer, and women with nonfamilial epithelial ovarian cancer. Multiple genetic alterations were identified in almost all tumors. The high frequency with which some alterations were identified suggests the location of genes that are commonly altered during ovarian tumor development. In multiple chromosome regions, there were significant differences in alteration frequency between the four tumor types suggesting that BRCA1/2 mutation status and a family history of ovarian cancer influences the somatic genetic pathway of ovarian cancer progression. These findings were supported by hierarchical cluster analysis, which identified genetic events that tend to occur together during tumorigenesis and several alterations that were specific to tumors of a particular type. In addition, some genetic alterations were strongly associated with differences in tumor differentiation and disease stage. Taken together, these data provide molecular genetic evidence to support previous findings from histopathological studies, which suggest that clinical features of ovarian and breast tumors differ with respect to BRCA1/2 mutation status and/or cancer family history.
- Published
- 2003
47. Comparison of techniques for the successful detection of BRCA1 mutations in fixed paraffin-embedded tissue.
- Author
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Bernstein JL, Thompson WD, Casey G, DiCioccio RA, Whittemore AS, Diep AT, Thakore SS, Vaziri S, Xue S, and Haile RW
- Subjects
- DNA Mutational Analysis, DNA, Neoplasm analysis, Female, Genetic Markers, Humans, Paraffin Embedding, DNA, Neoplasm genetics, Genes, BRCA1, Sequence Analysis, DNA methods
- Abstract
Genomic DNA isolated from archived paraffin-embedded tissues (PETs) has important applicability in genetic epidemiological studies. To determine the accuracy of the sequence data, using DNA derived from PET among patients with known mutations characterized from blood, we conducted a blinded factorial experiment to simultaneously examine the influence of mutation type, age of the PET, PCR product type, and Taq DNA polymerase on BRCA1 gene mutation detection. The probability of detecting sequencing artifacts was also investigated. We found that: (a) gene detection was most accurate for newer PET; (b) high fidelity Taq with shorter PCR amplicon length yielded the highest mutation detection success rate and lowest artifact rate; and (c) base substitutions were more often correctly identified than frameshift mutations or wild-type sequences. We concluded that DNA derived from PET that archived for less than 18 years can be used successfully for detecting BRCA1 gene mutations if quality control is strictly maintained.
- Published
- 2002
48. Carbohydrates and colorectal cancer risk among Chinese in North America.
- Author
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Borugian MJ, Sheps SB, Whittemore AS, Wu AH, Potter JD, and Gallagher RP
- Subjects
- China ethnology, Colorectal Neoplasms epidemiology, Female, Humans, Logistic Models, Male, North America epidemiology, Risk Factors, Asian statistics & numerical data, Colorectal Neoplasms ethnology, Dietary Carbohydrates
- Abstract
Previous studies have analyzed total carbohydrate as a dietary risk factor for colorectal cancer (CRC) but obtained conflicting results, perhaps attributable in part to the embedded potential confounder, fiber. The aim of this study was to analyze the nonfiber ("effective") carbohydrate component (eCarb) separately and to test the hypothesis that effective carbohydrate consumption is directly related to CRC risk. The data (473 cases and 1192 controls) were from a large, multicenter, case-control study of Chinese residing in North America. Multivariate logistic regression was used to perform a secondary analysis controlling for age; sex; consumption of fat, fiber, calcium, and total kilocalories; body mass (Quetelet's) index; family history; education; and years in North America. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to estimate risk among subgroups by sex and cancer site. A statistically significant positive association was observed between eCarb consumption and risk of CRC in both men (OR, 1.7 comparing highest with lowest tertile of eCarb consumption; 95% CI, 1.1-2.7) and women (OR, 2.7; 95% CI, 1.5-4.8). As expected, the ORs for total carbohydrate were somewhat lower than those for effective carbohydrate, but the differences were not large. A sex difference in risk by colorectal subsite was observed, with risk concentrated in the right colon for women (OR, 6.5; 95% CI, 2.4-18.4) and in the rectum for men (OR, 2.4; 95% CI, 1.2-4.8). These data indicate that increased eCarb and total carbohydrate consumption are both associated with increased risk of CRC in both sexes, and that among women, relative risk appears greatest for the right colon, whereas among men, relative risk appears greatest for the rectum.
- Published
- 2002
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