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1. Feasibility of collecting tumor samples of breast cancer patients diagnosed up to 50 years ago in the Child Health and Development Studies

Author: Krigbaum, NY, Rubin, RA, Cirillo, PM, Terry, MB, Habel, LA, Morris, C, and Cohn, BA
Subjects: Health Services and Systems, Biomedical and Clinical Sciences, Health Sciences, Oncology and Carcinogenesis, Cancer, Clinical Research, Prevention, Rare Diseases, Breast Cancer, Good Health and Well Being, Breast Neoplasms, Child, Child Development, Child Health, Cohort Studies, Feasibility Studies, Female, Follow-Up Studies, Humans, Middle Aged, Pilot Projects, Prospective Studies, Registries, Specimen Handling, Time Factors, breast cancer prevention, Child Health and Development Studies, pathology reports, PEDIGREE study, tumor sample collection, Medical and Health Sciences, Biomedical and clinical sciences, Health sciences
Abstract: Environmental exposures during pregnancy may increase breast cancer risk for mothers and female offspring. Tumor tissue assays may provide insight regarding the mechanisms. This study assessed the feasibility of obtaining tumor samples and pathology reports from mothers (F0) who were enrolled in the Child Health and Development Studies during pregnancy from 1959 to 1967 and their daughters (F1) who developed breast cancer over more than 50 years of follow-up. Breast cancer cases were identified through linkage to the California Cancer Registry and self-report. Written consent was obtained from 116 F0 and 95 F1 breast cancer survivors to access their pathology reports and tumor blocks. Of those contacted, 62% consented, 13% refused and 24% did not respond. We obtained tissue samples for 57% and pathology reports for 75%, and if diagnosis was made ⩽10 years we obtained tissue samples and pathology reports for 91% and 79%, respectively. Obtaining pathology reports and tumor tissues of two generations is feasible and will support investigation of the relationship between early-life exposures and molecular tumor markers. However, we found that more recent diagnosis increased the accessibility of tumor tissue. We recommend that cohorts request consent for obtaining future tumor tissues at study enrollment and implement real-time tissue collection to enhance success of collecting tumor samples and data.
Published: 2017

2. Breast and bowel cancers diagnosed in people 'too young to have cancer': A blueprint for research using family and twin studies

Author: Hopper, JL, Li, S, MacInnis, RJ, Dowty, JG, Nguyen, TL, Bui, M, Dite, GS, Esser, VFC, Ye, Z, Makalic, E, Schmidt, DF, Goudey, B, Alpen, K, Kapuscinski, M, Win, AK, Dugue, P-A, Milne, RL, Jayasekara, H, Brooks, JD, Malta, S, Calais-Ferreira, L, Campbell, AC, Young, JT, Nguyen-Dumont, T, Sung, J, Giles, GG, Buchanan, D, Winship, I, Terry, MB, Southey, MC, Jenkins, MA, Hopper, JL, Li, S, MacInnis, RJ, Dowty, JG, Nguyen, TL, Bui, M, Dite, GS, Esser, VFC, Ye, Z, Makalic, E, Schmidt, DF, Goudey, B, Alpen, K, Kapuscinski, M, Win, AK, Dugue, P-A, Milne, RL, Jayasekara, H, Brooks, JD, Malta, S, Calais-Ferreira, L, Campbell, AC, Young, JT, Nguyen-Dumont, T, Sung, J, Giles, GG, Buchanan, D, Winship, I, Terry, MB, Southey, MC, and Jenkins, MA
Abstract: Young breast and bowel cancers (e.g., those diagnosed before age 40 or 50 years) have far greater morbidity and mortality in terms of years of life lost, and are increasing in incidence, but have been less studied. For breast and bowel cancers, the familial relative risks, and therefore the familial variances in age-specific log(incidence), are much greater at younger ages, but little of these familial variances has been explained. Studies of families and twins can address questions not easily answered by studies of unrelated individuals alone. We describe existing and emerging family and twin data that can provide special opportunities for discovery. We present designs and statistical analyses, including novel ideas such as the VALID (Variance in Age-specific Log Incidence Decomposition) model for causes of variation in risk, the DEPTH (DEPendency of association on the number of Top Hits) and other approaches to analyse genome-wide association study data, and the within-pair, ICE FALCON (Inference about Causation from Examining FAmiliaL CONfounding) and ICE CRISTAL (Inference about Causation from Examining Changes in Regression coefficients and Innovative STatistical AnaLysis) approaches to causation and familial confounding. Example applications to breast and colorectal cancer are presented. Motivated by the availability of the resources of the Breast and Colon Cancer Family Registries, we also present some ideas for future studies that could be applied to, and compared with, cancers diagnosed at older ages and address the challenges posed by young breast and bowel cancers.
Published: 2024

3. Maternal weight gain in excess of pregnancy guidelines is related to daughters being overweight 40 years later

Author: Houghton, LC, Ester, WA, Lumey, LH, Michels, KB, Wei, Y, Cohn, BA, Susser, ES, and Terry, MB
Subjects: Reproductive Medicine, Biomedical and Clinical Sciences, Pediatric, Nutrition, Obesity, Prevention, Clinical Research, 2.3 Psychological, social and economic factors, Aetiology, Cancer, Reproductive health and childbirth, Metabolic and endocrine, Good Health and Well Being, Adult, Body Mass Index, Female, Humans, Maternal Nutritional Physiological Phenomena, Mothers, Nuclear Family, Overweight, Pregnancy, Prenatal Exposure Delayed Effects, Risk Factors, Weight Gain, gestational weight gain, life course, obesity, Paediatrics and Reproductive Medicine, Obstetrics & Reproductive Medicine, Reproductive medicine
Abstract: BackgroundExceeding the Institute of Medicine guidelines for pregnancy weight gain increases childhood and adolescent obesity. However, it is unknown if these effects extend to midlife.ObjectiveWe sought to determine if exceeding the Institute of Medicine guidelines for pregnancy weight gain increases risk of overweight/obesity in daughters 40 years later.Study designThis cohort study is based on adult offspring in the Child Health and Development Studies and the Collaborative Perinatal Project pregnancy cohorts originally enrolled in the 1960s. In 2005 through 2008, 1035 daughters in their 40s were recruited to the Early Determinants of Mammographic Density study. We classified maternal pregnancy weight gain as greater than vs less than or equal to the 2009 clinical guidelines. We used logistic regression to compare the odds ratios of daughters being overweight/obese (body mass index [BMI] ≥25) at a mean age of 44 years between mothers who did not gain or gained more than pregnancy weight gain guidelines, accounting for maternal prepregnant BMI, and daughter body size at birth and childhood. We also examined potential family related confounding through a comparison of sisters using generalized estimating equations, clustered on sibling units and adjusted for maternal age and race.ResultsMothers who exceeded guidelines for weight gain in pregnancy were more likely to have daughters who were overweight/obese in their 40s (odds ratio [OR], 3.4; 95% confidence interval {CI}, 2.0-5.7). This magnitude of association translates to a relative risk (RR) increase of 50% (RR = 1.5; 95% CI, 1.3-1.6). The association was of the same magnitude when examining only the siblings whose mother exceeded guidelines in 1 pregnancy and did not exceed the guidelines in the other pregnancy. The association was stronger with increasing maternal prepregnancy BMI (P trend 30). This pattern held irrespective of daughters' weight status at birth, at age 4 years, or at age 20 years.ConclusionOur findings support that obesity prevention before pregnancy and strategies to maintain weight gain during pregnancy within the IOM guidelines might reduce the risk of being overweight in midlife for the offspring.
Published: 2016

4. An original phylogenetic approach identified mitochondrial haplogroup T1a1 as inversely associated with breast cancer risk in BRCA2 mutation carriers

Author: Blein, S, Bardel, C, Danjean, V, McGuffog, L, Healey, S, Barrowdale, D, Lee, A, Dennis, J, Kuchenbaecker, KB, Soucy, P, Terry, MB, Chung, WK, Goldgar, DE, Buys, SS, Janavicius, R, Tihomirova, L, Tung, N, Dorfling, CM, van Rensburg, EJ, Neuhausen, SL, Ding, YC, Gerdes, AM, Ejlertsen, B, Nielsen, FC, Hansen, TVO, Osorio, A, Benitez, J, Conejero, RA, Segota, E, Weitzel, JN, Thelander, M, Peterlongo, P, Radice, P, Pensotti, V, Dolcetti, R, Bonanni, B, Peissel, B, Zaffaroni, D, Scuvera, G, Manoukian, S, Varesco, L, Capone, GL, Papi, L, Ottini, L, Yannoukakos, D, Konstantopoulou, I, Garber, J, Hamann, U, Donaldson, A, Brady, A, Brewer, C, Foo, C, Evans, DG, Frost, D, Eccles, D, Douglas, F, Cook, J, Adlard, J, Barwell, J, Walker, L, Izatt, L, Side, LE, Kennedy, MJ, Tischkowitz, M, Rogers, MT, Porteous, ME, Morrison, PJ, Platte, R, Eeles, R, Davidson, R, Hodgson, S, Cole, T, Godwin, AK, Isaacs, C, Claes, K, De Leeneer, K, Meindl, A, Gehrig, A, Wappenschmidt, B, Sutter, C, Engel, C, Niederacher, D, Steinemann, D, Plendl, H, Kast, K, Rhiem, K, Ditsch, N, Arnold, N, Varon-Mateeva, R, Schmutzler, RK, Preisler-Adams, S, Markov, NB, Wang-Gohrke, S, de Pauw, A, Lefol, C, Lasset, C, Leroux, D, Rouleau, E, Damiola, F, and Dreyfus, H
Subjects: Oncology & Carcinogenesis, Oncology and Carcinogenesis
Abstract: Introduction: Individuals carrying pathogenic mutations in the BRCA1 and BRCA2 genes have a high lifetime risk of breast cancer. BRCA1 and BRCA2 are involved in DNA double-strand break repair, DNA alterations that can be caused by exposure to reactive oxygen species, a main source of which are mitochondria. Mitochondrial genome variations affect electron transport chain efficiency and reactive oxygen species production. Individuals with different mitochondrial haplogroups differ in their metabolism and sensitivity to oxidative stress. Variability in mitochondrial genetic background can alter reactive oxygen species production, leading to cancer risk. In the present study, we tested the hypothesis that mitochondrial haplogroups modify breast cancer risk in BRCA1/2 mutation carriers. Methods: We genotyped 22,214 (11,421 affected, 10,793 unaffected) mutation carriers belonging to the Consortium of Investigators of Modifiers of BRCA1/2 for 129 mitochondrial polymorphisms using the iCOGS array. Haplogroup inference and association detection were performed using a phylogenetic approach. ALTree was applied to explore the reference mitochondrial evolutionary tree and detect subclades enriched in affected or unaffected individuals. Results: We discovered that subclade T1a1 was depleted in affected BRCA2 mutation carriers compared with the rest of clade T (hazard ratio (HR) = 0.55; 95% confidence interval (CI), 0.34 to 0.88; P = 0.01). Compared with the most frequent haplogroup in the general population (that is, H and T clades), the T1a1 haplogroup has a HR of 0.62 (95% CI, 0.40 to 0.95; P = 0.03). We also identified three potential susceptibility loci, including G13708A/rs28359178, which has demonstrated an inverse association with familial breast cancer risk. Conclusions: This study illustrates how original approaches such as the phylogeny-based method we used can empower classical molecular epidemiological studies aimed at identifying association or risk modification effects.
Published: 2015

5. Common variants at 12p11, 12q24, 9p21, 9q31.2 and in ZNF365 are associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers

Author: Antoniou, AC, Kuchenbaecker, KB, Soucy, P, Beesley, J, Chen, X, McGuffog, L, Lee, A, Barrowdale, D, Healey, S, Sinilnikova, OM, Caligo, MA, Loman, N, Harbst, K, Lindblom, A, Arver, B, Rosenquist, R, Karlsson, P, Nathanson, K, Domchek, S, Rebbeck, T, Jakubowska, A, Lubinski, J, Jaworska, K, Durda, K, Zlowowcka-Perlowska, E, Osorio, A, Duran, M, Andres, R, Benitez, J, Hamann, U, Hogervorst, FB, van Os, TA, Verhoef, S, Meijers-Heijboer, HEJ, Wijnen, J, Garcia, EBG, Ligtenberg, MJ, Kriege, M, Collee, M, Ausems, MGEM, Oosterwijk, JC, Peock, S, Frost, D, Ellis, SD, Platte, R, Fineberg, E, Evans, DG, Lalloo, F, Jacobs, C, Eeles, R, Adlard, J, Davidson, R, Cole, T, Cook, J, Paterson, J, Douglas, F, Brewer, C, Hodgson, S, Morrison, PJ, Walker, L, Rogers, MT, Donaldson, A, Dorkins, H, Godwin, AK, Bove, B, Stoppa-Lyonnet, D, Houdayer, C, Buecher, B, de Pauw, A, Mazoyer, S, Calender, A, Leone, M, Bressac-de Paillerets, B, Caron, O, Sobol, H, Frenay, M, Prieur, F, Ferrer, SF, Mortemousque, I, Buys, S, Daly, M, Miron, A, Terry, MB, Hopper, JL, John, EM, Southey, M, Goldgar, D, Singer, CF, Fink-Retter, A, Tea, M-K, Kaulich, DG, Hansen, TVO, Nielsen, FC, Barkardottir, RB, Gaudet, M, Kirchhoff, T, Joseph, V, Dutra-Clarke, A, Offit, K, and Piedmonte, M
Published: 2012

6. Germline mutations in CDH1 are infrequent in women with early-onset or familial lobular breast cancers

Author: Schrader, KA, Masciari, S, Boyd, N, Salamanca, C, Senz, J, Saunders, DN, Yorida, E, Maines-Bandiera, S, Kaurah, P, Tung, N, Robson, ME, Ryan, PD, Olopade, OI, Domchek, SM, Ford, J, Isaacs, C, Brown, P, Balmana, J, Razzak, AR, Miron, P, Coffey, K, Terry, MB, John, EM, Andrulis, IL, Knight, JA, O'Malley, FP, Daly, M, Bender, P, kConFab, Moore, R, Southey, MC, Hopper, JL, Garber, JE, and Huntsman, DG
Subjects: Biological Sciences, Biomedical and Clinical Sciences, Genetics, Oncology and Carcinogenesis, Clinical Research, Genetic Testing, Cancer, Breast Cancer, Human Genome, 2.1 Biological and endogenous factors, Aetiology, Adult, Age of Onset, Antigens, CD, Breast Neoplasms, Cadherins, Carcinoma, Lobular, DNA Mutational Analysis, Family, Female, Germ-Line Mutation, Humans, Middle Aged, kConFab, Medical and Health Sciences, Genetics & Heredity, Clinical sciences
Abstract: BackgroundGermline mutations in CDH1 are associated with hereditary diffuse gastric cancer; lobular breast cancer also occurs excessively in families with such condition.MethodTo determine if CDH1 is a susceptibility gene for lobular breast cancer in women without a family history of diffuse gastric cancer, germline DNA was analysed for the presence of CDH1 mutations in 318 women with lobular breast cancer who were diagnosed before the age of 45 years or had a family history of breast cancer and were not known, or known not, to be carriers of germline mutations in BRCA1 or BRCA2. Cases were ascertained through breast cancer registries and high-risk cancer genetic clinics (Breast Cancer Family Registry, the kConFab and a consortium of breast cancer genetics clinics in the United States and Spain). Additionally, Multiplex Ligation-dependent Probe Amplification was performed for 134 cases to detect large deletions.ResultsNo truncating mutations and no large deletions were detected. Six non-synonymous variants were found in seven families. Four (4/318 or 1.3%) are considered to be potentially pathogenic through in vitro and in silico analysis.ConclusionPotentially pathogenic germline CDH1 mutations in women with early-onset or familial lobular breast cancer are at most infrequent.
Published: 2011

7. A Likelihood Ratio Approach for Utilizing Case-Control Data in the Clinical Classification of Rare Sequence Variants: Application to BRCA1 and BRCA2

Author: Cutting, G, Zanti, M, O'Mahony, DG, Parsons, MT, Li, H, Dennis, J, Aittomakkiki, K, Andrulis, IL, Anton-Culver, H, Aronson, KJ, Augustinsson, A, Becher, H, Bojesen, SE, Bolla, MK, Brenner, H, Brown, MA, Buys, SS, Canzian, F, Caputo, SM, Castelao, JE, Chang-Claude, J, Czene, K, Daly, MB, De Nicolo, A, Devilee, P, Dork, T, Dunning, AM, Dwek, M, Eccles, DM, Engel, C, Evans, DG, Fasching, PA, Gago-Dominguez, M, Garcia-Closas, M, Garcia-Saenz, JA, Gentry-Maharaj, A, Geurts-Giele, WRR, Giles, GG, Glendon, G, Goldberg, MS, Garcia, EBG, Guendert, M, Guenel, P, Hahnen, E, Haiman, CA, Hall, P, Hamann, U, Harkness, EF, Hogervorst, FBL, Hollestelle, A, Hoppe, R, Hopper, JL, Houdayer, C, Houlston, RS, Howell, A, Investigators, A, Jakimovska, M, Jakubowska, A, Jernstrom, H, John, EM, Kaaks, R, Kitahara, CM, Koutros, S, Kraft, P, Kristensen, VN, Lacey, J, Lambrechts, D, Leone, M, Lindblom, A, Lush, M, Mannermaa, A, Manoochehri, M, Manoukian, S, Margolin, S, Martinez, ME, Menon, U, Milne, RL, Monteiro, AN, Murphy, RA, Neuhausen, SL, Nevanlinna, H, Newman, WG, Offit, K, Park, SK, James, P, Peterlongo, P, Peto, J, Plaseska-Karanfilska, D, Punie, K, Radice, P, Rashid, MU, Rennert, G, Romero, A, Rosenberg, EH, Saloustros, E, Sandler, DP, Schmidt, MK, Schmutzler, RK, Shu, X-O, Simard, J, Southey, MC, Stone, J, Stoppa-Lyonnet, D, Tamimi, RM, Tapper, WJ, Taylor, JA, Teo, SH, Teras, LR, Terry, MB, Thomassen, M, Troester, MA, Vachon, CM, Vega, A, Vreeswijk, MPG, Wang, Q, Wappenschmidt, B, Weinberg, CR, Wolk, A, Zheng, W, Feng, B, Couch, FJ, Spurdle, AB, Easton, DF, Goldgar, DE, Michailidou, K, Cutting, G, Zanti, M, O'Mahony, DG, Parsons, MT, Li, H, Dennis, J, Aittomakkiki, K, Andrulis, IL, Anton-Culver, H, Aronson, KJ, Augustinsson, A, Becher, H, Bojesen, SE, Bolla, MK, Brenner, H, Brown, MA, Buys, SS, Canzian, F, Caputo, SM, Castelao, JE, Chang-Claude, J, Czene, K, Daly, MB, De Nicolo, A, Devilee, P, Dork, T, Dunning, AM, Dwek, M, Eccles, DM, Engel, C, Evans, DG, Fasching, PA, Gago-Dominguez, M, Garcia-Closas, M, Garcia-Saenz, JA, Gentry-Maharaj, A, Geurts-Giele, WRR, Giles, GG, Glendon, G, Goldberg, MS, Garcia, EBG, Guendert, M, Guenel, P, Hahnen, E, Haiman, CA, Hall, P, Hamann, U, Harkness, EF, Hogervorst, FBL, Hollestelle, A, Hoppe, R, Hopper, JL, Houdayer, C, Houlston, RS, Howell, A, Investigators, A, Jakimovska, M, Jakubowska, A, Jernstrom, H, John, EM, Kaaks, R, Kitahara, CM, Koutros, S, Kraft, P, Kristensen, VN, Lacey, J, Lambrechts, D, Leone, M, Lindblom, A, Lush, M, Mannermaa, A, Manoochehri, M, Manoukian, S, Margolin, S, Martinez, ME, Menon, U, Milne, RL, Monteiro, AN, Murphy, RA, Neuhausen, SL, Nevanlinna, H, Newman, WG, Offit, K, Park, SK, James, P, Peterlongo, P, Peto, J, Plaseska-Karanfilska, D, Punie, K, Radice, P, Rashid, MU, Rennert, G, Romero, A, Rosenberg, EH, Saloustros, E, Sandler, DP, Schmidt, MK, Schmutzler, RK, Shu, X-O, Simard, J, Southey, MC, Stone, J, Stoppa-Lyonnet, D, Tamimi, RM, Tapper, WJ, Taylor, JA, Teo, SH, Teras, LR, Terry, MB, Thomassen, M, Troester, MA, Vachon, CM, Vega, A, Vreeswijk, MPG, Wang, Q, Wappenschmidt, B, Weinberg, CR, Wolk, A, Zheng, W, Feng, B, Couch, FJ, Spurdle, AB, Easton, DF, Goldgar, DE, and Michailidou, K
Abstract: A large number of variants identified through clinical genetic testing in disease susceptibility genes, are of uncertain significance (VUS). Following the recommendations of the American College of Medical Genetics and Genomics (ACMG) and Association for Molecular Pathology (AMP), the frequency in case-control datasets (PS4 criterion), can inform their interpretation. We present a novel case-control likelihood ratio-based method that incorporates gene-specific age-related penetrance. We demonstrate the utility of this method in the analysis of simulated and real datasets. In the analyses of simulated data, the likelihood ratio method was more powerful compared to other methods. Likelihood ratios were calculated for a case-control dataset of BRCA1 and BRCA2 variants from the Breast Cancer Association Consortium (BCAC), and compared with logistic regression results. A larger number of variants reached evidence in favor of pathogenicity, and a substantial number of variants had evidence against pathogenicity - findings that would not have been reached using other case-control analysis methods. Our novel method provides greater power to classify rare variants compared to classical case-control methods. As an initiative from the ENIGMA Analytical Working Group, we provide user-friendly scripts and pre-formatted excel calculators for implementation of the method for rare variants in BRCA1, BRCA2 and other high-risk genes with known penetrance.
Published: 2023

8. Associations of height, body mass index, and weight gain with breast cancer risk in carriers of a pathogenic variant in BRCA1 or BRCA2: the BRCA1 and BRCA2 Cohort Consortium

Author: Kast, KM, John, EL, Hopper, J, Andrieu, N, Nogues, C, Mouret-Fourme, E, Lasset, C, Fricker, J-P, Berthet, P, Mari, V, Salle, LK, Schmidt, M, Ausems, MGEM, Garcia, EBG, van de Beek, IR, Wevers, M, Evans, DG, Tischkowitz, M, Lalloo, F, Cook, J, Izatt, L, Tripathi, V, Snape, K, Musgrave, H, Sharif, S, Murray, JV, Colonna, SV, Andrulis, IL, Daly, MB, Southey, MC, de la Hoya, M, Osorio, A, Foretova, L, Berkova, D, Gerdes, A-M, Olah, E, Jakubowska, A, Singer, CF, Tan, Y, Augustinsson, A, Rantala, J, Simard, J, Schmutzler, RK, Milne, RL, Phillips, K-A, Terry, MB, Goldgar, D, van Leeuwen, FE, Mooij, TM, Antoniou, AC, Easton, DF, Rookus, MA, Engel, C, Kast, KM, John, EL, Hopper, J, Andrieu, N, Nogues, C, Mouret-Fourme, E, Lasset, C, Fricker, J-P, Berthet, P, Mari, V, Salle, LK, Schmidt, M, Ausems, MGEM, Garcia, EBG, van de Beek, IR, Wevers, M, Evans, DG, Tischkowitz, M, Lalloo, F, Cook, J, Izatt, L, Tripathi, V, Snape, K, Musgrave, H, Sharif, S, Murray, JV, Colonna, SV, Andrulis, IL, Daly, MB, Southey, MC, de la Hoya, M, Osorio, A, Foretova, L, Berkova, D, Gerdes, A-M, Olah, E, Jakubowska, A, Singer, CF, Tan, Y, Augustinsson, A, Rantala, J, Simard, J, Schmutzler, RK, Milne, RL, Phillips, K-A, Terry, MB, Goldgar, D, van Leeuwen, FE, Mooij, TM, Antoniou, AC, Easton, DF, Rookus, MA, and Engel, C
Abstract: INTRODUCTION: Height, body mass index (BMI), and weight gain are associated with breast cancer risk in the general population. It is unclear whether these associations also exist for carriers of pathogenic variants in the BRCA1 or BRCA2 genes. PATIENTS AND METHODS: An international pooled cohort of 8091 BRCA1/2 variant carriers was used for retrospective and prospective analyses separately for premenopausal and postmenopausal women. Cox regression was used to estimate breast cancer risk associations with height, BMI, and weight change. RESULTS: In the retrospective analysis, taller height was associated with risk of premenopausal breast cancer for BRCA2 variant carriers (HR 1.20 per 10 cm increase, 95% CI 1.04-1.38). Higher young-adult BMI was associated with lower premenopausal breast cancer risk for both BRCA1 (HR 0.75 per 5 kg/m2, 95% CI 0.66-0.84) and BRCA2 (HR 0.76, 95% CI 0.65-0.89) variant carriers in the retrospective analysis, with consistent, though not statistically significant, findings from the prospective analysis. In the prospective analysis, higher BMI and adult weight gain were associated with higher postmenopausal breast cancer risk for BRCA1 carriers (HR 1.20 per 5 kg/m2, 95% CI 1.02-1.42; and HR 1.10 per 5 kg weight gain, 95% CI 1.01-1.19, respectively). CONCLUSION: Anthropometric measures are associated with breast cancer risk for BRCA1 and BRCA2 variant carriers, with relative risk estimates that are generally consistent with those for women from the general population.
Published: 2023

9. Psychological, behavioural and biological factors associated with gastrointestinal symptoms in autistic adults and adults with autistic traits.

Author: Warreman, EB, Nooteboom, LA, Terry, MB, Hoek, HW, Leenen, PJM, van Rossum, EFC, Ramlal, D, Vermeiren, RRJM, and Ester, WA
Subjects: CONFIDENCE intervals, MULTIPLE regression analysis, GASTROINTESTINAL diseases, RISK assessment, PHYSICAL activity, AUTISM, ODDS ratio, COMORBIDITY, DISEASE risk factors, SYMPTOMS, ADULTS
Abstract: Gastrointestinal symptoms and their relation to physical and mental aspects in adults with an autism spectrum disorder (ASD) are poorly understood, despite their high prevalence. Therefore, the aim of this study is to examine psychological, behavioural and biological factors associated with gastrointestinal symptoms in adults with ASD (traits). We included 31,185 adults from the Lifelines Study. Using multivariable logistic regression, we analysed the association between gastrointestinal symptoms and psychological, behavioural (questionnaire-assessed) and physically measured biological factors in adults with ASD (n = 309), without ASD (n = 30,876), and in the quartiles with highest (n = 7783) and lowest (n = 7783) Autism Spectrum Quotient-10 sum scores. In the ASD-group, gastrointestinal symptoms were associated with psychiatric comorbidity (odds ratio: 2.71, 95% confidence interval: 1.51–4.85), more stress (odds ratio: 1.15, 95% confidence interval: 1.06–1.26), and worse perceived health (odds ratio: 2.32, 95% confidence interval: 1.62–3.34). In the quartile with the highest Autism Spectrum Quotient-10 sum scores, gastrointestinal symptoms were also associated with these psychological factors, and with less physical activity (odds ratio: 0.95, 95% confidence interval: 0.92–0.98). Our study demonstrates that not only adults with ASD but also adults with autistic traits are at increased risk for gastrointestinal symptoms, which is associated with psychological and behavioural factors. This suggests that an integrated psychosomatic approach of gastrointestinal symptoms in adults with ASD (traits) is needed. Little is known about factors related to the increased risk for gastrointestinal symptoms in adults with an autism spectrum disorder (ASD), while the negative impact of gastrointestinal symptoms is evident. Especially, the relationship between gastrointestinal symptoms and psychological, behavioural, and biological risk factors in adults with ASD (traits) is unclear. Autistic peer support workers and autism-advocates also emphasised the importance of identifying risk factors, because of the high prevalence of gastrointestinal problems in people with ASD. Therefore, our study investigated which psychological, behavioural, and biological factors are associated with gastrointestinal symptoms in adults with ASD or with autistic traits. We analysed data from 31,185 adults in the Dutch Lifelines Study. Questionnaires were used to evaluate the presence of an autism spectrum disorder diagnosis, autistic traits, gastrointestinal symptoms, psychological and behavioural factors. Biological factors were examined with body measurements. We found that not only adults with ASD but also adults with higher levels of autistic traits were at increased risk for gastrointestinal symptoms. Adults with ASD who experienced psychological problems (psychiatric problems, worse perceived health, chronic stress) had a higher risk for gastrointestinal symptoms than adults with ASD without these psychological problems. Moreover, adults with higher levels of autistic traits were less physically active, which was also associated with gastrointestinal symptoms. In conclusion, our study highlights the relevance of identifying psychological problems and evaluating physical activity when trying to help adults with ASD or autistic traits and gastrointestinal symptoms. This suggests that healthcare professionals should be more aware of behavioural and psychological risk factors when evaluating gastrointestinal symptoms in adults with ASD (traits). [ABSTRACT FROM AUTHOR]
Published: 2023
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10. Common variants in breast cancer risk loci predispose to distinct tumor subtypes

Author: Ahearn, TU, Zhang, H, Michailidou, K, Milne, RL, Bolla, MK, Dennis, J, Dunning, AM, Lush, M, Wang, Q, Andrulis, IL, Anton-Culver, H, Arndt, V, Aronson, KJ, Auer, PL, Augustinsson, A, Baten, A, Becher, H, Behrens, S, Benitez, J, Bermisheva, M, Blomqvist, C, Bojesen, SE, Bonanni, B, Borresen-Dale, A-L, Brauch, H, Brenner, H, Brooks-Wilson, A, Bruening, T, Burwinkel, B, Buys, SS, Canzian, F, Castelao, JE, Chang-Claude, J, Chanock, SJ, Chenevix-Trench, G, Clarke, CL, Collee, JM, Cox, A, Cross, SS, Czene, K, Daly, MB, Devilee, P, Dork, T, Dwek, M, Eccles, DM, Evans, DG, Fasching, PA, Figueroa, J, Floris, G, Gago-Dominguez, M, Gapstur, SM, Garcia-Saenz, JA, Gaudet, MM, Giles, GG, Goldberg, MS, Gonzalez-Neira, A, Alnaes, GIG, Grip, M, Guenel, P, Haiman, CA, Hall, P, Hamann, U, Harkness, EF, Heemskerk-Gerritsen, BAM, Holleczek, B, Hollestelle, A, Hooning, MJ, Hoover, RN, Hopper, JL, Howell, A, Jakimovska, M, Jakubowska, A, John, EM, Jones, ME, Jung, A, Kaaks, R, Kauppila, S, Keeman, R, Khusnutdinova, E, Kitahara, CM, Ko, Y-D, Koutros, S, Kristensen, VN, Kruger, U, Kubelka-Sabit, K, Kurian, AW, Kyriacou, K, Lambrechts, D, Lee, DG, Lindblom, A, Linet, M, Lissowska, J, Llaneza, A, Lo, W-Y, MacInnis, RJ, Mannermaa, A, Manoochehri, M, Margolin, S, Martinez, ME, McLean, C, Meindl, A, Menon, U, Nevanlinna, H, Newman, WG, Nodora, J, Offit, K, Olsson, H, Orr, N, Park-Simon, T-W, Patel, A, Peto, J, Pita, G, Plaseska-Karanfilska, D, Prentice, R, Punie, K, Pylkas, K, Radice, P, Rennert, G, Romero, A, Ruediger, T, Saloustros, E, Sampson, S, Sandler, DP, Sawyer, EJ, Schmutzler, RK, Schoemaker, MJ, Schottker, B, Sherman, ME, Shu, X-O, Smichkoska, S, Southey, MC, Spinelli, JJ, Swerdlow, AJ, Tamimi, RM, Tapper, WJ, Taylor, JA, Teras, LR, Terry, MB, Torres, D, Troester, MA, Vachon, CM, van Deurzen, CHM, van Veen, EM, Wagner, P, Weinberg, CR, Wendt, C, Wesseling, J, Winqvist, R, Wolk, A, Yang, XR, Zheng, W, Couch, FJ, Simard, J, Kraft, P, Easton, DF, Pharoah, PDP, Schmidt, MK, Garcia-Closas, M, Chatterjee, N, Ahearn, TU, Zhang, H, Michailidou, K, Milne, RL, Bolla, MK, Dennis, J, Dunning, AM, Lush, M, Wang, Q, Andrulis, IL, Anton-Culver, H, Arndt, V, Aronson, KJ, Auer, PL, Augustinsson, A, Baten, A, Becher, H, Behrens, S, Benitez, J, Bermisheva, M, Blomqvist, C, Bojesen, SE, Bonanni, B, Borresen-Dale, A-L, Brauch, H, Brenner, H, Brooks-Wilson, A, Bruening, T, Burwinkel, B, Buys, SS, Canzian, F, Castelao, JE, Chang-Claude, J, Chanock, SJ, Chenevix-Trench, G, Clarke, CL, Collee, JM, Cox, A, Cross, SS, Czene, K, Daly, MB, Devilee, P, Dork, T, Dwek, M, Eccles, DM, Evans, DG, Fasching, PA, Figueroa, J, Floris, G, Gago-Dominguez, M, Gapstur, SM, Garcia-Saenz, JA, Gaudet, MM, Giles, GG, Goldberg, MS, Gonzalez-Neira, A, Alnaes, GIG, Grip, M, Guenel, P, Haiman, CA, Hall, P, Hamann, U, Harkness, EF, Heemskerk-Gerritsen, BAM, Holleczek, B, Hollestelle, A, Hooning, MJ, Hoover, RN, Hopper, JL, Howell, A, Jakimovska, M, Jakubowska, A, John, EM, Jones, ME, Jung, A, Kaaks, R, Kauppila, S, Keeman, R, Khusnutdinova, E, Kitahara, CM, Ko, Y-D, Koutros, S, Kristensen, VN, Kruger, U, Kubelka-Sabit, K, Kurian, AW, Kyriacou, K, Lambrechts, D, Lee, DG, Lindblom, A, Linet, M, Lissowska, J, Llaneza, A, Lo, W-Y, MacInnis, RJ, Mannermaa, A, Manoochehri, M, Margolin, S, Martinez, ME, McLean, C, Meindl, A, Menon, U, Nevanlinna, H, Newman, WG, Nodora, J, Offit, K, Olsson, H, Orr, N, Park-Simon, T-W, Patel, A, Peto, J, Pita, G, Plaseska-Karanfilska, D, Prentice, R, Punie, K, Pylkas, K, Radice, P, Rennert, G, Romero, A, Ruediger, T, Saloustros, E, Sampson, S, Sandler, DP, Sawyer, EJ, Schmutzler, RK, Schoemaker, MJ, Schottker, B, Sherman, ME, Shu, X-O, Smichkoska, S, Southey, MC, Spinelli, JJ, Swerdlow, AJ, Tamimi, RM, Tapper, WJ, Taylor, JA, Teras, LR, Terry, MB, Torres, D, Troester, MA, Vachon, CM, van Deurzen, CHM, van Veen, EM, Wagner, P, Weinberg, CR, Wendt, C, Wesseling, J, Winqvist, R, Wolk, A, Yang, XR, Zheng, W, Couch, FJ, Simard, J, Kraft, P, Easton, DF, Pharoah, PDP, Schmidt, MK, Garcia-Closas, M, and Chatterjee, N
Abstract: BACKGROUND: Genome-wide association studies (GWAS) have identified multiple common breast cancer susceptibility variants. Many of these variants have differential associations by estrogen receptor (ER) status, but how these variants relate with other tumor features and intrinsic molecular subtypes is unclear. METHODS: Among 106,571 invasive breast cancer cases and 95,762 controls of European ancestry with data on 173 breast cancer variants identified in previous GWAS, we used novel two-stage polytomous logistic regression models to evaluate variants in relation to multiple tumor features (ER, progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and grade) adjusting for each other, and to intrinsic-like subtypes. RESULTS: Eighty-five of 173 variants were associated with at least one tumor feature (false discovery rate < 5%), most commonly ER and grade, followed by PR and HER2. Models for intrinsic-like subtypes found nearly all of these variants (83 of 85) associated at p < 0.05 with risk for at least one luminal-like subtype, and approximately half (41 of 85) of the variants were associated with risk of at least one non-luminal subtype, including 32 variants associated with triple-negative (TN) disease. Ten variants were associated with risk of all subtypes in different magnitude. Five variants were associated with risk of luminal A-like and TN subtypes in opposite directions. CONCLUSION: This report demonstrates a high level of complexity in the etiology heterogeneity of breast cancer susceptibility variants and can inform investigations of subtype-specific risk prediction.
Published: 2022

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

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

12. Rare germline copy number variants (CNVs) and breast cancer risk

Author: Dennis, J, Tyrer, JP, Walker, LC, Michailidou, K, Dorling, L, Bolla, MK, Wang, Q, Ahearn, TU, Andrulis, IL, Anton-Culver, H, Antonenkova, NN, Arndt, V, Aronson, KJ, Freeman, LEB, Beckmann, MW, Behrens, S, Benitez, J, Bermisheva, M, Bogdanova, N, Bojesen, SE, Brenner, H, Castelao, JE, Chang-Claude, J, Chenevix-Trench, G, Clarke, CL, Collee, JM, Couch, FJ, Cox, A, Cross, SS, Czene, K, Devilee, P, Dork, T, Dossus, L, Eliassen, AH, Eriksson, M, Evans, DG, Fasching, PA, Figueroa, J, Fletcher, O, Flyger, H, Fritschi, L, Gabrielson, M, Gago-Dominguez, M, Garcia-Closas, M, Giles, GG, Gonzalez-Neira, A, Guenel, P, Hahnen, E, Haiman, CA, Hall, P, Hollestelle, A, Hoppe, R, Hopper, JL, Howell, A, Jager, A, Jakubowska, A, John, EM, Johnson, N, Jones, ME, Jung, A, Kaaks, R, Keeman, R, Khusnutdinova, E, Kitahara, CM, Ko, Y-D, Kosma, V-M, Koutros, S, Kraft, P, Kristensen, VN, Kubelka-Sabit, K, Kurian, AW, Lacey, J, Lambrechts, D, Larson, NL, Linet, M, Ogrodniczak, A, Mannermaa, A, Manoukian, S, Margolin, S, Mavroudis, D, Milne, RL, Muranen, TA, Murphy, RA, Nevanlinna, H, Olson, JE, Olsson, H, Park-Simon, T-W, Perou, CM, Peterlongo, P, Plaseska-Karanfilska, D, Pylkas, K, Rennert, G, Saloustros, E, Sandler, DP, Sawyer, EJ, Schmidt, MK, Schmutzler, RK, Shibli, R, Smeets, A, Soucy, P, Southey, MC, Swerdlow, AJ, Tamimi, RM, Taylor, JA, Teras, LR, Terry, MB, Tomlinson, I, Troester, MA, Truong, T, Vachon, CM, Wendt, C, Winqvist, R, Wolk, A, Yang, XR, Zheng, W, Ziogas, A, Simard, J, Dunning, AM, Pharoah, PDP, Easton, DF, Dennis, J, Tyrer, JP, Walker, LC, Michailidou, K, Dorling, L, Bolla, MK, Wang, Q, Ahearn, TU, Andrulis, IL, Anton-Culver, H, Antonenkova, NN, Arndt, V, Aronson, KJ, Freeman, LEB, Beckmann, MW, Behrens, S, Benitez, J, Bermisheva, M, Bogdanova, N, Bojesen, SE, Brenner, H, Castelao, JE, Chang-Claude, J, Chenevix-Trench, G, Clarke, CL, Collee, JM, Couch, FJ, Cox, A, Cross, SS, Czene, K, Devilee, P, Dork, T, Dossus, L, Eliassen, AH, Eriksson, M, Evans, DG, Fasching, PA, Figueroa, J, Fletcher, O, Flyger, H, Fritschi, L, Gabrielson, M, Gago-Dominguez, M, Garcia-Closas, M, Giles, GG, Gonzalez-Neira, A, Guenel, P, Hahnen, E, Haiman, CA, Hall, P, Hollestelle, A, Hoppe, R, Hopper, JL, Howell, A, Jager, A, Jakubowska, A, John, EM, Johnson, N, Jones, ME, Jung, A, Kaaks, R, Keeman, R, Khusnutdinova, E, Kitahara, CM, Ko, Y-D, Kosma, V-M, Koutros, S, Kraft, P, Kristensen, VN, Kubelka-Sabit, K, Kurian, AW, Lacey, J, Lambrechts, D, Larson, NL, Linet, M, Ogrodniczak, A, Mannermaa, A, Manoukian, S, Margolin, S, Mavroudis, D, Milne, RL, Muranen, TA, Murphy, RA, Nevanlinna, H, Olson, JE, Olsson, H, Park-Simon, T-W, Perou, CM, Peterlongo, P, Plaseska-Karanfilska, D, Pylkas, K, Rennert, G, Saloustros, E, Sandler, DP, Sawyer, EJ, Schmidt, MK, Schmutzler, RK, Shibli, R, Smeets, A, Soucy, P, Southey, MC, Swerdlow, AJ, Tamimi, RM, Taylor, JA, Teras, LR, Terry, MB, Tomlinson, I, Troester, MA, Truong, T, Vachon, CM, Wendt, C, Winqvist, R, Wolk, A, Yang, XR, Zheng, W, Ziogas, A, Simard, J, Dunning, AM, Pharoah, PDP, and Easton, DF
Abstract: Germline copy number variants (CNVs) are pervasive in the human genome but potential disease associations with rare CNVs have not been comprehensively assessed in large datasets. We analysed rare CNVs in genes and non-coding regions for 86,788 breast cancer cases and 76,122 controls of European ancestry with genome-wide array data. Gene burden tests detected the strongest association for deletions in BRCA1 (P = 3.7E-18). Nine other genes were associated with a p-value < 0.01 including known susceptibility genes CHEK2 (P = 0.0008), ATM (P = 0.002) and BRCA2 (P = 0.008). Outside the known genes we detected associations with p-values < 0.001 for either overall or subtype-specific breast cancer at nine deletion regions and four duplication regions. Three of the deletion regions were in established common susceptibility loci. To the best of our knowledge, this is the first genome-wide analysis of rare CNVs in a large breast cancer case-control dataset. We detected associations with exonic deletions in established breast cancer susceptibility genes. We also detected suggestive associations with non-coding CNVs in known and novel loci with large effects sizes. Larger sample sizes will be required to reach robust levels of statistical significance.
Published: 2022

13. Cancer Risks Associated With BRCA1 and BRCA2 Pathogenic Variants

Author: Li, S, Silvestri, V, Leslie, G, Rebbeck, TR, Neuhausen, SL, Hopper, JL, Nielsen, HR, Lee, A, Yang, X, McGuffog, L, Parsons, MT, Andrulis, IL, Arnold, N, Belotti, M, Borg, A, Buecher, B, Buys, SS, Caputo, SM, Chung, WK, Colas, C, Colonna, S, Cook, J, Daly, MB, de la Hoya, M, de Pauw, A, Delhomelle, H, Eason, J, Engel, C, Evans, DG, Faust, U, Fehm, TN, Fostira, F, Fountzilas, G, Frone, M, Garcia-Barberan, V, Garre, P, Gauthier-Villars, M, Gehrig, A, Glendon, G, Goldgar, DE, Golmard, L, Greene, MH, Hahnen, E, Hamann, U, Hanson, H, Hassan, T, Hentschel, J, Horvath, J, Izatt, L, Janavicius, R, Jiao, Y, John, EM, Karlan, BY, Kim, S-W, Konstantopoulou, I, Kwong, A, Lauge, A, Lee, JW, Lesueur, F, Mebirouk, N, Meindl, A, Mouret-Fourme, E, Musgrave, H, Yie, JNY, Niederacher, D, Park, SK, Pedersen, IS, Ramser, J, Ramus, SJ, Rantala, J, Rashid, MU, Reichl, F, Ritter, J, Rump, A, Santamarina, M, Saule, C, Schmidt, G, Schmutzler, RK, Senter, L, Shariff, S, Singer, CF, Southey, MC, Stoppa-Lyonnet, D, Sutter, C, Tan, Y, Teo, SH, Terry, MB, Thomassen, M, Tischkowitz, M, Toland, AE, Torres, D, Vega, A, Wagner, SA, Wang-Gohrke, S, Wappenschmidt, B, Weber, BHF, Yannoukakos, D, Spurdle, AB, Easton, DF, Chenevix-Trench, G, Ottini, L, Antoniou, AC, Li, S, Silvestri, V, Leslie, G, Rebbeck, TR, Neuhausen, SL, Hopper, JL, Nielsen, HR, Lee, A, Yang, X, McGuffog, L, Parsons, MT, Andrulis, IL, Arnold, N, Belotti, M, Borg, A, Buecher, B, Buys, SS, Caputo, SM, Chung, WK, Colas, C, Colonna, S, Cook, J, Daly, MB, de la Hoya, M, de Pauw, A, Delhomelle, H, Eason, J, Engel, C, Evans, DG, Faust, U, Fehm, TN, Fostira, F, Fountzilas, G, Frone, M, Garcia-Barberan, V, Garre, P, Gauthier-Villars, M, Gehrig, A, Glendon, G, Goldgar, DE, Golmard, L, Greene, MH, Hahnen, E, Hamann, U, Hanson, H, Hassan, T, Hentschel, J, Horvath, J, Izatt, L, Janavicius, R, Jiao, Y, John, EM, Karlan, BY, Kim, S-W, Konstantopoulou, I, Kwong, A, Lauge, A, Lee, JW, Lesueur, F, Mebirouk, N, Meindl, A, Mouret-Fourme, E, Musgrave, H, Yie, JNY, Niederacher, D, Park, SK, Pedersen, IS, Ramser, J, Ramus, SJ, Rantala, J, Rashid, MU, Reichl, F, Ritter, J, Rump, A, Santamarina, M, Saule, C, Schmidt, G, Schmutzler, RK, Senter, L, Shariff, S, Singer, CF, Southey, MC, Stoppa-Lyonnet, D, Sutter, C, Tan, Y, Teo, SH, Terry, MB, Thomassen, M, Tischkowitz, M, Toland, AE, Torres, D, Vega, A, Wagner, SA, Wang-Gohrke, S, Wappenschmidt, B, Weber, BHF, Yannoukakos, D, Spurdle, AB, Easton, DF, Chenevix-Trench, G, Ottini, L, and Antoniou, AC
Abstract: PURPOSE: To provide precise age-specific risk estimates of cancers other than female breast and ovarian cancers associated with pathogenic variants (PVs) in BRCA1 and BRCA2 for effective cancer risk management. METHODS: We used data from 3,184 BRCA1 and 2,157 BRCA2 families in the Consortium of Investigators of Modifiers of BRCA1/2 to estimate age-specific relative (RR) and absolute risks for 22 first primary cancer types adjusting for family ascertainment. RESULTS: BRCA1 PVs were associated with risks of male breast (RR = 4.30; 95% CI, 1.09 to 16.96), pancreatic (RR = 2.36; 95% CI, 1.51 to 3.68), and stomach (RR = 2.17; 95% CI, 1.25 to 3.77) cancers. Associations with colorectal and gallbladder cancers were also suggested. BRCA2 PVs were associated with risks of male breast (RR = 44.0; 95% CI, 21.3 to 90.9), stomach (RR = 3.69; 95% CI, 2.40 to 5.67), pancreatic (RR = 3.34; 95% CI, 2.21 to 5.06), and prostate (RR = 2.22; 95% CI, 1.63 to 3.03) cancers. The stomach cancer RR was higher for females than males (6.89 v 2.76; P = .04). The absolute risks to age 80 years ranged from 0.4% for male breast cancer to approximately 2.5% for pancreatic cancer for BRCA1 carriers and from approximately 2.5% for pancreatic cancer to 27% for prostate cancer for BRCA2 carriers. CONCLUSION: In addition to female breast and ovarian cancers, BRCA1 and BRCA2 PVs are associated with increased risks of male breast, pancreatic, stomach, and prostate (only BRCA2 PVs) cancers, but not with the risks of other previously suggested cancers. The estimated age-specific risks will refine cancer risk management in men and women with BRCA1/2 PVs.
Published: 2022

14. Oral Contraceptive Use in BRCA1 and BRCA2 Mutation Carriers: Absolute Cancer Risks and Benefits

Author: Schrijver, LH, Mooij, TM, Pijpe, A, Sonke, GS, Mourits, MJE, Andrieu, N, Antoniou, AC, Easton, DF, Engel, C, Goldgar, D, John, EM, Kast, K, Milne, RL, Olsson, H, Phillips, K-A, Terry, MB, Hopper, JL, van Leeuwen, FE, Rookus, MA, Schrijver, LH, Mooij, TM, Pijpe, A, Sonke, GS, Mourits, MJE, Andrieu, N, Antoniou, AC, Easton, DF, Engel, C, Goldgar, D, John, EM, Kast, K, Milne, RL, Olsson, H, Phillips, K-A, Terry, MB, Hopper, JL, van Leeuwen, FE, and Rookus, MA
Abstract: BACKGROUND: To help BRCA1 and 2 mutation carriers make informed decisions regarding use of combined-type oral contraceptive preparation (COCP), absolute risk-benefit estimates are needed for COCP-associated cancer. METHODS: For a hypothetical cohort of 10 000 women, we calculated the increased or decreased cumulative incidence of COCP-associated (breast, ovarian, endometrial) cancer, examining 18 scenarios with differences in duration and timing of COCP use, uptake of prophylactic surgeries, and menopausal hormone therapy. RESULTS: COCP use initially increased breast cancer risk and decreased ovarian and endometrial cancer risk long term. For 10 000 BRCA1 mutation carriers, 10 years of COCP use from age 20 to 30 years resulted in 66 additional COCP-associated cancer cases by the age of 35 years, in addition to 625 cases expected for never users. By the age of 70 years such COCP use resulted in 907 fewer cancer cases than the expected 9093 cases in never users. Triple-negative breast cancer estimates resulted in 196 additional COCP-associated cases by age 40 years, in addition to the 1454 expected. For 10 000 BRCA2 mutation carriers using COCP from age 20 to 30 years, 80 excess cancer cases were estimated by age 40 years in addition to 651 expected cases; by the age of 70 years, we calculated 382 fewer cases compared with the 6156 cases expected. The long-term benefit of COCP use diminished after risk-reducing bilateral salpingo-oophorectomy followed by menopausal hormone therapy use. CONCLUSION: Although COCP use in BRCA1 and BRCA2 mutation carriers initially increases breast, ovarian, and endometrial cancer risk, it strongly decreases lifetime cancer risk. Risk-reducing bilateral salpingo-oophorectomy and menopausal hormone therapy use appear to counteract the long-term COCP-benefit.
Published: 2022

15. Women's thoughts on receiving and sharing genetic information: Considerations for genetic counseling

Author: Pfledderer, CD, Gren, LH, Frost, CJ, Andrulis, IL, Chung, WK, Genkinger, J, Glendon, G, Hopper, JL, John, EM, Southey, M, Terry, MB, Daly, MB, Pfledderer, CD, Gren, LH, Frost, CJ, Andrulis, IL, Chung, WK, Genkinger, J, Glendon, G, Hopper, JL, John, EM, Southey, M, Terry, MB, and Daly, MB
Abstract: Indications for genetic testing for inherited cancer syndromes are expanding both in the academic and the community setting. However, only a fraction of individuals who are candidates for testing pursue this option. Therefore, it is important to understand those factors that impact the uptake of genetic testing in individuals affected and unaffected with cancer. A successful translation of genomic risk stratification into clinical care will require that providers of this information are aware of the attitudes, perceived risks and benefits, and concerns of individuals who will be considering testing. The purpose of this study was to assess beliefs, attitudes and preferences for genetic risk information, by personal characteristics of women affected and unaffected by breast cancer enrolled in the Breast Cancer Family Registry Cohort. Data for this analysis came from eight survey questions, which asked participants (N = 9,048, 100% female) about their opinions regarding genetic information. Women reported that conveying the accuracy of the test was important and were interested in information related to personal level of risk, finding out about diseases that could be treated, and information that could be helpful to their families. Young women were most interested in how their own health needs might be impacted by genetic test results, while older women were more interested in how genetic information would benefit other members of the family. Interest in how the genetic test was performed was highest among Asian and Hispanic women. Women affected with breast cancer were more likely to report feeling sad about possibly passing down a breast cancer gene, while unaffected women were more uncertain about their future risk of cancer. The variety of informational needs identified has implications for how genetic counselors can tailor communication to individuals considering genetic testing.
Published: 2022

16. Physical activity, sedentary time and breast cancer risk: a Mendelian randomisation study

Author: Dixon-Suen, SC, Lewis, SJ, Martin, RM, English, DR, Boyle, T, Giles, GG, Michailidou, K, Bolla, MK, Wang, Q, Dennis, J, Lush, M, Ahearn, TU, Ambrosone, CB, Andrulis, IL, Anton-Culver, H, Arndt, V, Aronson, KJ, Augustinsson, A, Auvinen, P, Beane Freeman, LE, Becher, H, Beckmann, MW, Behrens, S, Bermisheva, M, Blomqvist, C, Bogdanova, N, Bojesen, SE, Bonanni, B, Brenner, H, Bruening, T, Buys, SS, Camp, NJ, Campa, D, Canzian, F, Castelao, JE, Cessna, MH, Chang-Claude, J, Chanock, SJ, Clarke, CL, Conroy, DM, Couch, FJ, Cox, A, Cross, SS, Czene, K, Daly, MB, Devilee, P, Doerk, T, Dwek, M, Eccles, DM, Eliassen, AH, Engel, C, Eriksson, M, Evans, DG, Fasching, PA, Fletcher, O, Flyger, H, Fritschi, L, Gabrielson, M, Gago-Dominguez, M, Garcia-Closas, M, Garcia-Saenz, JA, Goldberg, MS, Guenel, P, Guendert, M, Hahnen, E, Haiman, CA, Haeberle, L, Hakansson, N, Hall, P, Hamann, U, Hart, SN, Harvie, M, Hillemanns, P, Hollestelle, A, Hooning, MJ, Hoppe, R, Hopper, J, Howell, A, Hunter, DJ, Jakubowska, A, Janni, W, John, EM, Jung, A, Kaaks, R, Keeman, R, Kitahara, CM, Koutros, S, Kraft, P, Kristensen, VN, Kubelka-Sabit, K, Kurian, AW, Lacey, J, Lambrechts, D, Le Marchand, L, Lindblom, A, Loibl, S, Lubinski, J, Mannermaa, A, Manoochehri, M, Margolin, S, Martinez, ME, Mavroudis, D, Menon, U, Mulligan, AM, Murphy, RA, Nevanlinna, H, Nevelsteen, I, Newman, WG, Offit, K, Olshan, AF, Olsson, H, Orr, N, Patel, A, Peto, J, Plaseska-Karanfilska, D, Presneau, N, Rack, B, Radice, P, Rees-Punia, E, Rennert, G, Rennert, HS, Romero, A, Saloustros, E, Sandler, DP, Schmidt, MK, Schmutzler, RK, Schwentner, L, Scott, C, Shah, M, Shu, X-O, Simard, J, Southey, MC, Stone, J, Surowy, H, Swerdlow, AJ, Tamimi, RM, Tapper, WJ, Taylor, JA, Terry, MB, Tollenaar, RAEM, Troester, MA, Truong, T, Untch, M, Vachon, CM, Joseph, V, Wappenschmidt, B, Weinberg, CR, Wolk, A, Yannoukakos, D, Zheng, W, Ziogas, A, Dunning, AM, Pharoah, PDP, Easton, DF, Milne, RL, Lynch, BM, Dixon-Suen, SC, Lewis, SJ, Martin, RM, English, DR, Boyle, T, Giles, GG, Michailidou, K, Bolla, MK, Wang, Q, Dennis, J, Lush, M, Ahearn, TU, Ambrosone, CB, Andrulis, IL, Anton-Culver, H, Arndt, V, Aronson, KJ, Augustinsson, A, Auvinen, P, Beane Freeman, LE, Becher, H, Beckmann, MW, Behrens, S, Bermisheva, M, Blomqvist, C, Bogdanova, N, Bojesen, SE, Bonanni, B, Brenner, H, Bruening, T, Buys, SS, Camp, NJ, Campa, D, Canzian, F, Castelao, JE, Cessna, MH, Chang-Claude, J, Chanock, SJ, Clarke, CL, Conroy, DM, Couch, FJ, Cox, A, Cross, SS, Czene, K, Daly, MB, Devilee, P, Doerk, T, Dwek, M, Eccles, DM, Eliassen, AH, Engel, C, Eriksson, M, Evans, DG, Fasching, PA, Fletcher, O, Flyger, H, Fritschi, L, Gabrielson, M, Gago-Dominguez, M, Garcia-Closas, M, Garcia-Saenz, JA, Goldberg, MS, Guenel, P, Guendert, M, Hahnen, E, Haiman, CA, Haeberle, L, Hakansson, N, Hall, P, Hamann, U, Hart, SN, Harvie, M, Hillemanns, P, Hollestelle, A, Hooning, MJ, Hoppe, R, Hopper, J, Howell, A, Hunter, DJ, Jakubowska, A, Janni, W, John, EM, Jung, A, Kaaks, R, Keeman, R, Kitahara, CM, Koutros, S, Kraft, P, Kristensen, VN, Kubelka-Sabit, K, Kurian, AW, Lacey, J, Lambrechts, D, Le Marchand, L, Lindblom, A, Loibl, S, Lubinski, J, Mannermaa, A, Manoochehri, M, Margolin, S, Martinez, ME, Mavroudis, D, Menon, U, Mulligan, AM, Murphy, RA, Nevanlinna, H, Nevelsteen, I, Newman, WG, Offit, K, Olshan, AF, Olsson, H, Orr, N, Patel, A, Peto, J, Plaseska-Karanfilska, D, Presneau, N, Rack, B, Radice, P, Rees-Punia, E, Rennert, G, Rennert, HS, Romero, A, Saloustros, E, Sandler, DP, Schmidt, MK, Schmutzler, RK, Schwentner, L, Scott, C, Shah, M, Shu, X-O, Simard, J, Southey, MC, Stone, J, Surowy, H, Swerdlow, AJ, Tamimi, RM, Tapper, WJ, Taylor, JA, Terry, MB, Tollenaar, RAEM, Troester, MA, Truong, T, Untch, M, Vachon, CM, Joseph, V, Wappenschmidt, B, Weinberg, CR, Wolk, A, Yannoukakos, D, Zheng, W, Ziogas, A, Dunning, AM, Pharoah, PDP, Easton, DF, Milne, RL, and Lynch, BM
Abstract: OBJECTIVES: Physical inactivity and sedentary behaviour are associated with higher breast cancer risk in observational studies, but ascribing causality is difficult. Mendelian randomisation (MR) assesses causality by simulating randomised trial groups using genotype. We assessed whether lifelong physical activity or sedentary time, assessed using genotype, may be causally associated with breast cancer risk overall, pre/post-menopause, and by case-groups defined by tumour characteristics. METHODS: We performed two-sample inverse-variance-weighted MR using individual-level Breast Cancer Association Consortium case-control data from 130 957 European-ancestry women (69 838 invasive cases), and published UK Biobank data (n=91 105-377 234). Genetic instruments were single nucleotide polymorphisms (SNPs) associated in UK Biobank with wrist-worn accelerometer-measured overall physical activity (nsnps=5) or sedentary time (nsnps=6), or accelerometer-measured (nsnps=1) or self-reported (nsnps=5) vigorous physical activity. RESULTS: Greater genetically-predicted overall activity was associated with lower breast cancer overall risk (OR=0.59; 95% confidence interval (CI) 0.42 to 0.83 per-standard deviation (SD;~8 milligravities acceleration)) and for most case-groups. Genetically-predicted vigorous activity was associated with lower risk of pre/perimenopausal breast cancer (OR=0.62; 95% CI 0.45 to 0.87,≥3 vs. 0 self-reported days/week), with consistent estimates for most case-groups. Greater genetically-predicted sedentary time was associated with higher hormone-receptor-negative tumour risk (OR=1.77; 95% CI 1.07 to 2.92 per-SD (~7% time spent sedentary)), with elevated estimates for most case-groups. Results were robust to sensitivity analyses examining pleiotropy (including weighted-median-MR, MR-Egger). CONCLUSION: Our study provides strong evidence that greater overall physical activity, greater vigorous activity, and lower sedentary time are likely to reduce breast cancer r
Published: 2022

17. Mendelian randomisation study of smoking exposure in relation to breast cancer risk

Author: Park, HA, Neumeyer, S, Michailidou, K, Bolla, MK, Wang, Q, Dennis, J, Ahearn, TU, Andrulis, IL, Anton-Culver, H, Antonenkova, NN, Arndt, V, Aronson, KJ, Augustinsson, A, Baten, A, Beane Freeman, LE, Becher, H, Beckmann, MW, Behrens, S, Benitez, J, Bermisheva, M, Bogdanova, NV, Bojesen, SE, Brauch, H, Brenner, H, Brucker, SY, Burwinkel, B, Campa, D, Canzian, F, Castelao, JE, Chanock, SJ, Chenevix-Trench, G, Clarke, CL, Børresen-Dale, A-L, Grenaker Alnæs, GI, Sahlberg, KK, Ottestad, L, Kåresen, R, Schlichting, E, Holmen, MM, Sauer, T, Haakensen, V, Engebråten, O, Naume, B, Fosså, A, Kiserud, CE, Reinertsen, KV, Helland, Å, Riis, M, Geisler, J, Conroy, DM, Couch, FJ, Cox, A, Cross, SS, Czene, K, Daly, MB, Devilee, P, Dörk, T, dos-Santos-Silva, I, Dwek, M, Eccles, DM, Eliassen, AH, Engel, C, Eriksson, M, Evans, DG, Fasching, PA, Flyger, H, Fritschi, L, García-Closas, M, García-Sáenz, JA, Gaudet, MM, Giles, GG, Glendon, G, Goldberg, MS, Goldgar, DE, González-Neira, A, Grip, M, Guénel, P, Hahnen, E, Haiman, CA, Håkansson, N, Hall, P, Hamann, U, Han, S, Harkness, EF, Hart, SN, He, W, Heemskerk-Gerritsen, BAM, Hopper, JL, Hunter, DJ, Clarke, C, Marsh, D, Scott, R, Baxter, R, Yip, D, Carpenter, J, Davis, A, Pathmanathan, N, Simpson, P, Graham, D, Sachchithananthan, M, Amor, D, Andrews, L, Antill, Y, Balleine, R, Beesley, J, Bennett, I, Bogwitz, M, Botes, L, Brennan, M, Brown, M, Buckley, M, Burke, J, Butow, P, Caldon, L, Campbell, I, Chauhan, D, Chauhan, M, Christian, A, Cohen, P, Colley, A, Crook, A, Cui, J, Cummings, M, Dawson, S-J, DeFazio, A, Delatycki, M, Dickson, R, Dixon, J, Edkins, T, Edwards, S, Farshid, G, Fellows, A, Fenton, G, Field, M, Flanagan, J, Fong, P, Forrest, L, Fox, S, French, J, Friedlander, M, Gaff, C, Gattas, M, George, P, Greening, S, Harris, M, Hart, S, Hayward, N, Hopper, J, Hoskins, C, Hunt, C, James, P, Jenkins, M, Kidd, A, Kirk, J, Koehler, J, Kollias, J, Lakhani, S, Lawrence, M, Lindeman, G, Lipton, L, Lobb, L, Mann, G, McLachlan, SA, Meiser, B, Milne, R, Nightingale, S, O’Connell, S, O’Sullivan, S, Ortega, DG, Pachter, N, Patterson, B, Pearn, A, Phillips, K, Pieper, E, Rickard, E, Robinson, B, Saleh, M, Salisbury, E, Saunders, C, Saunus, J, Scott, C, Sexton, A, Shelling, A, Southey, M, Spurdle, A, Taylor, J, Taylor, R, Thorne, H, Trainer, A, Tucker, K, Visvader, J, Walker, L, Williams, R, Winship, I, Young, MA, Jager, A, Jakubowska, A, John, EM, Jung, A, Kaaks, R, Kapoor, PM, Keeman, R, Khusnutdinova, E, Kitahara, CM, Koppert, LB, Koutros, S, Kristensen, VN, Kurian, AW, Lacey, J, Lambrechts, D, Le Marchand, L, Lo, W-Y, Lubiński, J, Mannermaa, A, Manoochehri, M, Margolin, S, Martinez, ME, Mavroudis, D, Meindl, A, Menon, U, Milne, RL, Muranen, TA, Nevanlinna, H, Newman, WG, Nordestgaard, BG, Offit, K, Olshan, AF, Olsson, H, Park-Simon, T-W, Peterlongo, P, Peto, J, Plaseska-Karanfilska, D, Presneau, N, Radice, P, Rennert, G, Rennert, HS, Romero, A, Saloustros, E, Sawyer, EJ, Schmidt, MK, Schmutzler, RK, Schoemaker, MJ, Schwentner, L, Shah, M, Shu, X-O, Simard, J, Smeets, A, Southey, MC, Spinelli, JJ, Stevens, V, Swerdlow, AJ, Tamimi, RM, Tapper, WJ, Taylor, JA, Terry, MB, Tomlinson, I, Troester, MA, Truong, T, Vachon, CM, van Veen, EM, Vijai, J, Wang, S, Wendt, C, Winqvist, R, Wolk, A, Ziogas, A, Dunning, AM, Pharoah, PDP, Easton, DF, Zheng, W, Kraft, P, Chang-Claude, J, HUS Gynecology and Obstetrics, Department of Obstetrics and Gynecology, Park, Hanla A. [0000-0001-8055-3729], Dennis, Joe [0000-0003-4591-1214], Augustinsson, Annelie [0000-0003-3415-0536], Brenner, Hermann [0000-0002-6129-1572], Canzian, Federico [0000-0002-4261-4583], Cox, Angela [0000-0002-5138-1099], Devilee, Peter [0000-0002-8023-2009], Fasching, Peter A. [0000-0003-4885-8471], Harkness, Elaine F. [0000-0001-6625-7739], Hart, Steven N. [0000-0001-7714-2734], Heemskerk-Gerritsen, Bernadette A. M. [0000-0002-9724-6693], Jakubowska, Anna [0000-0002-5650-0501], Kapoor, Pooja Middha [0000-0001-5503-8215], Kurian, Allison W. [0000-0002-6175-9470], Newman, William G. [0000-0002-6382-4678], Peterlongo, Paolo [0000-0001-6951-6855], Peto, Julian [0000-0002-1685-8912], Sawyer, Elinor J. [0000-0001-8285-4111], Scott, Christopher [0000-0003-1340-0647], Smeets, Ann [0000-0002-5091-6602], Tomlinson, Ian [0000-0003-3037-1470], Truong, Thérèse [0000-0002-2943-6786], Pharoah, Paul D. P. [0000-0001-8494-732X], and Apollo - University of Cambridge Repository
Subjects: 0301 basic medicine, Oncology, Medicin och hälsovetenskap, Cancer Research, Genotyping Techniques, Breast Neoplasms, Case-Control Studies, Cigarette Smoking, Female, Genetic Pleiotropy, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Mendelian Randomization Analysis, Polymorphism, Single Nucleotide, ALCOHOL, Medical and Health Sciences, 0302 clinical medicine, Breast cancer, Pleiotropy, Epidemiology, Medicine, TOBACCO, Breast Neoplasms/epidemiology, Cigarette Smoking/adverse effects, WOMEN, ASSOCIATION, Single Nucleotide, 3. Good health, Substance abuse, 692/699/67/1347, 030220 oncology & carcinogenesis, Life Sciences & Biomedicine, 692/499, medicine.medical_specialty, 3122 Cancers, Single-nucleotide polymorphism, Article, 03 medical and health sciences, Internal medicine, ddc:610, Polymorphism, Genetic association, Science & Technology, business.industry, Cancer, medicine.disease, 030104 developmental biology, Clinical research, Risk factors, TISSUE, INFERENCE, CIGARETTE-SMOKING, business
Abstract: Background Despite a modest association between tobacco smoking and breast cancer risk reported by recent epidemiological studies, it is still equivocal whether smoking is causally related to breast cancer risk. Methods We applied Mendelian randomisation (MR) to evaluate a potential causal effect of cigarette smoking on breast cancer risk. Both individual-level data as well as summary statistics for 164 single-nucleotide polymorphisms (SNPs) reported in genome-wide association studies of lifetime smoking index (LSI) or cigarette per day (CPD) were used to obtain MR effect estimates. Data from 108,420 invasive breast cancer cases and 87,681 controls were used for the LSI analysis and for the CPD analysis conducted among ever-smokers from 26,147 cancer cases and 26,072 controls. Sensitivity analyses were conducted to address pleiotropy. Results Genetically predicted LSI was associated with increased breast cancer risk (OR 1.18 per SD, 95% CI: 1.07–1.30, P = 0.11 × 10–2), but there was no evidence of association for genetically predicted CPD (OR 1.02, 95% CI: 0.78–1.19, P = 0.85). The sensitivity analyses yielded similar results and showed no strong evidence of pleiotropic effect. Conclusion Our MR study provides supportive evidence for a potential causal association with breast cancer risk for lifetime smoking exposure but not cigarettes per day among smokers.
Published: 2021

18. Recreational Physical Activity and Outcomes After Breast Cancer in Women at High Familial Risk

Author: Kehm, RD, MacInnis, RJ, John, EM, Liao, Y, Kurian, AW, Genkinger, JM, Knight, JA, Colonna, S, Chung, WK, Milne, R, Zeinomar, N, Dite, GS, Southey, MC, Giles, GG, Mclachlan, S-A, Whitaker, KD, Friedlander, ML, Weideman, PC, Glendon, G, Nesci, S, Investigators, K, Phillips, K-A, Andrulis, IL, Buys, SS, Daly, MB, Hopper, JL, Terry, MB, Kehm, RD, MacInnis, RJ, John, EM, Liao, Y, Kurian, AW, Genkinger, JM, Knight, JA, Colonna, S, Chung, WK, Milne, R, Zeinomar, N, Dite, GS, Southey, MC, Giles, GG, Mclachlan, S-A, Whitaker, KD, Friedlander, ML, Weideman, PC, Glendon, G, Nesci, S, Investigators, K, Phillips, K-A, Andrulis, IL, Buys, SS, Daly, MB, Hopper, JL, and Terry, MB
Abstract: BACKGROUND: Recreational physical activity (RPA) is associated with improved survival after breast cancer (BC) in average-risk women, but evidence is limited for women who are at increased familial risk because of a BC family history or BRCA1 and BRCA2 pathogenic variants (BRCA1/2 PVs). METHODS: We estimated associations of RPA (self-reported average hours per week within 3 years of BC diagnosis) with all-cause mortality and second BC events (recurrence or new primary) after first invasive BC in women in the Prospective Family Study Cohort (n = 4610, diagnosed 1993-2011, aged 22-79 years at diagnosis). We fitted Cox proportional hazards regression models adjusted for age at diagnosis, demographics, and lifestyle factors. We tested for multiplicative interactions (Wald test statistic for cross-product terms) and additive interactions (relative excess risk due to interaction) by age at diagnosis, body mass index, estrogen receptor status, stage at diagnosis, BRCA1/2 PVs, and familial risk score estimated from multigenerational pedigree data. Statistical tests were 2-sided. RESULTS: We observed 1212 deaths and 473 second BC events over a median follow-up from study enrollment of 11.0 and 10.5 years, respectively. After adjusting for covariates, RPA (any vs none) was associated with lower all-cause mortality of 16.1% (95% confidence interval [CI] = 2.4% to 27.9%) overall, 11.8% (95% CI = -3.6% to 24.9%) in women without BRCA1/2 PVs, and 47.5% (95% CI = 17.4% to 66.6%) in women with BRCA1/2 PVs (RPA*BRCA1/2 multiplicative interaction P = .005; relative excess risk due to interaction = 0.87, 95% CI = 0.01 to 1.74). RPA was not associated with risk of second BC events. CONCLUSION: Findings support that RPA is associated with lower all-cause mortality in women with BC, particularly in women with BRCA1/2 PVs.
Published: 2021

19. Oral contraceptive use and ovarian cancer risk for BRCA1/2 mutation carriers: an international cohort study

Author: Schrijver, LH, Antoniou, AC, Olsson, H, Mooij, TM, Roos-Blom, M-J, Azarang, L, Adlard, J, Ahmed, M, Barrowdale, D, Davidson, R, Donaldson, A, Eeles, R, Evans, DG, Frost, D, Henderson, A, Izatt, L, Ong, K-R, Bonadona, V, Coupier, I, Faivre, L, Fricker, J-P, Gesta, P, van Engelen, K, Jager, A, Menko, FH, Mourits, MJE, Singer, CF, Tan, YY, Foretova, L, Navratilova, M, Schmutzler, RK, Ellberg, C, Gerdes, A-M, Caldes, T, Simard, J, Olah, E, Jakubowska, A, Rantala, J, Osorio, A, Hopper, JL, Phillips, K-A, Milne, RL, Terry, MB, Nogues, C, Engel, C, Kast, K, Goldgar, DE, van Leeuwen, FE, Easton, DF, Andrieu, N, Rookus, MA, Schrijver, LH, Antoniou, AC, Olsson, H, Mooij, TM, Roos-Blom, M-J, Azarang, L, Adlard, J, Ahmed, M, Barrowdale, D, Davidson, R, Donaldson, A, Eeles, R, Evans, DG, Frost, D, Henderson, A, Izatt, L, Ong, K-R, Bonadona, V, Coupier, I, Faivre, L, Fricker, J-P, Gesta, P, van Engelen, K, Jager, A, Menko, FH, Mourits, MJE, Singer, CF, Tan, YY, Foretova, L, Navratilova, M, Schmutzler, RK, Ellberg, C, Gerdes, A-M, Caldes, T, Simard, J, Olah, E, Jakubowska, A, Rantala, J, Osorio, A, Hopper, JL, Phillips, K-A, Milne, RL, Terry, MB, Nogues, C, Engel, C, Kast, K, Goldgar, DE, van Leeuwen, FE, Easton, DF, Andrieu, N, and Rookus, MA
Abstract: BACKGROUND: Ovarian cancer risk in BRCA1 and BRCA2 mutation carriers has been shown to decrease with longer duration of oral contraceptive use. Although the effects of using oral contraceptives in the general population are well established (approximately 50% risk reduction in ovarian cancer), the estimated risk reduction in mutation carriers is much less precise because of potential bias and small sample sizes. In addition, only a few studies on oral contraceptive use have examined the associations of duration of use, time since last use, starting age, and calendar year of start with risk of ovarian cancer. OBJECTIVE: This study aimed to investigate in more detail the associations of various characteristics of oral contraceptive use and risk of ovarian cancer, to provide healthcare providers and carriers with better risk estimates. STUDY DESIGN: In this international retrospective study, ovarian cancer risk associations were assessed using oral contraceptives data on 3989 BRCA1 and 2445 BRCA2 mutation carriers. Age-dependent-weighted Cox regression analyses were stratified by study and birth cohort and included breast cancer diagnosis as a covariate. To minimize survival bias, analyses were left truncated at 5 years before baseline questionnaire. Separate analyses were conducted for each aspect of oral contraceptive use and in a multivariate analysis, including all these aspects. In addition, the analysis of duration of oral contraceptive use was stratified by recency of use. RESULTS: Oral contraceptives were less often used by mutation carriers who were diagnosed with ovarian cancer (ever use: 58.6% for BRCA1 and 53.5% BRCA2) than by unaffected carriers (ever use: 88.9% for BRCA1 and 80.7% for BRCA2). The median duration of use was 7 years for both BRCA1 and BRCA2 carriers who developed ovarian cancer and 9 and 8 years for unaffected BRCA1 and BRCA2 carriers with ovarian cancer, respectively. For BRCA1 mutation carriers, univariate analyses have shown that both a
Published: 2021

20. Prospective Evaluation of the Addition of Polygenic Risk Scores to Breast Cancer Risk Models

Author: Li, SX, Milne, RL, Nguyen-Dumont, T, Wang, X, English, DR, Giles, GG, Southey, MC, Antoniou, AC, Lee, A, Li, S, Winship, I, Hopper, JL, Terry, MB, MacInnis, RJ, Li, SX, Milne, RL, Nguyen-Dumont, T, Wang, X, English, DR, Giles, GG, Southey, MC, Antoniou, AC, Lee, A, Li, S, Winship, I, Hopper, JL, Terry, MB, and MacInnis, RJ
Abstract: BACKGROUND: The Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm and the International Breast Cancer Intervention Study breast cancer risk models are used to provide advice on screening intervals and chemoprevention. We evaluated the performance of these models, which now incorporate polygenic risk scores (PRSs), using a prospective cohort study. METHODS: We used a case-cohort design, involving women in the Melbourne Collaborative Cohort Study aged 50-75 years when surveyed in 2003-2007, of whom 408 had a first primary breast cancer diagnosed within 10 years (cases), and 2783 were from the subcohort. Ten-year risks were calculated based on lifestyle factors, family history data, and a 313-variant PRS. Discrimination was assessed using a C-statistic compared with 0.50 and calibration using the ratio of expected to observed number of cases (E/O). RESULTS: When the PRS was added to models with lifestyle factors and family history, the C-statistic (95% confidence interval [CI]) increased from 0.57 (0.54 to 0.60) to 0.62 (0.60 to 0.65) using IBIS and from 0.56 (0.53 to 0.59) to 0.62 (0.59 to 0.64) using BOADICEA. IBIS underpredicted risk (E/O = 0.62, 95% CI = 0.48 to 0.80) for women in the lowest risk category (<1.7%) and overpredicted risk (E/O = 1.40, 95% CI = 1.18 to 1.67) in the highest risk category (≥5%), using the Hosmer-Lemeshow test for calibration in quantiles of risk and a 2-sided P value less than .001. BOADICEA underpredicted risk (E/O = 0.82, 95% CI = 0.67 to 0.99) in the second highest risk category (3.4%-5%); the Hosmer-Lemeshow test and a 2-sided P value was equal to .02. CONCLUSIONS: Although the inclusion of a 313 genetic variant PRS doubles discriminatory accuracy (relative to reference 0.50), models with and without this PRS have relatively modest discrimination and might require recalibration before their clinical and wider use are promoted.
Published: 2021

21. Prospective Evaluation over 15 Years of Six Breast Cancer Risk Models

Author: Li, SX, Milne, RL, Nguyen-Dumont, T, English, DR, Giles, GG, Southey, MC, Antoniou, AC, Lee, A, Winship, I, Hopper, JL, Terry, MB, MacInnis, RJ, Li, SX, Milne, RL, Nguyen-Dumont, T, English, DR, Giles, GG, Southey, MC, Antoniou, AC, Lee, A, Winship, I, Hopper, JL, Terry, MB, and MacInnis, RJ
Abstract: Prospective validation of risk models is needed to assess their clinical utility, particularly over the longer term. We evaluated the performance of six commonly used breast cancer risk models (IBIS, BOADICEA, BRCAPRO, BRCAPRO-BCRAT, BCRAT, and iCARE-lit). 15-year risk scores were estimated using lifestyle factors and family history measures from 7608 women in the Melbourne Collaborative Cohort Study who were aged 50-65 years and unaffected at commencement of follow-up two (conducted in 2003-2007), of whom 351 subsequently developed breast cancer. Risk discrimination was assessed using the C-statistic and calibration using the expected/observed number of incident cases across the spectrum of risk by age group (50-54, 55-59, 60-65 years) and family history of breast cancer. C-statistics were higher for BOADICEA (0.59, 95% confidence interval (CI) 0.56-0.62) and IBIS (0.57, 95% CI 0.54-0.61) than the other models (p-difference ≤ 0.04). No model except BOADICEA calibrated well across the spectrum of 15-year risk (p-value < 0.03). The performance of BOADICEA and IBIS was similar across age groups and for women with or without a family history. For middle-aged Australian women, BOADICEA and IBIS had the highest discriminatory accuracy of the six risk models, but apart from BOADICEA, no model was well-calibrated across the risk spectrum.
Published: 2021

22. Association of germline genetic variants with breast cancer-specific survival in patient subgroups defined by clinic-pathological variables related to tumor biology and type of systemic treatment

Author: Morra, A, Escala-Garcia, M, Beesley, J, Keeman, R, Canisius, S, Ahearn, TU, Andrulis, IL, Anton-Culver, H, Arndt, V, Auer, PL, Augustinsson, A, Freeman, LEB, Becher, H, Beckmann, MW, Behrens, S, Bojesen, SE, Bolla, MK, Brenner, H, Bruening, T, Buys, SS, Caan, B, Campa, D, Canzian, F, Castelao, JE, Chang-Claude, J, Chanock, SJ, Cheng, T-YD, Clarke, CL, Colonna, S, Couch, FJ, Cox, A, Cross, SS, Czene, K, Daly, MB, Dennis, J, Dork, T, Dossus, L, Dunning, AM, Dwek, M, Eccles, DM, Ekici, AB, Eliassen, AH, Eriksson, M, Evans, DG, Fasching, PA, Flyger, H, Fritschi, L, Gago-Dominguez, M, Garcia-Saenz, JA, Giles, GG, Grip, M, Guenel, P, Guendert, M, Hahnen, E, Haiman, CA, Hakansson, N, Hall, P, Hamann, U, Hart, SN, Hartikainen, JM, Hartmann, A, He, W, Hooning, MJ, Hoppe, R, Hopper, JL, Howell, A, Hunter, DJ, Jager, A, Jakubowska, A, Janni, W, John, EM, Jung, AY, Kaaks, R, Keupers, M, Kitahara, CM, Koutros, S, Kraft, P, Kristensen, VN, Kurian, AW, Lacey, J, Lambrechts, D, Le Marchand, L, Lindblom, A, Linet, M, Luben, RN, Lush, M, Mannermaa, A, Manoochehri, M, Margolin, S, Martens, JWM, Martinez, ME, Mavroudis, D, Michailidou, K, Milne, RL, Mulligan, AM, Muranen, TA, Nevanlinna, H, Newman, WG, Nielsen, SF, Nordestgaard, BG, Olshan, AF, Olsson, H, Orr, N, Park-Simon, T-W, Patel, A, Peissel, B, Peterlongo, P, Plaseska-Karanfilska, D, Prajzendanc, K, Prentice, R, Presneau, N, Rack, B, Rennert, G, Rennert, HS, Rhenius, V, Romero, A, Roylance, R, Lubinski, J, Ruebner, M, Saloustros, E, Sawyer, EJ, Schmutzler, RK, Schneeweiss, A, Scott, C, Shah, M, Smichkoska, S, Southey, MC, Stone, J, Surowy, H, Swerdlow, AJ, Tamimi, RM, Tapper, WJ, Teras, LR, Terry, MB, Tollenaar, RAEM, Tomlinson, I, Troester, MA, Truong, T, Vachon, CM, Wang, Q, Hurson, AN, Winqvist, R, Wolk, A, Ziogas, A, Brauch, H, Garcia-Closas, M, Pharoah, PDP, Easton, DF, Chenevix-Trench, G, Schmidt, MK, Morra, A, Escala-Garcia, M, Beesley, J, Keeman, R, Canisius, S, Ahearn, TU, Andrulis, IL, Anton-Culver, H, Arndt, V, Auer, PL, Augustinsson, A, Freeman, LEB, Becher, H, Beckmann, MW, Behrens, S, Bojesen, SE, Bolla, MK, Brenner, H, Bruening, T, Buys, SS, Caan, B, Campa, D, Canzian, F, Castelao, JE, Chang-Claude, J, Chanock, SJ, Cheng, T-YD, Clarke, CL, Colonna, S, Couch, FJ, Cox, A, Cross, SS, Czene, K, Daly, MB, Dennis, J, Dork, T, Dossus, L, Dunning, AM, Dwek, M, Eccles, DM, Ekici, AB, Eliassen, AH, Eriksson, M, Evans, DG, Fasching, PA, Flyger, H, Fritschi, L, Gago-Dominguez, M, Garcia-Saenz, JA, Giles, GG, Grip, M, Guenel, P, Guendert, M, Hahnen, E, Haiman, CA, Hakansson, N, Hall, P, Hamann, U, Hart, SN, Hartikainen, JM, Hartmann, A, He, W, Hooning, MJ, Hoppe, R, Hopper, JL, Howell, A, Hunter, DJ, Jager, A, Jakubowska, A, Janni, W, John, EM, Jung, AY, Kaaks, R, Keupers, M, Kitahara, CM, Koutros, S, Kraft, P, Kristensen, VN, Kurian, AW, Lacey, J, Lambrechts, D, Le Marchand, L, Lindblom, A, Linet, M, Luben, RN, Lush, M, Mannermaa, A, Manoochehri, M, Margolin, S, Martens, JWM, Martinez, ME, Mavroudis, D, Michailidou, K, Milne, RL, Mulligan, AM, Muranen, TA, Nevanlinna, H, Newman, WG, Nielsen, SF, Nordestgaard, BG, Olshan, AF, Olsson, H, Orr, N, Park-Simon, T-W, Patel, A, Peissel, B, Peterlongo, P, Plaseska-Karanfilska, D, Prajzendanc, K, Prentice, R, Presneau, N, Rack, B, Rennert, G, Rennert, HS, Rhenius, V, Romero, A, Roylance, R, Lubinski, J, Ruebner, M, Saloustros, E, Sawyer, EJ, Schmutzler, RK, Schneeweiss, A, Scott, C, Shah, M, Smichkoska, S, Southey, MC, Stone, J, Surowy, H, Swerdlow, AJ, Tamimi, RM, Tapper, WJ, Teras, LR, Terry, MB, Tollenaar, RAEM, Tomlinson, I, Troester, MA, Truong, T, Vachon, CM, Wang, Q, Hurson, AN, Winqvist, R, Wolk, A, Ziogas, A, Brauch, H, Garcia-Closas, M, Pharoah, PDP, Easton, DF, Chenevix-Trench, G, and Schmidt, MK
Abstract: BACKGROUND: Given the high heterogeneity among breast tumors, associations between common germline genetic variants and survival that may exist within specific subgroups could go undetected in an unstratified set of breast cancer patients. METHODS: We performed genome-wide association analyses within 15 subgroups of breast cancer patients based on prognostic factors, including hormone receptors, tumor grade, age, and type of systemic treatment. Analyses were based on 91,686 female patients of European ancestry from the Breast Cancer Association Consortium, including 7531 breast cancer-specific deaths over a median follow-up of 8.1 years. Cox regression was used to assess associations of common germline variants with 15-year and 5-year breast cancer-specific survival. We assessed the probability of these associations being true positives via the Bayesian false discovery probability (BFDP < 0.15). RESULTS: Evidence of associations with breast cancer-specific survival was observed in three patient subgroups, with variant rs5934618 in patients with grade 3 tumors (15-year-hazard ratio (HR) [95% confidence interval (CI)] 1.32 [1.20, 1.45], P = 1.4E-08, BFDP = 0.01, per G allele); variant rs4679741 in patients with ER-positive tumors treated with endocrine therapy (15-year-HR [95% CI] 1.18 [1.11, 1.26], P = 1.6E-07, BFDP = 0.09, per G allele); variants rs1106333 (15-year-HR [95% CI] 1.68 [1.39,2.03], P = 5.6E-08, BFDP = 0.12, per A allele) and rs78754389 (5-year-HR [95% CI] 1.79 [1.46,2.20], P = 1.7E-08, BFDP = 0.07, per A allele), in patients with ER-negative tumors treated with chemotherapy. CONCLUSIONS: We found evidence of four loci associated with breast cancer-specific survival within three patient subgroups. There was limited evidence for the existence of associations in other patient subgroups. However, the power for many subgroups is limited due to the low number of events. Even so, our results suggest that the impact of common germline genetic variants on breast
Published: 2021

23. A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers (vol 12, 1078, 2021)

Author: Coignard, J, Lush, M, Beesley, J, O'Mara, TA, Dennis, J, Tyrer, JP, Barnes, DR, McGuffog, L, Leslie, G, Bolla, MK, Adank, MA, Agata, S, Ahearn, T, Aittomaki, K, Andrulis, IL, Anton-Culver, H, Arndt, V, Arnold, N, Aronson, KJ, Arun, BK, Augustinsson, A, Azzollini, J, Barrowdale, D, Baynes, C, Becher, H, Bermisheva, M, Bernstein, L, Bialkowska, K, Blomqvist, C, Bojesen, SE, Bonanni, B, Borg, A, Brauch, H, Brenner, H, Burwinkel, B, Buys, SS, Caldes, T, Caligo, MA, Campa, D, Carter, BD, Castelao, JE, Chang-Claude, J, Chanock, SJ, Chung, WK, Claes, KBM, Clarke, CL, Collee, JM, Conroy, DM, Czene, K, Daly, MB, Devilee, P, Diez, O, Ding, YC, Domchek, SM, Doerk, T, dos-Santos-Silva, I, Dunning, AM, Dwek, M, Eccles, DM, Eliassen, AH, Engel, C, Eriksson, M, Evans, DG, Fasching, PA, Flyger, H, Fostira, F, Friedman, E, Fritschi, L, Frost, D, Gago-Dominguez, M, Gapstur, SM, Garber, J, Garcia-Barberan, V, Garcia-Closas, M, Garcia-Saenz, JA, Gaudet, MM, Gayther, SA, Gehrig, A, Georgoulias, V, Giles, GG, Godwin, AK, Goldberg, MS, Goldgar, DE, Gonzalez-Neira, A, Greene, MH, Guenel, P, Haeberle, L, Hahnen, E, Haiman, CA, Hakansson, N, Hall, P, Hamann, U, Harrington, PA, Hart, SN, He, W, Hogervorst, FBL, Hollestelle, A, Hopper, JL, Horcasitas, DJ, Hulick, PJ, Hunter, DJ, Imyanitov, EN, Fox, S, van der Hout, AH, Clarke, C, Jager, A, Jakubowska, A, James, PA, Jensen, UB, John, EM, Jones, ME, Kaaks, R, Kapoor, PM, Karlan, BY, Keeman, R, Khusnutdinova, E, Kiiski, JI, Ko, Y-D, Kosma, V-M, Kraft, P, Kurian, AW, Laitman, Y, Lambrechts, D, Le Marchand, L, Lester, J, Lesueur, F, Lindstrom, T, Lopez-Fernandez, A, Loud, JT, Luccarini, C, Mannermaa, A, Manoukian, S, Margolin, S, Martens, JWM, Mebirouk, N, Meindl, A, Miller, A, Milne, RL, Montagna, M, Nathanson, KL, Neuhausen, SL, Nevanlinna, H, Nielsen, FC, O'Brien, KM, Olopade, OI, Olson, JE, Olsson, H, Osorio, A, Ottini, L, Park-Simon, T-W, Parsons, MT, Pedersen, IS, Peshkin, B, Peterlongo, P, Peto, J, Pharoah, PDP, Phillips, K-A, Polley, EC, Poppe, B, Presneau, N, Pujana, MA, Punie, K, Radice, P, Rantala, J, Rashid, MU, Rennert, G, Rennert, HS, Robson, M, Romero, A, Rossing, M, Saloustros, E, Sandler, DP, Santella, R, Scheuner, MT, Schmidt, MK, Schmidt, G, Scott, C, Sharma, P, Soucy, P, Southey, MC, Spinelli, JJ, Steinsnyder, Z, Stone, J, Stoppa-Lyonnet, D, Swerdlow, A, Tamimi, RM, Tapper, WJ, Taylor, JA, Terry, MB, Teule, A, Thull, DL, Tischkowitz, M, Toland, AE, Torres, D, Trainer, AH, Truong, T, Tung, N, Vachon, CM, Vega, A, Vijai, J, Wang, Q, Wappenschmidt, B, Weinberg, CR, Weitzel, JN, Wendt, C, Wolk, A, Yadav, S, Yang, XR, Yannoukakos, D, Zheng, W, Ziogas, A, Zorn, KK, Park, SK, Thomassen, M, Offit, K, Schmutzler, RK, Couch, FJ, Simard, J, Chenevix-Trench, G, Easton, DF, Andrieu, N, Antoniou, AC, Coignard, J, Lush, M, Beesley, J, O'Mara, TA, Dennis, J, Tyrer, JP, Barnes, DR, McGuffog, L, Leslie, G, Bolla, MK, Adank, MA, Agata, S, Ahearn, T, Aittomaki, K, Andrulis, IL, Anton-Culver, H, Arndt, V, Arnold, N, Aronson, KJ, Arun, BK, Augustinsson, A, Azzollini, J, Barrowdale, D, Baynes, C, Becher, H, Bermisheva, M, Bernstein, L, Bialkowska, K, Blomqvist, C, Bojesen, SE, Bonanni, B, Borg, A, Brauch, H, Brenner, H, Burwinkel, B, Buys, SS, Caldes, T, Caligo, MA, Campa, D, Carter, BD, Castelao, JE, Chang-Claude, J, Chanock, SJ, Chung, WK, Claes, KBM, Clarke, CL, Collee, JM, Conroy, DM, Czene, K, Daly, MB, Devilee, P, Diez, O, Ding, YC, Domchek, SM, Doerk, T, dos-Santos-Silva, I, Dunning, AM, Dwek, M, Eccles, DM, Eliassen, AH, Engel, C, Eriksson, M, Evans, DG, Fasching, PA, Flyger, H, Fostira, F, Friedman, E, Fritschi, L, Frost, D, Gago-Dominguez, M, Gapstur, SM, Garber, J, Garcia-Barberan, V, Garcia-Closas, M, Garcia-Saenz, JA, Gaudet, MM, Gayther, SA, Gehrig, A, Georgoulias, V, Giles, GG, Godwin, AK, Goldberg, MS, Goldgar, DE, Gonzalez-Neira, A, Greene, MH, Guenel, P, Haeberle, L, Hahnen, E, Haiman, CA, Hakansson, N, Hall, P, Hamann, U, Harrington, PA, Hart, SN, He, W, Hogervorst, FBL, Hollestelle, A, Hopper, JL, Horcasitas, DJ, Hulick, PJ, Hunter, DJ, Imyanitov, EN, Fox, S, van der Hout, AH, Clarke, C, Jager, A, Jakubowska, A, James, PA, Jensen, UB, John, EM, Jones, ME, Kaaks, R, Kapoor, PM, Karlan, BY, Keeman, R, Khusnutdinova, E, Kiiski, JI, Ko, Y-D, Kosma, V-M, Kraft, P, Kurian, AW, Laitman, Y, Lambrechts, D, Le Marchand, L, Lester, J, Lesueur, F, Lindstrom, T, Lopez-Fernandez, A, Loud, JT, Luccarini, C, Mannermaa, A, Manoukian, S, Margolin, S, Martens, JWM, Mebirouk, N, Meindl, A, Miller, A, Milne, RL, Montagna, M, Nathanson, KL, Neuhausen, SL, Nevanlinna, H, Nielsen, FC, O'Brien, KM, Olopade, OI, Olson, JE, Olsson, H, Osorio, A, Ottini, L, Park-Simon, T-W, Parsons, MT, Pedersen, IS, Peshkin, B, Peterlongo, P, Peto, J, Pharoah, PDP, Phillips, K-A, Polley, EC, Poppe, B, Presneau, N, Pujana, MA, Punie, K, Radice, P, Rantala, J, Rashid, MU, Rennert, G, Rennert, HS, Robson, M, Romero, A, Rossing, M, Saloustros, E, Sandler, DP, Santella, R, Scheuner, MT, Schmidt, MK, Schmidt, G, Scott, C, Sharma, P, Soucy, P, Southey, MC, Spinelli, JJ, Steinsnyder, Z, Stone, J, Stoppa-Lyonnet, D, Swerdlow, A, Tamimi, RM, Tapper, WJ, Taylor, JA, Terry, MB, Teule, A, Thull, DL, Tischkowitz, M, Toland, AE, Torres, D, Trainer, AH, Truong, T, Tung, N, Vachon, CM, Vega, A, Vijai, J, Wang, Q, Wappenschmidt, B, Weinberg, CR, Weitzel, JN, Wendt, C, Wolk, A, Yadav, S, Yang, XR, Yannoukakos, D, Zheng, W, Ziogas, A, Zorn, KK, Park, SK, Thomassen, M, Offit, K, Schmutzler, RK, Couch, FJ, Simard, J, Chenevix-Trench, G, Easton, DF, Andrieu, N, and Antoniou, AC
Abstract: Breast cancer (BC) risk for BRCA1 and BRCA2 mutation carriers varies by genetic and familial factors. About 50 common variants have been shown to modify BC risk for mutation carriers. All but three, were identified in general population studies. Other mutation carrier-specific susceptibility variants may exist but studies of mutation carriers have so far been underpowered. We conduct a novel case-only genome-wide association study comparing genotype frequencies between 60,212 general population BC cases and 13,007 cases with BRCA1 or BRCA2 mutations. We identify robust novel associations for 2 variants with BC for BRCA1 and 3 for BRCA2 mutation carriers, P < 10-8, at 5 loci, which are not associated with risk in the general population. They include rs60882887 at 11p11.2 where MADD, SP11 and EIF1, genes previously implicated in BC biology, are predicted as potential targets. These findings will contribute towards customising BC polygenic risk scores for BRCA1 and BRCA2 mutation carriers.
Published: 2021

24. Functional annotation of the 2q35 breast cancer risk locus implicates a structural variant in influencing activity of a long-range enhancer element

Author: Baxter, JS, Johnson, N, Tomczyk, K, Gillespie, A, Maguire, S, Brough, R, Fachal, L, Michailidou, K, Bolla, MK, Wang, Q, Dennis, J, Ahearn, TU, Andrulis, IL, Anton-Culver, H, Antonenkova, NN, Arndt, V, Aronson, KJ, Augustinsson, A, Becher, H, Beckmann, MW, Behrens, S, Benitez, J, Bermisheva, M, Bogdanova, N, Bojesen, SE, Brenner, H, Brucker, SY, Cai, Q, Campa, D, Canzian, F, Castelao, JE, Chan, TL, Chang-Claude, J, Chanock, SJ, Chenevix-Trench, G, Choi, J-Y, Clarke, CL, Collaborators, N, Colonna, S, Conroy, DM, Couch, FJ, Cox, A, Cross, SS, Czene, K, Daly, MB, Devilee, P, Doerk, T, Dossus, L, Dwek, M, Eccles, DM, Ekici, AB, Eliassen, AH, Engel, C, Fasching, PA, Figueroa, J, Flyger, H, Gago-Dominguez, M, Gao, C, Garcia-Closas, M, Garcia-Saenz, JA, Ghoussaini, M, Giles, GG, Goldberg, MS, Gonzalez-Neira, A, Guenel, P, Guendert, M, Haeberle, L, Hahnen, E, Haiman, CA, Hall, P, Hamann, U, Hartman, M, Hatse, S, Hauke, J, Hollestelle, A, Hoppe, R, Hopper, JL, Hou, M-F, Ito, H, Iwasaki, M, Jager, A, Jakubowska, A, Janni, W, John, EM, Joseph, V, Jung, A, Kaaks, R, Kang, D, Keeman, R, Khusnutdinova, E, Kim, S-W, Kosma, V-M, Kraft, P, Kristensen, VN, Kubelka-Sabit, K, Kurian, AW, Kwong, A, Lacey, J, Lambrechts, D, Larson, NL, Larsson, SC, Le Marchand, L, Lejbkowicz, F, Li, J, Long, J, Lophatananon, A, LubiNski, J, Mannermaa, A, Manoochehri, M, Manoukian, S, Margolin, S, Matsuo, K, Mavroudis, D, Mayes, R, Menon, U, Milne, RL, Taib, NAM, Muir, K, Muranen, TA, Murphy, RA, Nevanlinna, H, O'Brien, KM, Offit, K, Olson, JE, Olsson, H, Park, SK, Park-Simon, T-W, Patel, A, Peterlongo, P, Peto, J, Plaseska-Karanfilska, D, Presneau, N, Pylkas, K, Rack, B, Rennert, G, Romero, A, Ruebner, M, Ruediger, T, Saloustros, E, Sandler, DP, Sawyer, EJ, Schmidt, MK, Schmutzler, RK, Schneeweiss, A, Schoemaker, MJ, Shah, M, Shen, C-Y, Shu, X-O, Simard, J, Southey, MC, Stone, J, Surowy, H, Swerdlow, AJ, Tamimi, RM, Tapper, WJ, Taylor, JA, Teo, SH, Teras, LR, Terry, MB, Toland, AE, Tomlinson, I, Truong, T, Tseng, C-C, Untch, M, Vachon, CM, van den Ouweland, AMW, Wang, SS, Weinberg, CR, Wendt, C, Winham, SJ, Winqvist, R, Wolk, A, Wu, AH, Yamaji, T, Zheng, W, Ziogas, A, Pharoah, PDP, Dunning, AM, Easton, DF, Pettitt, SJ, Lord, CJ, Haider, S, Orr, N, Fletcher, O, Baxter, JS, Johnson, N, Tomczyk, K, Gillespie, A, Maguire, S, Brough, R, Fachal, L, Michailidou, K, Bolla, MK, Wang, Q, Dennis, J, Ahearn, TU, Andrulis, IL, Anton-Culver, H, Antonenkova, NN, Arndt, V, Aronson, KJ, Augustinsson, A, Becher, H, Beckmann, MW, Behrens, S, Benitez, J, Bermisheva, M, Bogdanova, N, Bojesen, SE, Brenner, H, Brucker, SY, Cai, Q, Campa, D, Canzian, F, Castelao, JE, Chan, TL, Chang-Claude, J, Chanock, SJ, Chenevix-Trench, G, Choi, J-Y, Clarke, CL, Collaborators, N, Colonna, S, Conroy, DM, Couch, FJ, Cox, A, Cross, SS, Czene, K, Daly, MB, Devilee, P, Doerk, T, Dossus, L, Dwek, M, Eccles, DM, Ekici, AB, Eliassen, AH, Engel, C, Fasching, PA, Figueroa, J, Flyger, H, Gago-Dominguez, M, Gao, C, Garcia-Closas, M, Garcia-Saenz, JA, Ghoussaini, M, Giles, GG, Goldberg, MS, Gonzalez-Neira, A, Guenel, P, Guendert, M, Haeberle, L, Hahnen, E, Haiman, CA, Hall, P, Hamann, U, Hartman, M, Hatse, S, Hauke, J, Hollestelle, A, Hoppe, R, Hopper, JL, Hou, M-F, Ito, H, Iwasaki, M, Jager, A, Jakubowska, A, Janni, W, John, EM, Joseph, V, Jung, A, Kaaks, R, Kang, D, Keeman, R, Khusnutdinova, E, Kim, S-W, Kosma, V-M, Kraft, P, Kristensen, VN, Kubelka-Sabit, K, Kurian, AW, Kwong, A, Lacey, J, Lambrechts, D, Larson, NL, Larsson, SC, Le Marchand, L, Lejbkowicz, F, Li, J, Long, J, Lophatananon, A, LubiNski, J, Mannermaa, A, Manoochehri, M, Manoukian, S, Margolin, S, Matsuo, K, Mavroudis, D, Mayes, R, Menon, U, Milne, RL, Taib, NAM, Muir, K, Muranen, TA, Murphy, RA, Nevanlinna, H, O'Brien, KM, Offit, K, Olson, JE, Olsson, H, Park, SK, Park-Simon, T-W, Patel, A, Peterlongo, P, Peto, J, Plaseska-Karanfilska, D, Presneau, N, Pylkas, K, Rack, B, Rennert, G, Romero, A, Ruebner, M, Ruediger, T, Saloustros, E, Sandler, DP, Sawyer, EJ, Schmidt, MK, Schmutzler, RK, Schneeweiss, A, Schoemaker, MJ, Shah, M, Shen, C-Y, Shu, X-O, Simard, J, Southey, MC, Stone, J, Surowy, H, Swerdlow, AJ, Tamimi, RM, Tapper, WJ, Taylor, JA, Teo, SH, Teras, LR, Terry, MB, Toland, AE, Tomlinson, I, Truong, T, Tseng, C-C, Untch, M, Vachon, CM, van den Ouweland, AMW, Wang, SS, Weinberg, CR, Wendt, C, Winham, SJ, Winqvist, R, Wolk, A, Wu, AH, Yamaji, T, Zheng, W, Ziogas, A, Pharoah, PDP, Dunning, AM, Easton, DF, Pettitt, SJ, Lord, CJ, Haider, S, Orr, N, and Fletcher, O
Abstract: A combination of genetic and functional approaches has identified three independent breast cancer risk loci at 2q35. A recent fine-scale mapping analysis to refine these associations resulted in 1 (signal 1), 5 (signal 2), and 42 (signal 3) credible causal variants at these loci. We used publicly available in silico DNase I and ChIP-seq data with in vitro reporter gene and CRISPR assays to annotate signals 2 and 3. We identified putative regulatory elements that enhanced cell-type-specific transcription from the IGFBP5 promoter at both signals (30- to 40-fold increased expression by the putative regulatory element at signal 2, 2- to 3-fold by the putative regulatory element at signal 3). We further identified one of the five credible causal variants at signal 2, a 1.4 kb deletion (esv3594306), as the likely causal variant; the deletion allele of this variant was associated with an average additional increase in IGFBP5 expression of 1.3-fold (MCF-7) and 2.2-fold (T-47D). We propose a model in which the deletion allele of esv3594306 juxtaposes two transcription factor binding regions (annotated by estrogen receptor alpha ChIP-seq peaks) to generate a single extended regulatory element. This regulatory element increases cell-type-specific expression of the tumor suppressor gene IGFBP5 and, thereby, reduces risk of estrogen receptor-positive breast cancer (odds ratio = 0.77, 95% CI 0.74-0.81, p = 3.1 × 10-31).
Published: 2021

25. A competing risks model with binary time varying covariates for estimation of breast cancer risks in BRCA1 families

Author: Choi, Y-H, Jung, H, Buys, S, Daly, M, John, EM, Hopper, J, Andrulis, I, Terry, MB, Briollais, L, Choi, Y-H, Jung, H, Buys, S, Daly, M, John, EM, Hopper, J, Andrulis, I, Terry, MB, and Briollais, L
Abstract: Mammographic screening and prophylactic surgery such as risk-reducing salpingo oophorectomy can potentially reduce breast cancer risks among mutation carriers of BRCA families. The evaluation of these interventions is usually complicated by the fact that their effects on breast cancer may change over time and by the presence of competing risks. We introduce a correlated competing risks model to model breast and ovarian cancer risks within BRCA1 families that accounts for time-varying covariates. Different parametric forms for the effects of time-varying covariates are proposed for more flexibility and a correlated gamma frailty model is specified to account for the correlated competing events.We also introduce a new ascertainment correction approach that accounts for the selection of families through probands affected with either breast or ovarian cancer, or unaffected. Our simulation studies demonstrate the good performances of our proposed approach in terms of bias and precision of the estimators of model parameters and cause-specific penetrances over different levels of familial correlations. We applied our new approach to 498 BRCA1 mutation carrier families recruited through the Breast Cancer Family Registry. Our results demonstrate the importance of the functional form of the time-varying covariate effect when assessing the role of risk-reducing salpingo oophorectomy on breast cancer. In particular, under the best fitting time-varying covariate model, the overall effect of risk-reducing salpingo oophorectomy on breast cancer risk was statistically significant in women with BRCA1 mutation.
Published: 2021

26. A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers.

Author: Coignard, J, Lush, M, Beesley, J, O'Mara, TA, Dennis, J, Tyrer, JP, Barnes, DR, McGuffog, L, Leslie, G, Bolla, MK, Adank, MA, Agata, S, Ahearn, T, Aittomäki, K, Andrulis, IL, Anton-Culver, H, Arndt, V, Arnold, N, Aronson, KJ, Arun, BK, Augustinsson, A, Azzollini, J, Barrowdale, D, Baynes, C, Becher, H, Bermisheva, M, Bernstein, L, Białkowska, K, Blomqvist, C, Bojesen, SE, Bonanni, B, Borg, A, Brauch, H, Brenner, H, Burwinkel, B, Buys, SS, Caldés, T, Caligo, MA, Campa, D, Carter, BD, Castelao, JE, Chang-Claude, J, Chanock, SJ, Chung, WK, Claes, KBM, Clarke, CL, GEMO Study Collaborators, EMBRACE Collaborators, Collée, JM, Conroy, DM, Czene, K, Daly, MB, Devilee, P, Diez, O, Ding, YC, Domchek, SM, Dörk, T, Dos-Santos-Silva, I, Dunning, AM, Dwek, M, Eccles, DM, Eliassen, AH, Engel, C, Eriksson, M, Evans, DG, Fasching, PA, Flyger, H, Fostira, F, Friedman, E, Fritschi, L, Frost, D, Gago-Dominguez, M, Gapstur, SM, Garber, J, Garcia-Barberan, V, García-Closas, M, García-Sáenz, JA, Gaudet, MM, Gayther, SA, Gehrig, A, Georgoulias, V, Giles, GG, Godwin, AK, Goldberg, MS, Goldgar, DE, González-Neira, A, Greene, MH, Guénel, P, Haeberle, L, Hahnen, E, Haiman, CA, Håkansson, N, Hall, P, Hamann, U, Harrington, PA, Hart, SN, He, W, Hogervorst, FBL, Hollestelle, A, Hopper, JL, Horcasitas, DJ, Hulick, PJ, Hunter, DJ, Imyanitov, EN, KConFab Investigators, HEBON Investigators, ABCTB Investigators, Jager, A, Jakubowska, A, James, PA, Jensen, UB, John, EM, Jones, ME, Kaaks, R, Kapoor, PM, Karlan, BY, Keeman, R, Khusnutdinova, E, Kiiski, JI, Ko, Y-D, Kosma, V-M, Kraft, P, Kurian, AW, Laitman, Y, Lambrechts, D, Le Marchand, L, Lester, J, Lesueur, F, Lindstrom, T, Lopez-Fernández, A, Loud, JT, Luccarini, C, Mannermaa, A, Manoukian, S, Margolin, S, Martens, JWM, Mebirouk, N, Meindl, A, Miller, A, Milne, RL, Montagna, M, Nathanson, KL, Neuhausen, SL, Nevanlinna, H, Nielsen, FC, O'Brien, KM, Olopade, OI, Olson, JE, Olsson, H, Osorio, A, Ottini, L, Park-Simon, T-W, Parsons, MT, Pedersen, IS, Peshkin, B, Peterlongo, P, Peto, J, Pharoah, PDP, Phillips, K-A, Polley, EC, Poppe, B, Presneau, N, Pujana, MA, Punie, K, Radice, P, Rantala, J, Rashid, MU, Rennert, G, Rennert, HS, Robson, M, Romero, A, Rossing, M, Saloustros, E, Sandler, DP, Santella, R, Scheuner, MT, Schmidt, MK, Schmidt, G, Scott, C, Sharma, P, Soucy, P, Southey, MC, Spinelli, JJ, Steinsnyder, Z, Stone, J, Stoppa-Lyonnet, D, Swerdlow, A, Tamimi, RM, Tapper, WJ, Taylor, JA, Terry, MB, Teulé, A, Thull, DL, Tischkowitz, M, Toland, AE, Torres, D, Trainer, AH, Truong, T, Tung, N, Vachon, CM, Vega, A, Vijai, J, Wang, Q, Wappenschmidt, B, Weinberg, CR, Weitzel, JN, Wendt, C, Wolk, A, Yadav, S, Yang, XR, Yannoukakos, D, Zheng, W, Ziogas, A, Zorn, KK, Park, SK, Thomassen, M, Offit, K, Schmutzler, RK, Couch, FJ, Simard, J, Chenevix-Trench, G, Easton, DF, Andrieu, N, Antoniou, AC, Coignard, J, Lush, M, Beesley, J, O'Mara, TA, Dennis, J, Tyrer, JP, Barnes, DR, McGuffog, L, Leslie, G, Bolla, MK, Adank, MA, Agata, S, Ahearn, T, Aittomäki, K, Andrulis, IL, Anton-Culver, H, Arndt, V, Arnold, N, Aronson, KJ, Arun, BK, Augustinsson, A, Azzollini, J, Barrowdale, D, Baynes, C, Becher, H, Bermisheva, M, Bernstein, L, Białkowska, K, Blomqvist, C, Bojesen, SE, Bonanni, B, Borg, A, Brauch, H, Brenner, H, Burwinkel, B, Buys, SS, Caldés, T, Caligo, MA, Campa, D, Carter, BD, Castelao, JE, Chang-Claude, J, Chanock, SJ, Chung, WK, Claes, KBM, Clarke, CL, GEMO Study Collaborators, EMBRACE Collaborators, Collée, JM, Conroy, DM, Czene, K, Daly, MB, Devilee, P, Diez, O, Ding, YC, Domchek, SM, Dörk, T, Dos-Santos-Silva, I, Dunning, AM, Dwek, M, Eccles, DM, Eliassen, AH, Engel, C, Eriksson, M, Evans, DG, Fasching, PA, Flyger, H, Fostira, F, Friedman, E, Fritschi, L, Frost, D, Gago-Dominguez, M, Gapstur, SM, Garber, J, Garcia-Barberan, V, García-Closas, M, García-Sáenz, JA, Gaudet, MM, Gayther, SA, Gehrig, A, Georgoulias, V, Giles, GG, Godwin, AK, Goldberg, MS, Goldgar, DE, González-Neira, A, Greene, MH, Guénel, P, Haeberle, L, Hahnen, E, Haiman, CA, Håkansson, N, Hall, P, Hamann, U, Harrington, PA, Hart, SN, He, W, Hogervorst, FBL, Hollestelle, A, Hopper, JL, Horcasitas, DJ, Hulick, PJ, Hunter, DJ, Imyanitov, EN, KConFab Investigators, HEBON Investigators, ABCTB Investigators, Jager, A, Jakubowska, A, James, PA, Jensen, UB, John, EM, Jones, ME, Kaaks, R, Kapoor, PM, Karlan, BY, Keeman, R, Khusnutdinova, E, Kiiski, JI, Ko, Y-D, Kosma, V-M, Kraft, P, Kurian, AW, Laitman, Y, Lambrechts, D, Le Marchand, L, Lester, J, Lesueur, F, Lindstrom, T, Lopez-Fernández, A, Loud, JT, Luccarini, C, Mannermaa, A, Manoukian, S, Margolin, S, Martens, JWM, Mebirouk, N, Meindl, A, Miller, A, Milne, RL, Montagna, M, Nathanson, KL, Neuhausen, SL, Nevanlinna, H, Nielsen, FC, O'Brien, KM, Olopade, OI, Olson, JE, Olsson, H, Osorio, A, Ottini, L, Park-Simon, T-W, Parsons, MT, Pedersen, IS, Peshkin, B, Peterlongo, P, Peto, J, Pharoah, PDP, Phillips, K-A, Polley, EC, Poppe, B, Presneau, N, Pujana, MA, Punie, K, Radice, P, Rantala, J, Rashid, MU, Rennert, G, Rennert, HS, Robson, M, Romero, A, Rossing, M, Saloustros, E, Sandler, DP, Santella, R, Scheuner, MT, Schmidt, MK, Schmidt, G, Scott, C, Sharma, P, Soucy, P, Southey, MC, Spinelli, JJ, Steinsnyder, Z, Stone, J, Stoppa-Lyonnet, D, Swerdlow, A, Tamimi, RM, Tapper, WJ, Taylor, JA, Terry, MB, Teulé, A, Thull, DL, Tischkowitz, M, Toland, AE, Torres, D, Trainer, AH, Truong, T, Tung, N, Vachon, CM, Vega, A, Vijai, J, Wang, Q, Wappenschmidt, B, Weinberg, CR, Weitzel, JN, Wendt, C, Wolk, A, Yadav, S, Yang, XR, Yannoukakos, D, Zheng, W, Ziogas, A, Zorn, KK, Park, SK, Thomassen, M, Offit, K, Schmutzler, RK, Couch, FJ, Simard, J, Chenevix-Trench, G, Easton, DF, Andrieu, N, and Antoniou, AC
Abstract: Breast cancer (BC) risk for BRCA1 and BRCA2 mutation carriers varies by genetic and familial factors. About 50 common variants have been shown to modify BC risk for mutation carriers. All but three, were identified in general population studies. Other mutation carrier-specific susceptibility variants may exist but studies of mutation carriers have so far been underpowered. We conduct a novel case-only genome-wide association study comparing genotype frequencies between 60,212 general population BC cases and 13,007 cases with BRCA1 or BRCA2 mutations. We identify robust novel associations for 2 variants with BC for BRCA1 and 3 for BRCA2 mutation carriers, P < 10-8, at 5 loci, which are not associated with risk in the general population. They include rs60882887 at 11p11.2 where MADD, SP11 and EIF1, genes previously implicated in BC biology, are predicted as potential targets. These findings will contribute towards customising BC polygenic risk scores for BRCA1 and BRCA2 mutation carriers.
Published: 2021

27. Author Correction: A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers.

Author: Coignard, J, Lush, M, Beesley, J, O'Mara, TA, Dennis, J, Tyrer, JP, Barnes, DR, McGuffog, L, Leslie, G, Bolla, MK, Adank, MA, Agata, S, Ahearn, T, Aittomäki, K, Andrulis, IL, Anton-Culver, H, Arndt, V, Arnold, N, Aronson, KJ, Arun, BK, Augustinsson, A, Azzollini, J, Barrowdale, D, Baynes, C, Becher, H, Bermisheva, M, Bernstein, L, Białkowska, K, Blomqvist, C, Bojesen, SE, Bonanni, B, Borg, A, Brauch, H, Brenner, H, Burwinkel, B, Buys, SS, Caldés, T, Caligo, MA, Campa, D, Carter, BD, Castelao, JE, Chang-Claude, J, Chanock, SJ, Chung, WK, Claes, KBM, Clarke, CL, GEMO Study Collaborators, EMBRACE Collaborators, Collée, JM, Conroy, DM, Czene, K, Daly, MB, Devilee, P, Diez, O, Ding, YC, Domchek, SM, Dörk, T, Dos-Santos-Silva, I, Dunning, AM, Dwek, M, Eccles, DM, Eliassen, AH, Engel, C, Eriksson, M, Evans, DG, Fasching, PA, Flyger, H, Fostira, F, Friedman, E, Fritschi, L, Frost, D, Gago-Dominguez, M, Gapstur, SM, Garber, J, Garcia-Barberan, V, García-Closas, M, García-Sáenz, JA, Gaudet, MM, Gayther, SA, Gehrig, A, Georgoulias, V, Giles, GG, Godwin, AK, Goldberg, MS, Goldgar, DE, González-Neira, A, Greene, MH, Guénel, P, Haeberle, L, Hahnen, E, Haiman, CA, Håkansson, N, Hall, P, Hamann, U, Harrington, PA, Hart, SN, He, W, Hogervorst, FBL, Hollestelle, A, Hopper, JL, Horcasitas, DJ, Hulick, PJ, Hunter, DJ, Imyanitov, EN, KConFab Investigators, HEBON Investigators, ABCTB Investigators, Jager, A, Jakubowska, A, James, PA, Jensen, UB, John, EM, Jones, ME, Kaaks, R, Kapoor, PM, Karlan, BY, Keeman, R, Khusnutdinova, E, Kiiski, JI, Ko, Y-D, Kosma, V-M, Kraft, P, Kurian, AW, Laitman, Y, Lambrechts, D, Le Marchand, L, Lester, J, Lesueur, F, Lindstrom, T, Lopez-Fernández, A, Loud, JT, Luccarini, C, Mannermaa, A, Manoukian, S, Margolin, S, Martens, JWM, Mebirouk, N, Meindl, A, Miller, A, Milne, RL, Montagna, M, Nathanson, KL, Neuhausen, SL, Nevanlinna, H, Nielsen, FC, O'Brien, KM, Olopade, OI, Olson, JE, Olsson, H, Osorio, A, Ottini, L, Park-Simon, T-W, Parsons, MT, Pedersen, IS, Peshkin, B, Peterlongo, P, Peto, J, Pharoah, PDP, Phillips, K-A, Polley, EC, Poppe, B, Presneau, N, Pujana, MA, Punie, K, Radice, P, Rantala, J, Rashid, MU, Rennert, G, Rennert, HS, Robson, M, Romero, A, Rossing, M, Saloustros, E, Sandler, DP, Santella, R, Scheuner, MT, Schmidt, MK, Schmidt, G, Scott, C, Sharma, P, Soucy, P, Southey, MC, Spinelli, JJ, Steinsnyder, Z, Stone, J, Stoppa-Lyonnet, D, Swerdlow, A, Tamimi, RM, Tapper, WJ, Taylor, JA, Terry, MB, Teulé, A, Thull, DL, Tischkowitz, M, Toland, AE, Torres, D, Trainer, AH, Truong, T, Tung, N, Vachon, CM, Vega, A, Vijai, J, Wang, Q, Wappenschmidt, B, Weinberg, CR, Weitzel, JN, Wendt, C, Wolk, A, Yadav, S, Yang, XR, Yannoukakos, D, Zheng, W, Ziogas, A, Zorn, KK, Park, SK, Thomassen, M, Offit, K, Schmutzler, RK, Couch, FJ, Simard, J, Chenevix-Trench, G, Easton, DF, Andrieu, N, Antoniou, AC, Coignard, J, Lush, M, Beesley, J, O'Mara, TA, Dennis, J, Tyrer, JP, Barnes, DR, McGuffog, L, Leslie, G, Bolla, MK, Adank, MA, Agata, S, Ahearn, T, Aittomäki, K, Andrulis, IL, Anton-Culver, H, Arndt, V, Arnold, N, Aronson, KJ, Arun, BK, Augustinsson, A, Azzollini, J, Barrowdale, D, Baynes, C, Becher, H, Bermisheva, M, Bernstein, L, Białkowska, K, Blomqvist, C, Bojesen, SE, Bonanni, B, Borg, A, Brauch, H, Brenner, H, Burwinkel, B, Buys, SS, Caldés, T, Caligo, MA, Campa, D, Carter, BD, Castelao, JE, Chang-Claude, J, Chanock, SJ, Chung, WK, Claes, KBM, Clarke, CL, GEMO Study Collaborators, EMBRACE Collaborators, Collée, JM, Conroy, DM, Czene, K, Daly, MB, Devilee, P, Diez, O, Ding, YC, Domchek, SM, Dörk, T, Dos-Santos-Silva, I, Dunning, AM, Dwek, M, Eccles, DM, Eliassen, AH, Engel, C, Eriksson, M, Evans, DG, Fasching, PA, Flyger, H, Fostira, F, Friedman, E, Fritschi, L, Frost, D, Gago-Dominguez, M, Gapstur, SM, Garber, J, Garcia-Barberan, V, García-Closas, M, García-Sáenz, JA, Gaudet, MM, Gayther, SA, Gehrig, A, Georgoulias, V, Giles, GG, Godwin, AK, Goldberg, MS, Goldgar, DE, González-Neira, A, Greene, MH, Guénel, P, Haeberle, L, Hahnen, E, Haiman, CA, Håkansson, N, Hall, P, Hamann, U, Harrington, PA, Hart, SN, He, W, Hogervorst, FBL, Hollestelle, A, Hopper, JL, Horcasitas, DJ, Hulick, PJ, Hunter, DJ, Imyanitov, EN, KConFab Investigators, HEBON Investigators, ABCTB Investigators, Jager, A, Jakubowska, A, James, PA, Jensen, UB, John, EM, Jones, ME, Kaaks, R, Kapoor, PM, Karlan, BY, Keeman, R, Khusnutdinova, E, Kiiski, JI, Ko, Y-D, Kosma, V-M, Kraft, P, Kurian, AW, Laitman, Y, Lambrechts, D, Le Marchand, L, Lester, J, Lesueur, F, Lindstrom, T, Lopez-Fernández, A, Loud, JT, Luccarini, C, Mannermaa, A, Manoukian, S, Margolin, S, Martens, JWM, Mebirouk, N, Meindl, A, Miller, A, Milne, RL, Montagna, M, Nathanson, KL, Neuhausen, SL, Nevanlinna, H, Nielsen, FC, O'Brien, KM, Olopade, OI, Olson, JE, Olsson, H, Osorio, A, Ottini, L, Park-Simon, T-W, Parsons, MT, Pedersen, IS, Peshkin, B, Peterlongo, P, Peto, J, Pharoah, PDP, Phillips, K-A, Polley, EC, Poppe, B, Presneau, N, Pujana, MA, Punie, K, Radice, P, Rantala, J, Rashid, MU, Rennert, G, Rennert, HS, Robson, M, Romero, A, Rossing, M, Saloustros, E, Sandler, DP, Santella, R, Scheuner, MT, Schmidt, MK, Schmidt, G, Scott, C, Sharma, P, Soucy, P, Southey, MC, Spinelli, JJ, Steinsnyder, Z, Stone, J, Stoppa-Lyonnet, D, Swerdlow, A, Tamimi, RM, Tapper, WJ, Taylor, JA, Terry, MB, Teulé, A, Thull, DL, Tischkowitz, M, Toland, AE, Torres, D, Trainer, AH, Truong, T, Tung, N, Vachon, CM, Vega, A, Vijai, J, Wang, Q, Wappenschmidt, B, Weinberg, CR, Weitzel, JN, Wendt, C, Wolk, A, Yadav, S, Yang, XR, Yannoukakos, D, Zheng, W, Ziogas, A, Zorn, KK, Park, SK, Thomassen, M, Offit, K, Schmutzler, RK, Couch, FJ, Simard, J, Chenevix-Trench, G, Easton, DF, Andrieu, N, and Antoniou, AC
Abstract: A Correction to this paper has been published: https://doi.org/10.1038/s41467-021-23162-4.
Published: 2021

28. Common variants in breast cancer risk loci predispose to distinct tumor subtypes

Author: Ahearn, TU, Zhang, H, Michailidou, K, Milne, RL, Bolla, MK, Dennis, J, Dunning, AM, Lush, M, Wang, Q, Andrulis, IL, Anton-Culver, H, Arndt, V, Aronson, KJ, Auer, PL, Augustinsson, A, Baten, A, Becher, H, Behrens, S, Benitez, J, Bermisheva, M, Blomqvist, C, Bojesen, SE, Bonanni, B, Børresen-Dale, A-L, Brauch, H, Brenner, H, Brooks-Wilson, A, Brüning, T, Burwinkel, B, Buys, SS, Canzian, F, Castelao, JE, Chang-Claude, J, Chanock, SJ, Chenevix-Trench, G, Clarke, CL, Sahlberg, KK, Ottestad, L, Kåresen, R, Schlichting, E, Holmen, MM, Sauer, T, Haakensen, V, Engebråten, O, Naume, B, Fosså, A, Kiserud, CE, Reinertsen, KV, Helland, Å, Riis, M, Geisler, J, Collée, JM, Cox, A, Cross, SS, Czene, K, Daly, MB, Devilee, P, Dörk, T, Dwek, M, Eccles, DM, Evans, DG, Fasching, PA, Figueroa, J, Floris, G, Gago-Dominguez, M, Gapstur, SM, García-Sáenz, JA, Gaudet, MM, Giles, GG, Goldberg, MS, González-Neira, A, Alnæs, GIG, Grip, M, Guénel, P, Haiman, CA, Hall, P, Hamann, U, Harkness, EF, Heemskerk-Gerritsen, BAM, Holleczek, B, Hollestelle, A, Hooning, MJ, Hoover, RN, Hopper, JL, Howell, A, Clarke, C, Balleine, R, Baxter, R, Braye, S, Carpenter, J, Dahlstrom, J, Forbes, J, Lee, C, Marsh, D, Morey, A, Pathmanathan, N, Scott, R, Simpson, P, Spigelman, A, Wilcken, N, Yip, D, Zeps, N, Fox, S, Campbell, I, Bowtell, D, Spurdle, A, Webb, P, de Fazio, A, Tassell, M, Kirk, J, Lindeman, G, Price, M, Southey, M, Milne, R, Deb, S, Jakimovska, M, Jakubowska, A, John, EM, Jones, ME, Jung, A, Kaaks, R, Kauppila, S, Keeman, R, Khusnutdinova, E, Kitahara, CM, Ko, Y-D, Koutros, S, Kristensen, VN, Krüger, U, Kubelka-Sabit, K, Kurian, AW, Kyriacou, K, Lambrechts, D, Lee, DG, Lindblom, A, Linet, M, Lissowska, J, Llaneza, A, Lo, W-Y, MacInnis, RJ, Mannermaa, A, Manoochehri, M, Margolin, S, Martinez, ME, McLean, C, Meindl, A, Menon, U, Nevanlinna, H, Newman, WG, Nodora, J, Offit, K, Olsson, H, Orr, N, Park-Simon, T-W, Patel, AV, Peto, J, Pita, G, Plaseska-Karanfilska, D, Prentice, R, Punie, K, Pylkäs, K, Radice, P, Rennert, G, Romero, A, Rüdiger, T, Saloustros, E, Sampson, S, Sandler, DP, Sawyer, EJ, Schmutzler, RK, Schoemaker, MJ, Schöttker, B, Sherman, ME, Shu, X-O, Smichkoska, S, Southey, MC, Spinelli, JJ, Swerdlow, AJ, Tamimi, RM, Tapper, WJ, Taylor, JA, Teras, LR, Terry, MB, Torres, D, Troester, MA, Vachon, CM, van Deurzen, CHM, van Veen, EM, Wagner, P, Weinberg, CR, Wendt, C, Wesseling, J, Winqvist, R, Wolk, A, Yang, XR, Zheng, W, Couch, FJ, Simard, J, Kraft, P, Easton, DF, Pharoah, PDP, Schmidt, MK, García-Closas, M, Chatterjee, N, Ahearn, Thomas U [0000-0003-0771-7752], Easton, Douglas [0000-0003-2444-3247], Pharoah, Paul [0000-0001-8494-732X], Apollo - University of Cambridge Repository, Medicum, HUS Comprehensive Cancer Center, Department of Oncology, Clinicum, Department of Obstetrics and Gynecology, Biosciences, HUS Gynecology and Obstetrics, Clinical Genetics, Medical Oncology, and Pathology
Subjects: False discovery rate, Oncology, Common breast cancer susceptibility variants, Receptor, ErbB-2, Estrogen receptor, PROGRESSION, Etiologic heterogeneity, Logistic regression, Basic medicine, Breast cancer, 0302 clinical medicine, PRIMARY THERAPY, HETEROGENEITY, RC254-282, HISTOLOGICAL GRADE, 0303 health sciences, Breast Neoplasms/epidemiology, Receptors, Estrogen/genetics, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, INTERNATIONAL EXPERT CONSENSUS, humanities, Receptor, ErbB-2/genetics, 3. Good health, Receptors, Estrogen, Receptors, Progesterone/genetics, 030220 oncology & carcinogenesis, Female, Biomarkers, Tumor/genetics, Receptors, Progesterone, Medical Genetics, Research Article, Risk, medicine.medical_specialty, SUSCEPTIBILITY LOCI, 3122 Cancers, Breast Neoplasms, Single-nucleotide polymorphism, Biology, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Internal medicine, Progesterone receptor, Biomarkers, Tumor, medicine, Genetic predisposition, Humans, ddc:610, GENOME-WIDE ASSOCIATION, Genetic association, Medicinsk genetik, 030304 developmental biology, Cancer och onkologi, medicine.disease, Cancer and Oncology, Clinical medicine, Genome-Wide Association Study
Abstract: Background Genome-wide association studies (GWAS) have identified multiple common breast cancer susceptibility variants. Many of these variants have differential associations by estrogen receptor (ER) status, but how these variants relate with other tumor features and intrinsic molecular subtypes is unclear. Methods Among 106,571 invasive breast cancer cases and 95,762 controls of European ancestry with data on 173 breast cancer variants identified in previous GWAS, we used novel two-stage polytomous logistic regression models to evaluate variants in relation to multiple tumor features (ER, progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and grade) adjusting for each other, and to intrinsic-like subtypes. Results Eighty-five of 173 variants were associated with at least one tumor feature (false discovery rate p Conclusion This report demonstrates a high level of complexity in the etiology heterogeneity of breast cancer susceptibility variants and can inform investigations of subtype-specific risk prediction.
Published: 2020

29. Association of tamoxifen use and reduced risk of contralateral breast cancer for BRCA1 and BRCA2 mutation carriers

Author: Phillips KA, Milne RL, Rookus MA, Goldgar D, Friedlander M, McLachlan SA, Buys S, Antoniou AC, Birch K, Terry MB, Easton DF, Weideman P, Daly M, Andrieu N, John EM, Hooning MJ, Andrulis IL, Caldes T, Olsson H, and Hopper JL
Subjects: Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282, Genetics, QH426-470
Published: 2012
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30. Integrating DNA methylation measures to improve clinical risk assessment: are we there yet? The case of BRCA1 methylation marks to improve clinical risk assessment of breast cancer

Author: Wong, EM, Southey, MC, Terry, MB, Wong, EM, Southey, MC, and Terry, MB
Abstract: Current risk prediction models estimate the probability of developing breast cancer over a defined period based on information such as family history, non-genetic breast cancer risk factors, genetic information from high and moderate risk breast cancer susceptibility genes and, over the past several years, polygenic risk scores (PRS) from more than 300 common variants. The inclusion of additional data such as PRS improves risk stratification, but it is anticipated that the inclusion of epigenetic marks could further improve model performance accuracy. Here, we present the case for including information on DNA methylation marks to improve the accuracy of these risk prediction models, and consider how this approach contrasts genetic information, as identifying DNA methylation marks associated with breast cancer risk differs inherently according to the source of DNA, approaches to the measurement of DNA methylation, and the timing of measurement. We highlight several DNA-methylation-specific challenges that should be considered when incorporating information on DNA methylation marks into risk prediction models, using BRCA1, a highly penetrant breast cancer susceptibility gene, as an example. Only after careful consideration of study design and DNA methylation measurement will prospective performance of the incorporation of information regarding DNA methylation marks into risk prediction models be valid.
Published: 2020

31. Germline HOXB13 mutations p.G84E and p.R217C do not confer an increased breast cancer risk

Author: Liu, J, van der Smissen, WJCP, Collee, JM, Bolla, MK, Wang, Q, Michailidou, K, Dennis, J, Ahearn, TU, Aittomaki, K, Ambrosone, CB, Andrulis, IL, Anton-Culver, H, Antonenkova, NN, Arndt, V, Arnold, N, Aronson, KJ, Augustinsson, A, Auvinen, P, Becher, H, Beckmann, MW, Behrens, S, Bermisheva, M, Bernstein, L, Bogdanova, N, Bogdanova-Markov, N, Bojesen, SE, Brauch, H, Brenner, H, Briceno, I, Brucker, SY, Bruening, T, Burwinkel, B, Cai, Q, Cai, H, Campa, D, Canzian, F, Castelao, JE, Chang-Claude, J, Chanock, SJ, Choi, J-Y, Christiaens, M, Clarke, CL, Couch, FJ, Czene, K, Daly, MB, Devilee, P, dos-Santos-Silva, I, Dwek, M, Eccles, DM, Eliassen, AH, Fasching, PA, Figueroa, J, Flyger, H, Fritschi, L, Gago-Dominguez, M, Gapstur, SM, Garcia-Closas, M, Garcia-Saenz, JA, Gaudet, MM, Giles, GG, Goldberg, MS, Goldgar, DE, Guenel, P, Haiman, CA, Hakansson, N, Hall, P, Harrington, PA, Hart, SN, Hartman, M, Hillemanns, P, Hopper, JL, Hou, M-F, Hunter, DJ, Huo, D, Ito, H, Iwasaki, M, Jakimovska, M, Jakubowska, A, John, EM, Kaaks, R, Kang, D, Keeman, R, Khusnutdinova, E, Kim, S-W, Kraft, P, Kristensen, VN, Kurian, AW, Le Marchand, L, Li, J, Lindblom, A, Lophatananon, A, Luben, RN, Lubinski, J, Mannermaa, A, Manoochehri, M, Manoukian, S, Margolin, S, Mariapun, S, Matsuo, K, Maurer, T, Mavroudis, D, Meindl, A, Menon, U, Milne, RL, Muir, K, Mulligan, AM, Neuhausen, SL, Nevanlinna, H, Offit, K, Olopade, O, Olson, JE, Olsson, H, Orr, N, Park, SK, Peterlongo, P, Peto, J, Plaseska-Karanfilska, D, Presneau, N, Rack, B, Rau-Murthy, R, Rennert, G, Rennert, HS, Rhenius, V, Romero, A, Ruebner, M, Saloustros, E, Schmutzler, RK, Schneeweiss, A, Scott, C, Shah, M, Shen, C-Y, Shu, X-O, Simard, J, Sohn, C, Southey, MC, Spinelli, JJ, Tamimi, RM, Tapper, WJ, Teo, SH, Terry, MB, Torres, D, Truong, T, Untch, M, Vachon, CM, van Asperen, CJ, Wolk, A, Yamaji, T, Zheng, W, Ziogas, A, Ziv, E, Torres-Mejia, G, Doerk, T, Swerdlow, AJ, Hamann, U, Schmidt, MK, Dunning, AM, Pharoah, PDP, Easton, DF, Hooning, MJ, Martens, JWM, Hollestelle, A, Liu, J, van der Smissen, WJCP, Collee, JM, Bolla, MK, Wang, Q, Michailidou, K, Dennis, J, Ahearn, TU, Aittomaki, K, Ambrosone, CB, Andrulis, IL, Anton-Culver, H, Antonenkova, NN, Arndt, V, Arnold, N, Aronson, KJ, Augustinsson, A, Auvinen, P, Becher, H, Beckmann, MW, Behrens, S, Bermisheva, M, Bernstein, L, Bogdanova, N, Bogdanova-Markov, N, Bojesen, SE, Brauch, H, Brenner, H, Briceno, I, Brucker, SY, Bruening, T, Burwinkel, B, Cai, Q, Cai, H, Campa, D, Canzian, F, Castelao, JE, Chang-Claude, J, Chanock, SJ, Choi, J-Y, Christiaens, M, Clarke, CL, Couch, FJ, Czene, K, Daly, MB, Devilee, P, dos-Santos-Silva, I, Dwek, M, Eccles, DM, Eliassen, AH, Fasching, PA, Figueroa, J, Flyger, H, Fritschi, L, Gago-Dominguez, M, Gapstur, SM, Garcia-Closas, M, Garcia-Saenz, JA, Gaudet, MM, Giles, GG, Goldberg, MS, Goldgar, DE, Guenel, P, Haiman, CA, Hakansson, N, Hall, P, Harrington, PA, Hart, SN, Hartman, M, Hillemanns, P, Hopper, JL, Hou, M-F, Hunter, DJ, Huo, D, Ito, H, Iwasaki, M, Jakimovska, M, Jakubowska, A, John, EM, Kaaks, R, Kang, D, Keeman, R, Khusnutdinova, E, Kim, S-W, Kraft, P, Kristensen, VN, Kurian, AW, Le Marchand, L, Li, J, Lindblom, A, Lophatananon, A, Luben, RN, Lubinski, J, Mannermaa, A, Manoochehri, M, Manoukian, S, Margolin, S, Mariapun, S, Matsuo, K, Maurer, T, Mavroudis, D, Meindl, A, Menon, U, Milne, RL, Muir, K, Mulligan, AM, Neuhausen, SL, Nevanlinna, H, Offit, K, Olopade, O, Olson, JE, Olsson, H, Orr, N, Park, SK, Peterlongo, P, Peto, J, Plaseska-Karanfilska, D, Presneau, N, Rack, B, Rau-Murthy, R, Rennert, G, Rennert, HS, Rhenius, V, Romero, A, Ruebner, M, Saloustros, E, Schmutzler, RK, Schneeweiss, A, Scott, C, Shah, M, Shen, C-Y, Shu, X-O, Simard, J, Sohn, C, Southey, MC, Spinelli, JJ, Tamimi, RM, Tapper, WJ, Teo, SH, Terry, MB, Torres, D, Truong, T, Untch, M, Vachon, CM, van Asperen, CJ, Wolk, A, Yamaji, T, Zheng, W, Ziogas, A, Ziv, E, Torres-Mejia, G, Doerk, T, Swerdlow, AJ, Hamann, U, Schmidt, MK, Dunning, AM, Pharoah, PDP, Easton, DF, Hooning, MJ, Martens, JWM, and Hollestelle, A
Abstract: In breast cancer, high levels of homeobox protein Hox-B13 (HOXB13) have been associated with disease progression of ER-positive breast cancer patients and resistance to tamoxifen treatment. Since HOXB13 p.G84E is a prostate cancer risk allele, we evaluated the association between HOXB13 germline mutations and breast cancer risk in a previous study consisting of 3,270 familial non-BRCA1/2 breast cancer cases and 2,327 controls from the Netherlands. Although both recurrent HOXB13 mutations p.G84E and p.R217C were not associated with breast cancer risk, the risk estimation for p.R217C was not very precise. To provide more conclusive evidence regarding the role of HOXB13 in breast cancer susceptibility, we here evaluated the association between HOXB13 mutations and increased breast cancer risk within 81 studies of the international Breast Cancer Association Consortium containing 68,521 invasive breast cancer patients and 54,865 controls. Both HOXB13 p.G84E and p.R217C did not associate with the development of breast cancer in European women, neither in the overall analysis (OR = 1.035, 95% CI = 0.859-1.246, P = 0.718 and OR = 0.798, 95% CI = 0.482-1.322, P = 0.381 respectively), nor in specific high-risk subgroups or breast cancer subtypes. Thus, although involved in breast cancer progression, HOXB13 is not a material breast cancer susceptibility gene.
Published: 2020

32. A network analysis to identify mediators of germline-driven differences in breast cancer prognosis

Author: Escala-Garcia, M, Abraham, J, Andrulis, IL, Anton-Culver, H, Arndt, V, Ashworth, A, Auer, PL, Auvinen, P, Beckmann, MW, Beesley, J, Behrens, S, Benitez, J, Bermisheva, M, Blomqvist, C, Blot, W, Bogdanova, NV, Bojesen, SE, Bolla, MK, Borresen-Dale, A-L, Brauch, H, Brenner, H, Brucker, SY, Burwinkel, B, Caldas, C, Canzian, F, Chang-Claude, J, Chanock, SJ, Chin, S-F, Clarke, CL, Couch, FJ, Cox, A, Cross, SS, Czene, K, Daly, MB, Dennis, J, Devilee, P, Dunn, JA, Dunning, AM, Dwek, M, Earl, HM, Eccles, DM, Eliassen, AH, Ellberg, C, Evans, DG, Fasching, PA, Figueroa, J, Flyger, H, Gago-Dominguez, M, Gapstur, SM, Garcia-Closas, M, Garcia-Saenz, JA, Gaudet, MM, George, A, Giles, GG, Goldgar, DE, Gonzalez-Neira, A, Grip, M, Guenel, P, Guo, Q, Haiman, CA, Hakansson, N, Hamann, U, Harrington, PA, Hiller, L, Hooning, MJ, Hopper, JL, Howell, A, Huang, C-S, Huang, G, Hunter, DJ, Jakubowska, A, John, EM, Kaaks, R, Kapoor, PM, Keeman, R, Kitahara, CM, Koppert, LB, Kraft, P, Kristensen, VN, Lambrechts, D, Le Marchand, L, Lejbkowicz, F, Lindblom, A, Lubinski, J, Mannermaa, A, Manoochehri, M, Manoukian, S, Margolin, S, Martinez, ME, Maurer, T, Mavroudis, D, Meindl, A, Milne, RL, Mulligan, AM, Neuhausen, SL, Nevanlinna, H, Newman, WG, Olshan, AF, Olson, JE, Olsson, H, Orr, N, Peterlongo, P, Petridis, C, Prentice, RL, Presneau, N, Punie, K, Ramachandran, D, Rennert, G, Romero, A, Sachchithananthan, M, Saloustros, E, Sawyer, EJ, Schmutzler, RK, Schwentner, L, Scott, C, Simard, J, Sohn, C, Southey, MC, Swerdlow, AJ, Tamimi, RM, Tapper, WJ, Teixeira, MR, Terry, MB, Thorne, H, Tollenaar, RAEM, Tomlinson, I, Troester, MA, Truong, T, Turnbull, C, Vachon, CM, van der Kolk, LE, Wang, Q, Winqvist, R, Wolk, A, Yang, XR, Ziogas, A, Pharoah, PDP, Hall, P, Wessels, LFA, Chenevix-Trench, G, Bader, GD, Doerk, T, Easton, DF, Canisius, S, Schmidt, MK, Escala-Garcia, M, Abraham, J, Andrulis, IL, Anton-Culver, H, Arndt, V, Ashworth, A, Auer, PL, Auvinen, P, Beckmann, MW, Beesley, J, Behrens, S, Benitez, J, Bermisheva, M, Blomqvist, C, Blot, W, Bogdanova, NV, Bojesen, SE, Bolla, MK, Borresen-Dale, A-L, Brauch, H, Brenner, H, Brucker, SY, Burwinkel, B, Caldas, C, Canzian, F, Chang-Claude, J, Chanock, SJ, Chin, S-F, Clarke, CL, Couch, FJ, Cox, A, Cross, SS, Czene, K, Daly, MB, Dennis, J, Devilee, P, Dunn, JA, Dunning, AM, Dwek, M, Earl, HM, Eccles, DM, Eliassen, AH, Ellberg, C, Evans, DG, Fasching, PA, Figueroa, J, Flyger, H, Gago-Dominguez, M, Gapstur, SM, Garcia-Closas, M, Garcia-Saenz, JA, Gaudet, MM, George, A, Giles, GG, Goldgar, DE, Gonzalez-Neira, A, Grip, M, Guenel, P, Guo, Q, Haiman, CA, Hakansson, N, Hamann, U, Harrington, PA, Hiller, L, Hooning, MJ, Hopper, JL, Howell, A, Huang, C-S, Huang, G, Hunter, DJ, Jakubowska, A, John, EM, Kaaks, R, Kapoor, PM, Keeman, R, Kitahara, CM, Koppert, LB, Kraft, P, Kristensen, VN, Lambrechts, D, Le Marchand, L, Lejbkowicz, F, Lindblom, A, Lubinski, J, Mannermaa, A, Manoochehri, M, Manoukian, S, Margolin, S, Martinez, ME, Maurer, T, Mavroudis, D, Meindl, A, Milne, RL, Mulligan, AM, Neuhausen, SL, Nevanlinna, H, Newman, WG, Olshan, AF, Olson, JE, Olsson, H, Orr, N, Peterlongo, P, Petridis, C, Prentice, RL, Presneau, N, Punie, K, Ramachandran, D, Rennert, G, Romero, A, Sachchithananthan, M, Saloustros, E, Sawyer, EJ, Schmutzler, RK, Schwentner, L, Scott, C, Simard, J, Sohn, C, Southey, MC, Swerdlow, AJ, Tamimi, RM, Tapper, WJ, Teixeira, MR, Terry, MB, Thorne, H, Tollenaar, RAEM, Tomlinson, I, Troester, MA, Truong, T, Turnbull, C, Vachon, CM, van der Kolk, LE, Wang, Q, Winqvist, R, Wolk, A, Yang, XR, Ziogas, A, Pharoah, PDP, Hall, P, Wessels, LFA, Chenevix-Trench, G, Bader, GD, Doerk, T, Easton, DF, Canisius, S, and Schmidt, MK
Abstract: Identifying the underlying genetic drivers of the heritability of breast cancer prognosis remains elusive. We adapt a network-based approach to handle underpowered complex datasets to provide new insights into the potential function of germline variants in breast cancer prognosis. This network-based analysis studies ~7.3 million variants in 84,457 breast cancer patients in relation to breast cancer survival and confirms the results on 12,381 independent patients. Aggregating the prognostic effects of genetic variants across multiple genes, we identify four gene modules associated with survival in estrogen receptor (ER)-negative and one in ER-positive disease. The modules show biological enrichment for cancer-related processes such as G-alpha signaling, circadian clock, angiogenesis, and Rho-GTPases in apoptosis.
Published: 2020

33. Risk-reducing salpingo-oophorectomy, natural menopause, and breast cancer risk: an international prospective cohort of BRCA1 and BRCA2 mutation carriers (vol 22, 8, 2020)

Author: Mavaddat, N, Antoniou, AC, Mooij, TM, Hooning, MJ, Heemskerk-Gerritsen, BA, Nogues, C, Gauthier-Villars, M, Caron, O, Gesta, P, Pujol, P, Lortholary, A, Barrowdale, D, Frost, D, Evans, DG, Izatt, L, Adlard, J, Eeles, R, Brewer, C, Tischkowitz, M, Henderson, A, Cook, J, Eccles, D, van Engelen, K, Mourits, MJE, Ausems, MGEM, Koppert, LB, Hopper, JL, John, EM, Chung, WK, Andrulis, IL, Daly, MB, Buys, SS, Benitez, J, Caldes, T, Jakubowska, A, Simard, J, Singer, CF, Tan, Y, Olah, E, Navratilova, M, Foretova, L, Gerdes, A-M, Roos-Blom, M-J, Van Leeuwen, FE, Arver, B, Olsson, H, Schmutzler, RK, Engel, C, Kast, K, Phillips, K-A, Terry, MB, Milne, RL, Goldgar, DE, Rookus, MA, Andrieu, N, Easton, DF, Mavaddat, N, Antoniou, AC, Mooij, TM, Hooning, MJ, Heemskerk-Gerritsen, BA, Nogues, C, Gauthier-Villars, M, Caron, O, Gesta, P, Pujol, P, Lortholary, A, Barrowdale, D, Frost, D, Evans, DG, Izatt, L, Adlard, J, Eeles, R, Brewer, C, Tischkowitz, M, Henderson, A, Cook, J, Eccles, D, van Engelen, K, Mourits, MJE, Ausems, MGEM, Koppert, LB, Hopper, JL, John, EM, Chung, WK, Andrulis, IL, Daly, MB, Buys, SS, Benitez, J, Caldes, T, Jakubowska, A, Simard, J, Singer, CF, Tan, Y, Olah, E, Navratilova, M, Foretova, L, Gerdes, A-M, Roos-Blom, M-J, Van Leeuwen, FE, Arver, B, Olsson, H, Schmutzler, RK, Engel, C, Kast, K, Phillips, K-A, Terry, MB, Milne, RL, Goldgar, DE, Rookus, MA, Andrieu, N, and Easton, DF
Abstract: After publication of the original article [1], we were notified that columns in Table 2 were erroneously displayed.
Published: 2020

34. Risk-reducing salpingo-oophorectomy, natural menopause, and breast cancer risk: an international prospective cohort of BRCA1 and BRCA2 mutation carriers

Author: Mavaddat, N, Antoniou, AC, Mooij, TM, Hooning, MJ, Heemskerk-Gerritsen, BA, Nogues, C, Laborde, L, Breysse, E, Stoppa-Lyonnet, D, Gauthier-Villars, M, Buecher, B, Caron, O, Fourme-Mouret, E, Fricker, J-P, Lasset, C, Bonadona, V, Berthet, P, Faivre, L, Luporsi, E, Mari, V, Gladieff, L, Gesta, P, Sobol, H, Eisinger, F, Longy, M, Dugast, C, Colas, C, Coupier, I, Pujol, P, Corsini, C, Lortholary, A, Vennin, P, Adenis, C, Nguyen, TD, Delnatte, C, Tinat, J, Tennevet, I, Limacher, J-M, Maugard, C, Bignon, Y-J, Demange, L, Penet, C, Dreyfus, H, Cohen-Haguenauer, O, Venat-Bouvet, L, Leroux, D, Zattara-Cannoni, H, Fert-Ferrer, S, Bera, O, Ellis, S, Barrowdale, D, Frost, D, Evans, DG, Izatt, L, Adlard, J, Eeles, R, Brewer, C, Tischkowitz, M, Henderson, A, Cook, J, Eccles, D, Hogervorst, FBL, Collee, JM, van Asperen, CJ, Mensenkamp, AR, Ausems, MGEM, Meijers-Heijboer, HEJ, van Engelen, K, Blok, MJ, Oosterwijk, JC, Verloop, J, van den Broek, E, Mourits, MJE, Koppert, LB, Hopper, JL, John, EM, Chung, WK, Andrulis, IL, Daly, MB, Buys, SS, Benitez, J, Caldes, T, Jakubowska, A, Simard, J, Singer, CF, Tan, Y, Olah, E, Navratilova, M, Foretova, L, Gerdes, A-M, Roos-Blom, M-J, Van Leeuwen, FE, Arver, B, Olsson, H, Schmutzler, RK, Engel, C, Kast, K, Phillips, K-A, Terry, MB, Milne, RL, Goldgar, DE, Rookus, MA, Andrieu, N, Easton, DF, Mavaddat, N, Antoniou, AC, Mooij, TM, Hooning, MJ, Heemskerk-Gerritsen, BA, Nogues, C, Laborde, L, Breysse, E, Stoppa-Lyonnet, D, Gauthier-Villars, M, Buecher, B, Caron, O, Fourme-Mouret, E, Fricker, J-P, Lasset, C, Bonadona, V, Berthet, P, Faivre, L, Luporsi, E, Mari, V, Gladieff, L, Gesta, P, Sobol, H, Eisinger, F, Longy, M, Dugast, C, Colas, C, Coupier, I, Pujol, P, Corsini, C, Lortholary, A, Vennin, P, Adenis, C, Nguyen, TD, Delnatte, C, Tinat, J, Tennevet, I, Limacher, J-M, Maugard, C, Bignon, Y-J, Demange, L, Penet, C, Dreyfus, H, Cohen-Haguenauer, O, Venat-Bouvet, L, Leroux, D, Zattara-Cannoni, H, Fert-Ferrer, S, Bera, O, Ellis, S, Barrowdale, D, Frost, D, Evans, DG, Izatt, L, Adlard, J, Eeles, R, Brewer, C, Tischkowitz, M, Henderson, A, Cook, J, Eccles, D, Hogervorst, FBL, Collee, JM, van Asperen, CJ, Mensenkamp, AR, Ausems, MGEM, Meijers-Heijboer, HEJ, van Engelen, K, Blok, MJ, Oosterwijk, JC, Verloop, J, van den Broek, E, Mourits, MJE, Koppert, LB, Hopper, JL, John, EM, Chung, WK, Andrulis, IL, Daly, MB, Buys, SS, Benitez, J, Caldes, T, Jakubowska, A, Simard, J, Singer, CF, Tan, Y, Olah, E, Navratilova, M, Foretova, L, Gerdes, A-M, Roos-Blom, M-J, Van Leeuwen, FE, Arver, B, Olsson, H, Schmutzler, RK, Engel, C, Kast, K, Phillips, K-A, Terry, MB, Milne, RL, Goldgar, DE, Rookus, MA, Andrieu, N, and Easton, DF
Abstract: BACKGROUND: The effect of risk-reducing salpingo-oophorectomy (RRSO) on breast cancer risk for BRCA1 and BRCA2 mutation carriers is uncertain. Retrospective analyses have suggested a protective effect but may be substantially biased. Prospective studies have had limited power, particularly for BRCA2 mutation carriers. Further, previous studies have not considered the effect of RRSO in the context of natural menopause. METHODS: A multi-centre prospective cohort of 2272 BRCA1 and 1605 BRCA2 mutation carriers was followed for a mean of 5.4 and 4.9 years, respectively; 426 women developed incident breast cancer. RRSO was modelled as a time-dependent covariate in Cox regression, and its effect assessed in premenopausal and postmenopausal women. RESULTS: There was no association between RRSO and breast cancer for BRCA1 (HR = 1.23; 95% CI 0.94-1.61) or BRCA2 (HR = 0.88; 95% CI 0.62-1.24) mutation carriers. For BRCA2 mutation carriers, HRs were 0.68 (95% CI 0.40-1.15) and 1.07 (95% CI 0.69-1.64) for RRSO carried out before or after age 45 years, respectively. The HR for BRCA2 mutation carriers decreased with increasing time since RRSO (HR = 0.51; 95% CI 0.26-0.99 for 5 years or longer after RRSO). Estimates for premenopausal women were similar. CONCLUSION: We found no evidence that RRSO reduces breast cancer risk for BRCA1 mutation carriers. A potentially beneficial effect for BRCA2 mutation carriers was observed, particularly after 5 years following RRSO. These results may inform counselling and management of carriers with respect to RRSO.
Published: 2020

35. Recreational Physical Activity Is Associated with Reduced Breast Cancer Risk in Adult Women at High Risk for Breast Cancer: A Cohort Study of Women Selected for Familial and Genetic Risk

Author: Kehm, RD, Genkinger, JM, MacInnis, RJ, John, EM, Phillips, K-A, Dite, GS, Milne, RL, Zeinomar, N, Liao, Y, Knight, JA, Southey, MC, Chung, WK, Giles, GG, McLachlan, S-A, Whitaker, KD, Friedlander, M, Weideman, PC, Glendon, G, Nesci, S, Andrulis, IL, Buys, SS, Daly, MB, Hopper, JL, Terry, MB, Kehm, RD, Genkinger, JM, MacInnis, RJ, John, EM, Phillips, K-A, Dite, GS, Milne, RL, Zeinomar, N, Liao, Y, Knight, JA, Southey, MC, Chung, WK, Giles, GG, McLachlan, S-A, Whitaker, KD, Friedlander, M, Weideman, PC, Glendon, G, Nesci, S, Andrulis, IL, Buys, SS, Daly, MB, Hopper, JL, and Terry, MB
Abstract: Although physical activity is associated with lower breast cancer risk for average-risk women, it is not known if this association applies to women at high familial/genetic risk. We examined the association of recreational physical activity (self-reported by questionnaire) with breast cancer risk using the Prospective Family Study Cohort, which is enriched with women who have a breast cancer family history (N = 15,550). We examined associations of adult and adolescent recreational physical activity (quintiles of age-adjusted total metabolic equivalents per week) with breast cancer risk using multivariable Cox proportional hazards regression, adjusted for demographics, lifestyle factors, and body mass index. We tested for multiplicative interactions of physical activity with predicted absolute breast cancer familial risk based on pedigree data and with BRCA1 and BRCA2 mutation status. Baseline recreational physical activity level in the highest four quintiles compared with the lowest quintile was associated with a 20% lower breast cancer risk (HR, 0.80; 95% confidence interval, 0.68-0.93). The association was not modified by familial risk or BRCA mutation status (P interactions >0.05). No overall association was found for adolescent recreational physical activity. Recreational physical activity in adulthood may lower breast cancer risk for women across the spectrum of familial risk. SIGNIFICANCE: These findings suggest that physical activity might reduce breast cancer risk by about 20% for women across the risk continuum, including women at higher-than-average risk due to their family history or genetic susceptibility.See related commentary by Niehoff et al., p. 23.
Published: 2020

36. Transcriptome-wide association study of breast cancer risk by estrogen-receptor status

Author: Feng, H, Gusev, A, Pasaniuc, B, Wu, L, Long, J, Abu-full, Z, Aittomaki, K, Andrulis, IL, Anton-Culver, H, Antoniou, AC, Arason, A, Arndt, V, Aronson, KJ, Arun, BK, Asseryanis, E, Auer, PL, Azzollini, J, Balmana, J, Barkardottir, RB, Barnes, DR, Barrowdale, D, Beckmann, MW, Behrens, S, Benitez, J, Bermisheva, M, Bialkowska, K, Blanco, A, Blomqvist, C, Boeckx, B, Bogdanova, NV, Bojesen, SE, Bolla, MK, Bonanni, B, Borg, A, Brauch, H, Brenner, H, Briceno, I, Broeks, A, Bruening, T, Burwinkel, B, Cai, Q, Caldes, T, Caligo, MA, Campbell, I, Canisius, S, Campa, D, Carter, BD, Carter, J, Castelao, JE, Chang-Claude, J, Chanock, SJ, Christiansen, H, Chung, WK, Claes, KBM, Clarke, CL, Couch, FJ, Cox, A, Cross, SS, Cybulski, C, Czene, K, Daly, MB, de la Hoya, M, De Leeneer, K, Dennis, J, Devilee, P, Diez, O, Domchek, SM, Doerk, T, dos-Santos-Silva, I, Dunning, AM, Dwek, M, Eccles, DM, Ejlertsen, B, Ellberg, C, Engel, C, Eriksson, M, Fasching, PA, Fletcher, O, Flyger, H, Fostira, F, Friedman, E, Fritschi, L, Frost, D, Gabrielson, M, Ganz, PA, Gapstur, SM, Garber, J, Garcia-Closas, M, Garcia-Saenz, JA, Gaudet, MM, Giles, GG, Glendon, G, Godwin, AK, Goldberg, MS, Goldgar, DE, Gonzalez-Neira, A, Greene, MH, Gronwald, J, Guenel, P, Haiman, CA, Hall, P, Hamann, U, Hake, C, He, W, Heyworth, J, Hogervorst, FBL, Hollestelle, A, Hooning, MJ, Hoover, RN, Hopper, JL, Huang, G, Hulick, PJ, Humphreys, K, Imyanitov, EN, Isaacs, C, Jakimovska, M, Jakubowska, A, James, P, Janavicius, R, Jankowitz, RC, John, EM, Johnson, N, Joseph, V, Jung, A, Karlan, BY, Khusnutdinova, E, Kiiski, J, Konstantopoulou, I, Kristensen, VN, Laitman, Y, Lambrechts, D, Lazaro, C, Leroux, D, Leslie, G, Lester, J, Lesueur, F, Lindor, N, Lindstrom, S, Lo, W-Y, Loud, JT, Lubinski, J, Makalic, E, Mannermaa, A, Manoochehri, M, Manoukian, S, Margolin, S, Martens, JWM, Martinez, ME, Matricardi, L, Maurer, T, Mavroudis, D, McGuffog, L, Meindl, A, Menon, U, Michailidou, K, Kapoor, PM, Miller, A, Montagna, M, Moreno, F, Moserle, L, Mulligan, AM, Muranen, TA, Nathanson, KL, Neuhausen, SL, Nevanlinna, H, Nevelsteen, I, Nielsen, FC, Nikitina-Zake, L, Offit, K, Olah, E, Olopade, O, Olsson, H, Osorio, A, Papp, J, Park-Simon, T-W, Parsons, MT, Pedersen, IS, Peixoto, A, Peterlongo, P, Peto, J, Pharoah, PDP, Phillips, K-A, Plaseska-Karanfilska, D, Poppe, B, Pradhan, N, Prajzendanc, K, Presneau, N, Punie, K, Pylkas, K, Radice, P, Rantala, J, Rashid, MU, Rennert, G, Risch, HA, Robson, M, Romero, A, Saloustros, E, Sandler, DP, Santos, C, Sawyer, EJ, Schmidt, MK, Schmidt, DF, Schmutzler, RK, Schoemaker, MJ, Scott, RJ, Sharma, P, Shu, X-O, Simard, J, Singer, CF, Skytte, A-B, Soucy, P, Southey, MC, Spinelli, JJ, Spurdle, AB, Stone, J, Swerdlow, AJ, Tapper, WJ, Taylor, JA, Teixeira, MR, Terry, MB, Teule, A, Thomassen, M, Thoene, K, Thull, DL, Tischkowitz, M, Toland, AE, Tollenaar, RAEM, Torres, D, Truong, T, Tung, N, Vachon, CM, van Asperen, CJ, van den Ouweland, AMW, van Rensburg, EJ, Vega, A, Viel, A, Vieiro-Balo, P, Wang, Q, Wappenschmidt, B, Weinberg, CR, Weitzel, J, Wendt, C, Winqvist, R, Yang, XR, Yannoukakos, D, Ziogas, A, Milne, RL, Easton, DF, Chenevix-Trench, G, Zheng, W, Kraft, P, Jiang, X, Feng, H, Gusev, A, Pasaniuc, B, Wu, L, Long, J, Abu-full, Z, Aittomaki, K, Andrulis, IL, Anton-Culver, H, Antoniou, AC, Arason, A, Arndt, V, Aronson, KJ, Arun, BK, Asseryanis, E, Auer, PL, Azzollini, J, Balmana, J, Barkardottir, RB, Barnes, DR, Barrowdale, D, Beckmann, MW, Behrens, S, Benitez, J, Bermisheva, M, Bialkowska, K, Blanco, A, Blomqvist, C, Boeckx, B, Bogdanova, NV, Bojesen, SE, Bolla, MK, Bonanni, B, Borg, A, Brauch, H, Brenner, H, Briceno, I, Broeks, A, Bruening, T, Burwinkel, B, Cai, Q, Caldes, T, Caligo, MA, Campbell, I, Canisius, S, Campa, D, Carter, BD, Carter, J, Castelao, JE, Chang-Claude, J, Chanock, SJ, Christiansen, H, Chung, WK, Claes, KBM, Clarke, CL, Couch, FJ, Cox, A, Cross, SS, Cybulski, C, Czene, K, Daly, MB, de la Hoya, M, De Leeneer, K, Dennis, J, Devilee, P, Diez, O, Domchek, SM, Doerk, T, dos-Santos-Silva, I, Dunning, AM, Dwek, M, Eccles, DM, Ejlertsen, B, Ellberg, C, Engel, C, Eriksson, M, Fasching, PA, Fletcher, O, Flyger, H, Fostira, F, Friedman, E, Fritschi, L, Frost, D, Gabrielson, M, Ganz, PA, Gapstur, SM, Garber, J, Garcia-Closas, M, Garcia-Saenz, JA, Gaudet, MM, Giles, GG, Glendon, G, Godwin, AK, Goldberg, MS, Goldgar, DE, Gonzalez-Neira, A, Greene, MH, Gronwald, J, Guenel, P, Haiman, CA, Hall, P, Hamann, U, Hake, C, He, W, Heyworth, J, Hogervorst, FBL, Hollestelle, A, Hooning, MJ, Hoover, RN, Hopper, JL, Huang, G, Hulick, PJ, Humphreys, K, Imyanitov, EN, Isaacs, C, Jakimovska, M, Jakubowska, A, James, P, Janavicius, R, Jankowitz, RC, John, EM, Johnson, N, Joseph, V, Jung, A, Karlan, BY, Khusnutdinova, E, Kiiski, J, Konstantopoulou, I, Kristensen, VN, Laitman, Y, Lambrechts, D, Lazaro, C, Leroux, D, Leslie, G, Lester, J, Lesueur, F, Lindor, N, Lindstrom, S, Lo, W-Y, Loud, JT, Lubinski, J, Makalic, E, Mannermaa, A, Manoochehri, M, Manoukian, S, Margolin, S, Martens, JWM, Martinez, ME, Matricardi, L, Maurer, T, Mavroudis, D, McGuffog, L, Meindl, A, Menon, U, Michailidou, K, Kapoor, PM, Miller, A, Montagna, M, Moreno, F, Moserle, L, Mulligan, AM, Muranen, TA, Nathanson, KL, Neuhausen, SL, Nevanlinna, H, Nevelsteen, I, Nielsen, FC, Nikitina-Zake, L, Offit, K, Olah, E, Olopade, O, Olsson, H, Osorio, A, Papp, J, Park-Simon, T-W, Parsons, MT, Pedersen, IS, Peixoto, A, Peterlongo, P, Peto, J, Pharoah, PDP, Phillips, K-A, Plaseska-Karanfilska, D, Poppe, B, Pradhan, N, Prajzendanc, K, Presneau, N, Punie, K, Pylkas, K, Radice, P, Rantala, J, Rashid, MU, Rennert, G, Risch, HA, Robson, M, Romero, A, Saloustros, E, Sandler, DP, Santos, C, Sawyer, EJ, Schmidt, MK, Schmidt, DF, Schmutzler, RK, Schoemaker, MJ, Scott, RJ, Sharma, P, Shu, X-O, Simard, J, Singer, CF, Skytte, A-B, Soucy, P, Southey, MC, Spinelli, JJ, Spurdle, AB, Stone, J, Swerdlow, AJ, Tapper, WJ, Taylor, JA, Teixeira, MR, Terry, MB, Teule, A, Thomassen, M, Thoene, K, Thull, DL, Tischkowitz, M, Toland, AE, Tollenaar, RAEM, Torres, D, Truong, T, Tung, N, Vachon, CM, van Asperen, CJ, van den Ouweland, AMW, van Rensburg, EJ, Vega, A, Viel, A, Vieiro-Balo, P, Wang, Q, Wappenschmidt, B, Weinberg, CR, Weitzel, J, Wendt, C, Winqvist, R, Yang, XR, Yannoukakos, D, Ziogas, A, Milne, RL, Easton, DF, Chenevix-Trench, G, Zheng, W, Kraft, P, and Jiang, X
Abstract: Previous transcriptome-wide association studies (TWAS) have identified breast cancer risk genes by integrating data from expression quantitative loci and genome-wide association studies (GWAS), but analyses of breast cancer subtype-specific associations have been limited. In this study, we conducted a TWAS using gene expression data from GTEx and summary statistics from the hitherto largest GWAS meta-analysis conducted for breast cancer overall, and by estrogen receptor subtypes (ER+ and ER-). We further compared associations with ER+ and ER- subtypes, using a case-only TWAS approach. We also conducted multigene conditional analyses in regions with multiple TWAS associations. Two genes, STXBP4 and HIST2H2BA, were specifically associated with ER+ but not with ER- breast cancer. We further identified 30 TWAS-significant genes associated with overall breast cancer risk, including four that were not identified in previous studies. Conditional analyses identified single independent breast-cancer gene in three of six regions harboring multiple TWAS-significant genes. Our study provides new information on breast cancer genetics and biology, particularly about genomic differences between ER+ and ER- breast cancer.
Published: 2020

37. Alcohol Consumption, Cigarette Smoking, and Risk of Breast Cancer for BRCA1 and BRCA2 Mutation Carriers: Results from The BRCA1 and BRCA2 Cohort Consortium

Author: Li, H, Terry, MB, Antoniou, AC, Phillips, K-A, Kast, K, Mooij, TM, Engel, C, Nogues, C, Stoppa-Lyonnet, D, Lasset, C, Berthet, P, Mari, V, Caron, O, Barrowdale, D, Frost, D, Brewer, C, Evans, DG, Izatt, L, Side, L, Walker, L, Tischkowitz, M, Rogers, MT, Porteous, ME, Snape, K, Meijers-Heijboer, HEJ, Gille, JJP, Blok, MJ, Hoogerbrugge, N, Daly, MB, Andrulis, IL, Buys, SS, John, EM, McLachlan, S-A, Friedlander, M, Tan, YY, Osorio, A, Caldes, T, Jakubowska, A, Simard, J, Singer, CF, Olah, E, Navratilova, M, Foretova, L, Gerdes, A-M, Roos-Blom, M-J, Arver, B, Olsson, H, Schmutzler, RK, Hopper, JL, Milne, RL, Easton, DF, Van Leeuwen, FE, Rookus, MA, Andrieu, N, Goldgar, DE, Li, H, Terry, MB, Antoniou, AC, Phillips, K-A, Kast, K, Mooij, TM, Engel, C, Nogues, C, Stoppa-Lyonnet, D, Lasset, C, Berthet, P, Mari, V, Caron, O, Barrowdale, D, Frost, D, Brewer, C, Evans, DG, Izatt, L, Side, L, Walker, L, Tischkowitz, M, Rogers, MT, Porteous, ME, Snape, K, Meijers-Heijboer, HEJ, Gille, JJP, Blok, MJ, Hoogerbrugge, N, Daly, MB, Andrulis, IL, Buys, SS, John, EM, McLachlan, S-A, Friedlander, M, Tan, YY, Osorio, A, Caldes, T, Jakubowska, A, Simard, J, Singer, CF, Olah, E, Navratilova, M, Foretova, L, Gerdes, A-M, Roos-Blom, M-J, Arver, B, Olsson, H, Schmutzler, RK, Hopper, JL, Milne, RL, Easton, DF, Van Leeuwen, FE, Rookus, MA, Andrieu, N, and Goldgar, DE
Abstract: BACKGROUND: Tobacco smoking and alcohol consumption have been intensively studied in the general population to assess their effects on the risk of breast cancer, but very few studies have examined these effects in BRCA1 and BRCA2 mutation carriers. Given the high breast cancer risk for mutation carriers and the importance of BRCA1 and BRCA2 in DNA repair, better evidence on the associations of these lifestyle factors with breast cancer risk is essential. METHODS: Using a large international pooled cohort of BRCA1 and BRCA2 mutation carriers, we conducted retrospective (5,707 BRCA1 mutation carriers and 3,525 BRCA2 mutation carriers) and prospective (2,276 BRCA1 mutation carriers and 1,610 BRCA2 mutation carriers) analyses of alcohol and tobacco consumption using Cox proportional hazards models. RESULTS: For both BRCA1 and BRCA2 mutation carriers, none of the smoking-related variables was associated with breast cancer risk, except smoking for more than 5 years before a first full-term pregnancy (FFTP) when compared with parous women who never smoked. For BRCA1 mutation carriers, the HR from retrospective analysis (HRR) was 1.19 [95% confidence interval (CI), 1.02-1.39] and the HR from prospective analysis (HRP) was 1.36 (95% CI, 0.99-1.87). For BRCA2 mutation carriers, smoking for more than 5 years before an FFTP showed an association of a similar magnitude, but the confidence limits were wider (HRR = 1.25; 95% CI, 1.01-1.55 and HRP = 1.30; 95% CI, 0.83-2.01). For both carrier groups, alcohol consumption was not associated with breast cancer risk. CONCLUSIONS: The finding that smoking during the prereproductive years increases breast cancer risk for mutation carriers warrants further investigation. IMPACT: This is the largest prospective study of BRCA mutation carriers to assess these important risk factors.
Published: 2020

38. Breast Cancer Polygenic Risk Score and Contralateral Breast Cancer Risk.

Author: Kramer I, Hooning MJ, Mavaddat N, Hauptmann M, Keeman R, Steyerberg EW, Giardiello D, Antoniou AC, Pharoah PDP, Canisius S, Abu-Ful Z, Andrulis IL, Anton-Culver H, Aronson KJ, Augustinsson A, Becher H, Beckmann MW, Behrens S, Benitez J, Bermisheva M, Bogdanova NV, Bojesen SE, Bolla MK, Bonanni B, Brauch H, Bremer M, Brucker SY, Burwinkel B, Castelao JE, Chan TL, Chang-Claude J, Chanock SJ, Chenevix-Trench G, Choi J-Y, Clarke CL, NBCS Collaborators, Collée JM, Couch FJ, Cox A, Cross SS, Czene K, Daly MB, Devilee P, Dörk T, Dos-Santos-Silva I, Dunning AM, Dwek M, Eccles DM, Evans DG, Fasching PA, Flyger H, Gago-Dominguez M, García-Closas M, García-Sáenz JA, Giles GG, Goldgar DE, González-Neira A, Haiman CA, Håkansson N, Hamann U, Hartman M, Heemskerk-Gerritsen BAM, Hollestelle A, Hopper JL, Hou M-F, Howell A, ABCTB Investigators, kConFab Investigators, Ito H, Jakimovska M, Jakubowska A, Janni W, John EM, Jung A, Kang D, Kets CM, Khusnutdinova E, Ko Y-D, Kristensen VN, Kurian AW, Kwong A, Lambrechts D, Le Marchand L, Li J, Lindblom A, Lubiński J, Mannermaa A, Manoochehri M, Margolin S, Matsuo K, Mavroudis D, Meindl A, Milne RL, Mulligan AM, Muranen TA, Neuhausen SL, Nevanlinna H, Newman WG, Olshan AF, Olson JE, Olsson H, Park-Simon T-W, Peto J, Petridis C, Plaseska-Karanfilska D, Presneau N, Pylkäs K, Radice P, Rennert G, Romero A, Roylance R, Saloustros E, Sawyer EJ, Schmutzler RK, Schwentner L, Scott C, See M-H, Shah M, Shen C-Y, Shu X-O, Siesling S, Slager S, Sohn C, Southey MC, Spinelli JJ, Stone J, Tapper WJ, Tengström M, Teo SH, Terry MB, Tollenaar RAEM, Tomlinson I, Troester MA, Vachon CM, van Ongeval C, van Veen EM, Winqvist R, Wolk A, Zheng W, Ziogas A, Easton DF, Hall P, Schmidt MK, Kramer I, Hooning MJ, Mavaddat N, Hauptmann M, Keeman R, Steyerberg EW, Giardiello D, Antoniou AC, Pharoah PDP, Canisius S, Abu-Ful Z, Andrulis IL, Anton-Culver H, Aronson KJ, Augustinsson A, Becher H, Beckmann MW, Behrens S, Benitez J, Bermisheva M, Bogdanova NV, Bojesen SE, Bolla MK, Bonanni B, Brauch H, Bremer M, Brucker SY, Burwinkel B, Castelao JE, Chan TL, Chang-Claude J, Chanock SJ, Chenevix-Trench G, Choi J-Y, Clarke CL, NBCS Collaborators, Collée JM, Couch FJ, Cox A, Cross SS, Czene K, Daly MB, Devilee P, Dörk T, Dos-Santos-Silva I, Dunning AM, Dwek M, Eccles DM, Evans DG, Fasching PA, Flyger H, Gago-Dominguez M, García-Closas M, García-Sáenz JA, Giles GG, Goldgar DE, González-Neira A, Haiman CA, Håkansson N, Hamann U, Hartman M, Heemskerk-Gerritsen BAM, Hollestelle A, Hopper JL, Hou M-F, Howell A, ABCTB Investigators, kConFab Investigators, Ito H, Jakimovska M, Jakubowska A, Janni W, John EM, Jung A, Kang D, Kets CM, Khusnutdinova E, Ko Y-D, Kristensen VN, Kurian AW, Kwong A, Lambrechts D, Le Marchand L, Li J, Lindblom A, Lubiński J, Mannermaa A, Manoochehri M, Margolin S, Matsuo K, Mavroudis D, Meindl A, Milne RL, Mulligan AM, Muranen TA, Neuhausen SL, Nevanlinna H, Newman WG, Olshan AF, Olson JE, Olsson H, Park-Simon T-W, Peto J, Petridis C, Plaseska-Karanfilska D, Presneau N, Pylkäs K, Radice P, Rennert G, Romero A, Roylance R, Saloustros E, Sawyer EJ, Schmutzler RK, Schwentner L, Scott C, See M-H, Shah M, Shen C-Y, Shu X-O, Siesling S, Slager S, Sohn C, Southey MC, Spinelli JJ, Stone J, Tapper WJ, Tengström M, Teo SH, Terry MB, Tollenaar RAEM, Tomlinson I, Troester MA, Vachon CM, van Ongeval C, van Veen EM, Winqvist R, Wolk A, Zheng W, Ziogas A, Easton DF, Hall P, and Schmidt MK
Abstract: Previous research has shown that polygenic risk scores (PRSs) can be used to stratify women according to their risk of developing primary invasive breast cancer. This study aimed to evaluate the association between a recently validated PRS of 313 germline variants (PRS313) and contralateral breast cancer (CBC) risk. We included 56,068 women of European ancestry diagnosed with first invasive breast cancer from 1990 onward with follow-up from the Breast Cancer Association Consortium. Metachronous CBC risk (N = 1,027) according to the distribution of PRS313 was quantified using Cox regression analyses. We assessed PRS313 interaction with age at first diagnosis, family history, morphology, ER status, PR status, and HER2 status, and (neo)adjuvant therapy. In studies of Asian women, with limited follow-up, CBC risk associated with PRS313 was assessed using logistic regression for 340 women with CBC compared with 12,133 women with unilateral breast cancer. Higher PRS313 was associated with increased CBC risk: hazard ratio per standard deviation (SD) = 1.25 (95%CI = 1.18-1.33) for Europeans, and an OR per SD = 1.15 (95%CI = 1.02-1.29) for Asians. The absolute lifetime risks of CBC, accounting for death as competing risk, were 12.4% for European women at the 10th percentile and 20.5% at the 90th percentile of PRS313. We found no evidence of confounding by or interaction with individual characteristics, characteristics of the primary tumor, or treatment. The C-index for the PRS313 alone was 0.563 (95%CI = 0.547-0.586). In conclusion, PRS313 is an independent factor associated with CBC risk and can be incorporated into CBC risk prediction models to help improve stratification and optimize surveillance and treatment strategies.
Published: 2020

39. The Influence of Number and Timing of Pregnancies on Breast Cancer Risk for Women With BRCA1 or BRCA2 Mutations

Author: Terry, MB, Liao, Y, Kast, K, Antoniou, AC, McDonald, JA, Mooij, TM, Engel, C, Nogues, C, Buecher, B, Mari, V, Moretta-Serra, J, Gladieff, L, Luporsi, E, Barrowdale, D, Frost, D, Henderson, A, Brewer, C, Evans, DG, Eccles, D, Cook, J, Ong, K-R, Izatt, L, Ahmed, M, Morrison, PJ, Dommering, CJ, Oosterwijk, JC, Ausems, MGEM, Kriege, M, Buys, SS, Andrulis, IL, John, EM, Daly, M, Friedlander, M, McLachlan, SA, Osorio, A, Caldes, T, Jakubowska, A, Simard, J, Singer, CF, Tan, Y, Olah, E, Navratilova, M, Foretova, L, Gerdes, A-M, Roos-Blom, M-J, Arver, B, Olsson, H, Schmutzler, RK, Hopper, JL, van Leeuwen, FE, Goldgar, D, Milne, RL, Easton, DF, Rookus, MA, Andrieu, N, and EMBRACE, GENEPSO, BCFR, HEBON, kConFab and IBCCS
Subjects: endocrine system diseases, skin and connective tissue diseases
Abstract: Background: Full-term pregnancy (FTP) is associated with a reduced breast cancer (BC) risk over time, but women are at increased BC risk in the immediate years following an FTP. No large prospective studies, however, have examined whether the number and timing of pregnancies are associated with BC risk for BRCA1 and BRCA2 mutation carriers. Methods: Using weighted and time-varying Cox proportional hazards models, we investigated whether reproductive events are associated with BC risk for mutation carriers using a retrospective cohort (5707 BRCA1 and 3525 BRCA2 mutation carriers) and a prospective cohort (2276 BRCA1 and 1610 BRCA2 mutation carriers), separately for each cohort and the combined prospective and retrospective cohort. Results: For BRCA1 mutation carriers, there was no overall association with parity compared with nulliparity (combined hazard ratio [HRc] = 0.99, 95% confidence interval [CI] = 0.83 to 1.18). Relative to being uniparous, an increased number of FTPs was associated with decreased BC risk (HRc = 0.79, 95% CI = 0.69 to 0.91; HRc = 0.70, 95% CI = 0.59 to 0.82; HRc = 0.50, 95% CI = 0.40 to 0.63, for 2, 3, and ≥4 FTPs, respectively, Ptrend < .0001) and increasing duration of breastfeeding was associated with decreased BC risk (combined cohort Ptrend = .0003). Relative to being nulliparous, uniparous BRCA1 mutation carriers were at increased BC risk in the prospective analysis (prospective hazard ration [HRp] = 1.69, 95% CI = 1.09 to 2.62). For BRCA2 mutation carriers, being parous was associated with a 30% increase in BC risk (HRc = 1.33, 95% CI = 1.05 to 1.69), and there was no apparent decrease in risk associated with multiparity except for having at least 4 FTPs vs. 1 FTP (HRc = 0.72, 95% CI = 0.54 to 0.98). Conclusions: These findings suggest differential associations with parity between BRCA1 and BRCA2 mutation carriers with higher risk for uniparous BRCA1 carriers and parous BRCA2 carriers.
Published: 2019

40. Shared heritability and functional enrichment across six solid cancers

Author: Jiang, X, Finucane, HK, Schumacher, FR, Schmit, SL, Tyrer, JP, Han, Y, Michailidou, K, Lesseur, C, Kuchenbaecker, KB, Dennis, J, Conti, DV, Casey, G, Gaudet, MM, Huyghe, JR, Albanes, D, Aldrich, MC, Andrew, AS, Andrulis, IL, Anton-Culver, H, Antoniou, AC, Antonenkova, NN, Arnold, SM, Aronson, KJ, Arun, BK, Bandera, EV, Barkardottir, RB, Barnes, DR, Batra, J, Beckmann, MW, Benitez, J, Benlloch, S, Berchuck, A, Berndt, SI, Bickeboeller, H, Bien, SA, Blomqvist, C, Boccia, S, Bogdanova, NV, Bojesen, SE, Bolla, MK, Brauch, H, Brenner, H, Brenton, JD, Brook, MN, Brunet, J, Brunnstrom, H, Buchanan, DD, Burwinkel, B, Butzow, R, Cadoni, G, Caldes, T, Caligo, MA, Campbell, I, Campbell, PT, Cancel-Tassin, G, Cannon-Albright, L, Campa, D, Caporaso, N, Carvalho, AL, Chan, AT, Chang-Claude, J, Chanock, SJ, Chen, C, Christiani, DC, Claes, KBM, Claessens, F, Clements, J, Collee, JM, Correa, MC, Couch, FJ, Cox, A, Cunningham, JM, Cybulski, C, Czene, K, Daly, MB, defazio, A, Devilee, P, Diez, O, Gago-Dominguez, M, Donovan, JL, Doerk, T, Duell, EJ, Dunning, AM, Dwek, M, Eccles, DM, Edlund, CK, Edwards, DRV, Ellberg, C, Evans, DG, Fasching, PA, Ferris, RL, Liloglou, T, Figueiredo, JC, Fletcher, O, Fortner, RT, Fostira, F, Franceschi, S, Friedman, E, Gallinger, SJ, Ganz, PA, Garber, J, Garcia-Saenz, JA, Gayther, SA, Giles, GG, Godwin, AK, Goldberg, MS, Goldgar, DE, Goode, EL, Goodman, MT, Goodman, G, Grankvist, K, Greene, MH, Gronberg, H, Gronwald, J, Guenel, P, Hakansson, N, Hall, P, Hamann, U, Hamdy, FC, Hamilton, RJ, Hampe, J, Haugen, A, Heitz, F, Herrero, R, Hillemanns, P, Hoffmeister, M, Hogdall, E, Hong, Y-C, Hopper, JL, Houlston, R, Hulick, PJ, Hunter, DJ, Huntsman, DG, Idos, G, Imyanitov, EN, Ingles, SA, Isaacs, C, Jakubowska, A, James, P, Jenkins, MA, Johansson, M, John, EM, Joshi, AD, Kaneva, R, Karlan, BY, Kelemen, LE, Kuhl, T, Khaw, K-T, Khusnutdinova, E, Kibel, AS, Kiemeney, LA, Kim, J, Kjaer, SK, Knight, JA, Kogevinas, M, Kote-Jarai, Z, Koutros, S, Kristensen, VN, Kupryjanczyk, J, Lacko, M, Lam, S, Lambrechts, D, Landi, MT, Lazarus, P, Le, ND, Lee, E, Lejbkowicz, F, Lenz, H-J, Leslie, G, Lessel, D, Lester, J, Levine, DA, Li, L, Li, CI, Lindblom, A, Lindor, NM, Liu, G, Loupakis, F, Lubinski, J, Maehle, L, Maier, C, Mannermaa, A, Le Marchand, L, Margolin, S, May, T, McGuffog, L, Meindl, A, Middha, P, Miller, A, Milne, RL, MacInnis, RJ, Modugno, F, Montagna, M, Moreno, V, Moysich, KB, Mucci, L, Muir, K, Mulligan, AM, Nathanson, KL, Neal, DE, Ness, AR, Neuhausen, SL, Nevanlinna, H, Newcomb, PA, Newcomb, LF, Nielsen, FC, Nikitina-Zake, L, Nordestgaard, BG, Nussbaum, RL, Offit, K, Olah, E, Al Olama, AA, Olopade, OI, Olshan, AF, Olsson, H, Osorio, A, Pandha, H, Park, JY, Pashayan, N, Parsons, MT, Pejovic, T, Penney, KL, Peters, WHM, Phelan, CM, Phipps, AI, Plaseska-Karanfilska, D, Pring, M, Prokofyeva, D, Radice, P, Stefansson, K, Ramus, SJ, Raskin, L, Rennert, G, Rennert, HS, van Rensburg, EJ, Riggan, MJ, Risch, HA, Risch, A, Roobol, MJ, Rosenstein, BS, Rossing, MA, De Ruyck, K, Saloustros, E, Sandler, DP, Sawyer, EJ, Schabath, MB, Schleutker, J, Schmidt, MK, Setiawan, VW, Shen, H, Siegel, EM, Sieh, W, Singer, CF, Slattery, ML, Sorensen, KD, Southey, MC, Spurdle, AB, Stanford, JL, Stevens, VL, Stintzing, S, Stone, J, Sundfeldt, K, Sutphen, R, Swerdlow, AJ, Tajara, EH, Tangen, CM, Tardon, A, Taylor, JA, Teare, MD, Teixeira, MR, Terry, MB, Terry, KL, Thibodeau, SN, Thomassen, M, Bjorge, L, Tischkowitz, M, Toland, AE, Torres, D, Townsend, PA, Travis, RC, Tung, N, Tworoger, SS, Ulrich, CM, Usmani, N, Vachon, CM, Van Nieuwenhuysen, E, Vega, A, Aguado-Barrera, ME, Wang, Q, Webb, PM, Weinberg, CR, Weinstein, S, Weissler, MC, Weitzel, JN, West, CML, White, E, Whittemore, AS, Wichmann, H-E, Wiklund, F, Winqvist, R, Wolk, A, Woll, P, Woods, M, Wu, AH, Wu, X, Yannoukakos, D, Zheng, W, Zienolddiny, S, Ziogas, A, Zorn, KK, Lane, JM, Saxena, R, Thomas, D, Hung, RJ, Diergaarde, B, Mckay, J, Peters, U, Hsu, L, Garcia-Closas, M, Eeles, RA, Chenevix-Trench, G, Brennan, PJ, Haiman, CA, Simard, J, Easton, DF, Gruber, SB, Pharoah, PDP, Price, AL, Pasaniuc, B, Amos, CI, Kraft, P, Lindstrom, S, Jiang, X, Finucane, HK, Schumacher, FR, Schmit, SL, Tyrer, JP, Han, Y, Michailidou, K, Lesseur, C, Kuchenbaecker, KB, Dennis, J, Conti, DV, Casey, G, Gaudet, MM, Huyghe, JR, Albanes, D, Aldrich, MC, Andrew, AS, Andrulis, IL, Anton-Culver, H, Antoniou, AC, Antonenkova, NN, Arnold, SM, Aronson, KJ, Arun, BK, Bandera, EV, Barkardottir, RB, Barnes, DR, Batra, J, Beckmann, MW, Benitez, J, Benlloch, S, Berchuck, A, Berndt, SI, Bickeboeller, H, Bien, SA, Blomqvist, C, Boccia, S, Bogdanova, NV, Bojesen, SE, Bolla, MK, Brauch, H, Brenner, H, Brenton, JD, Brook, MN, Brunet, J, Brunnstrom, H, Buchanan, DD, Burwinkel, B, Butzow, R, Cadoni, G, Caldes, T, Caligo, MA, Campbell, I, Campbell, PT, Cancel-Tassin, G, Cannon-Albright, L, Campa, D, Caporaso, N, Carvalho, AL, Chan, AT, Chang-Claude, J, Chanock, SJ, Chen, C, Christiani, DC, Claes, KBM, Claessens, F, Clements, J, Collee, JM, Correa, MC, Couch, FJ, Cox, A, Cunningham, JM, Cybulski, C, Czene, K, Daly, MB, defazio, A, Devilee, P, Diez, O, Gago-Dominguez, M, Donovan, JL, Doerk, T, Duell, EJ, Dunning, AM, Dwek, M, Eccles, DM, Edlund, CK, Edwards, DRV, Ellberg, C, Evans, DG, Fasching, PA, Ferris, RL, Liloglou, T, Figueiredo, JC, Fletcher, O, Fortner, RT, Fostira, F, Franceschi, S, Friedman, E, Gallinger, SJ, Ganz, PA, Garber, J, Garcia-Saenz, JA, Gayther, SA, Giles, GG, Godwin, AK, Goldberg, MS, Goldgar, DE, Goode, EL, Goodman, MT, Goodman, G, Grankvist, K, Greene, MH, Gronberg, H, Gronwald, J, Guenel, P, Hakansson, N, Hall, P, Hamann, U, Hamdy, FC, Hamilton, RJ, Hampe, J, Haugen, A, Heitz, F, Herrero, R, Hillemanns, P, Hoffmeister, M, Hogdall, E, Hong, Y-C, Hopper, JL, Houlston, R, Hulick, PJ, Hunter, DJ, Huntsman, DG, Idos, G, Imyanitov, EN, Ingles, SA, Isaacs, C, Jakubowska, A, James, P, Jenkins, MA, Johansson, M, John, EM, Joshi, AD, Kaneva, R, Karlan, BY, Kelemen, LE, Kuhl, T, Khaw, K-T, Khusnutdinova, E, Kibel, AS, Kiemeney, LA, Kim, J, Kjaer, SK, Knight, JA, Kogevinas, M, Kote-Jarai, Z, Koutros, S, Kristensen, VN, Kupryjanczyk, J, Lacko, M, Lam, S, Lambrechts, D, Landi, MT, Lazarus, P, Le, ND, Lee, E, Lejbkowicz, F, Lenz, H-J, Leslie, G, Lessel, D, Lester, J, Levine, DA, Li, L, Li, CI, Lindblom, A, Lindor, NM, Liu, G, Loupakis, F, Lubinski, J, Maehle, L, Maier, C, Mannermaa, A, Le Marchand, L, Margolin, S, May, T, McGuffog, L, Meindl, A, Middha, P, Miller, A, Milne, RL, MacInnis, RJ, Modugno, F, Montagna, M, Moreno, V, Moysich, KB, Mucci, L, Muir, K, Mulligan, AM, Nathanson, KL, Neal, DE, Ness, AR, Neuhausen, SL, Nevanlinna, H, Newcomb, PA, Newcomb, LF, Nielsen, FC, Nikitina-Zake, L, Nordestgaard, BG, Nussbaum, RL, Offit, K, Olah, E, Al Olama, AA, Olopade, OI, Olshan, AF, Olsson, H, Osorio, A, Pandha, H, Park, JY, Pashayan, N, Parsons, MT, Pejovic, T, Penney, KL, Peters, WHM, Phelan, CM, Phipps, AI, Plaseska-Karanfilska, D, Pring, M, Prokofyeva, D, Radice, P, Stefansson, K, Ramus, SJ, Raskin, L, Rennert, G, Rennert, HS, van Rensburg, EJ, Riggan, MJ, Risch, HA, Risch, A, Roobol, MJ, Rosenstein, BS, Rossing, MA, De Ruyck, K, Saloustros, E, Sandler, DP, Sawyer, EJ, Schabath, MB, Schleutker, J, Schmidt, MK, Setiawan, VW, Shen, H, Siegel, EM, Sieh, W, Singer, CF, Slattery, ML, Sorensen, KD, Southey, MC, Spurdle, AB, Stanford, JL, Stevens, VL, Stintzing, S, Stone, J, Sundfeldt, K, Sutphen, R, Swerdlow, AJ, Tajara, EH, Tangen, CM, Tardon, A, Taylor, JA, Teare, MD, Teixeira, MR, Terry, MB, Terry, KL, Thibodeau, SN, Thomassen, M, Bjorge, L, Tischkowitz, M, Toland, AE, Torres, D, Townsend, PA, Travis, RC, Tung, N, Tworoger, SS, Ulrich, CM, Usmani, N, Vachon, CM, Van Nieuwenhuysen, E, Vega, A, Aguado-Barrera, ME, Wang, Q, Webb, PM, Weinberg, CR, Weinstein, S, Weissler, MC, Weitzel, JN, West, CML, White, E, Whittemore, AS, Wichmann, H-E, Wiklund, F, Winqvist, R, Wolk, A, Woll, P, Woods, M, Wu, AH, Wu, X, Yannoukakos, D, Zheng, W, Zienolddiny, S, Ziogas, A, Zorn, KK, Lane, JM, Saxena, R, Thomas, D, Hung, RJ, Diergaarde, B, Mckay, J, Peters, U, Hsu, L, Garcia-Closas, M, Eeles, RA, Chenevix-Trench, G, Brennan, PJ, Haiman, CA, Simard, J, Easton, DF, Gruber, SB, Pharoah, PDP, Price, AL, Pasaniuc, B, Amos, CI, Kraft, P, and Lindstrom, S
Abstract: Quantifying the genetic correlation between cancers can provide important insights into the mechanisms driving cancer etiology. Using genome-wide association study summary statistics across six cancer types based on a total of 296,215 cases and 301,319 controls of European ancestry, here we estimate the pair-wise genetic correlations between breast, colorectal, head/neck, lung, ovary and prostate cancer, and between cancers and 38 other diseases. We observed statistically significant genetic correlations between lung and head/neck cancer (rg = 0.57, p = 4.6 × 10-8), breast and ovarian cancer (rg = 0.24, p = 7 × 10-5), breast and lung cancer (rg = 0.18, p =1.5 × 10-6) and breast and colorectal cancer (rg = 0.15, p = 1.1 × 10-4). We also found that multiple cancers are genetically correlated with non-cancer traits including smoking, psychiatric diseases and metabolic characteristics. Functional enrichment analysis revealed a significant excess contribution of conserved and regulatory regions to cancer heritability. Our comprehensive analysis of cross-cancer heritability suggests that solid tumors arising across tissues share in part a common germline genetic basis.
Published: 2019

41. The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer

Author: Figlioli, G, Bogliolo, M, Catucci, I, Caleca, L, Viz Lasheras, S, Pujol, R, Kiiski, J, Muranen, TA, Barnes, DR, Dennis, J, Michailidou, K, Bolla, MK, Leslie, G, Aalfs, CM, Adank, MA, Adlard, J, Agata, S, Cadoo, K, Agnarsson, BA, Ahearn, T, Aittomaki, K, Ambrosone, CB, Andrews, L, Anton-Culver, H, Antonenkova, NN, Arndt, V, Arnold, N, Aronson, KJ, Arun, BK, Asseryanis, E, Auber, B, Auvinen, P, Azzollini, J, Balmana, J, Barkardottir, RB, Barrowdale, D, Barwell, J, Freeman, LEB, Beauparlant, CJ, Beckmann, MW, Behrens, S, Benitez, J, Berger, R, Bermisheva, M, Blanco, AM, Blomqvist, C, Bogdanova, N, Bojesen, A, Bojesen, SE, Bonanni, B, Borg, A, Brady, AF, Brauch, H, Brenner, H, Bruening, T, Burwinkel, B, Buys, SS, Caldes, T, Caliebe, A, Caligo, MA, Campa, D, Campbell, IG, Canzian, F, Castelao, JE, Chang-Claude, J, Chanock, SJ, Claes, KBM, Clarke, CL, Collavoli, A, Conner, TA, Cox, DG, Cybulski, C, Czene, K, Daly, MB, de la Hoya, M, Devilee, P, Diez, O, Ding, YC, Dite, GS, Ditsch, N, Domchek, SM, Dorfling, CM, dos-Santos-Silva, I, Durda, K, Dwek, M, Eccles, DM, Ekici, AB, Eliassen, AH, Ellberg, C, Eriksson, M, Evans, DG, Fasching, PA, Figueroa, J, Flyger, H, Foulkes, WD, Friebel, TM, Friedman, E, Gabrielson, M, Gaddam, P, Gago-Dominguez, M, Gao, C, Gapstur, SM, Garber, J, Garcia-Closas, M, Garcia-Saenz, JA, Gaudet, MM, Gayther, SA, Giles, GG, Glendon, G, Godwin, AK, Goldberg, MS, Goldgar, DE, Guenel, P, Gutierrez-Barrera, AM, Haeberle, L, Haiman, CA, Hakansson, N, Hall, P, Hamann, U, Harrington, PA, Hein, A, Heyworth, J, Hillemanns, P, Hollestelle, A, Hopper, JL, Hosgood, HD, Howell, A, Hu, C, Hulick, PJ, Hunter, DJ, Imyanitov, EN, Isaacs, C, Jakimovska, M, Jakubowska, A, James, P, Janavicius, R, Janni, W, John, EM, Jones, ME, Jung, A, Kaaks, R, Karlan, BY, Khusnutdinova, E, Kitahara, CM, Konstantopoulou, I, Koutros, S, Kraft, P, Lambrechts, D, Lazaro, C, Le Marchand, L, Lester, J, Lesueur, F, Lilyquist, J, Loud, JT, Lu, KH, Luben, RN, Lubinski, J, Mannermaa, A, Manoochehri, M, Manoukian, S, Margolin, S, Martens, JWM, Maurer, T, Mavroudis, D, Mebirouk, N, Meindl, A, Menon, U, Miller, A, Montagna, M, Nathanson, KL, Neuhausen, SL, Newman, WG, Nguyen-Dumont, T, Nielsen, FC, Nielsen, S, Nikitina-Zake, L, Offit, K, Olah, E, Olopade, O, Olshan, AF, Olson, JE, Olsson, H, Osorio, A, Ottini, L, Peissel, B, Peixoto, A, Peto, J, Plaseska-Karanfilska, D, Pocza, T, Presneau, N, Angel Pujana, M, Punie, K, Rack, B, Rantala, J, Rashid, MU, Rau-Murthy, R, Rennert, G, Lejbkowicz, F, Rhenius, V, Romero, A, Rookus, MA, Ross, EA, Rossing, M, Rudaitis, V, Ruebner, M, Saloustros, E, Sanden, K, Santamarina, M, Scheuner, MT, Schmutzler, RK, Schneider, M, Scott, C, Senter, L, Shah, M, Sharma, P, Shu, X-O, Simard, J, Singer, CF, Sohn, C, Soucy, P, Southey, MC, Spinelli, JJ, Steele, L, Stoppa-Lyonnet, D, Tapper, WJ, Teixeira, MR, Terry, MB, Thomassen, M, Thompson, J, Thull, DL, Tischkowitz, M, Tollenaar, RAEM, Torres, D, Troester, MA, Truong, T, Tung, N, Untch, M, Vachon, CM, van Rensburg, EJ, van Veen, EM, Vega, A, Viel, A, Wappenschmidt, B, Weitzel, JN, Wendt, C, Wieme, G, Wolk, A, Yang, XR, Zheng, W, Ziogas, A, Zorn, KK, Dunning, AM, Lush, M, Wang, Q, McGuffog, L, Parsons, MT, Pharoah, PDP, Fostira, F, Toland, AE, Andrulis, IL, Ramus, SJ, Swerdlow, AJ, Greene, MH, Chung, WK, Milne, RL, Chenevix-Trench, G, Doerk, T, Schmidt, MK, Easton, DF, Radice, P, Hahnen, E, Antoniou, AC, Couch, FJ, Nevanlinna, H, Surralles, J, Peterlongo, P, Balleine, R, Baxter, R, Braye, S, Carpenter, J, Dahlstrom, J, Forbes, J, Lee, CS, Marsh, D, Morey, A, Pathmanathan, N, Scott, R, Simpson, P, Spigelman, A, Wilcken, N, Yip, D, Zeps, N, Belotti, M, Bertrand, O, Birot, A-M, Buecher, B, Caputo, S, Dupre, A, Fourme, E, Gauthier-Villars, M, Golmard, L, Le Mentec, M, Moncoutier, V, de Pauw, A, Saule, C, Boutry-Kryza, N, Calender, A, Giraud, S, Leone, M, Bressac-de-Paillerets, B, Caron, O, Guillaud-Bataille, M, Bignon, Y-J, Uhrhammer, N, Bonadona, V, Lasset, C, Berthet, P, Castera, L, Vaur, D, Bourdon, V, Nogues, C, Noguchi, T, Popovici, C, Remenieras, A, Sobol, H, Coupier, I, Pujol, P, Adenis, C, Dumont, A, Revillion, F, Muller, D, Barouk-Simonet, E, Bonnet, F, Bubien, V, Longy, M, Sevenet, N, Gladieff, L, Guimbaud, R, Feillel, V, Toulas, C, Dreyfus, H, Leroux, CD, Peysselon, M, Rebischung, C, Legrand, C, Baurand, A, Bertolone, G, Coron, F, Faivre, L, Jacquot, C, Lizard, S, Kientz, C, Lebrun, M, Prieur, F, Fert-Ferrer, S, Mari, V, Venat-Bouvet, L, Bezieau, S, Delnatte, C, Mortemousque, I, Colas, C, Coulet, F, Soubrier, F, Warcoin, M, Bronner, M, Sokolowska, J, Collonge-Rame, M-A, Damette, A, Gesta, P, Lallaoui, H, Chiesa, J, Molina-Gomes, D, Ingster, O, Manouvrier-Hanu, S, Lejeune, S, Aghmesheh, M, Greening, S, Amor, D, Gattas, M, Botes, L, Buckley, M, Friedlander, M, Koehler, J, Meiser, B, Saleh, M, Salisbury, E, Trainer, A, Tucker, K, Antill, Y, Dobrovic, A, Fellows, A, Fox, S, Harris, M, Nightingale, S, Phillips, K, Sambrook, J, Thorne, H, Armitage, S, Arnold, L, Kefford, R, Kirk, J, Rickard, E, Bastick, P, Beesley, J, Hayward, N, Spurdle, A, Walker, L, Beilby, J, Saunders, C, Bennett, I, Blackburn, A, Bogwitz, M, Gaff, C, Lindeman, G, Pachter, N, Sexton, A, Visvader, J, Taylor, J, Winship, I, Brennan, M, Brown, M, French, J, Edwards, S, Burgess, M, Burke, J, Patterson, B, Butow, P, Culling, B, Caldon, L, Callen, D, Chauhan, D, Eisenbruch, M, Heiniger, L, Chauhan, M, Christian, A, Dixon, J, Kidd, A, Cohen, P, Colley, A, Fenton, G, Crook, A, Dickson, R, Field, M, Cui, J, Cummings, M, Dawson, S-J, DeFazio, A, Delatycki, M, Dudding, T, Edkins, T, Farshid, G, Flanagan, J, Fong, P, Forrest, L, Gallego-Ortega, D, George, P, Gill, G, Kollias, J, Haan, E, Hart, S, Jenkins, M, Hunt, C, Lakhani, S, Lipton, L, Lobb, L, Mann, G, McLachlan, SA, O'Connell, S, O'Sullivan, S, Pieper, E, Robinson, B, Saunus, J, Scott, E, Shelling, A, Williams, R, Young, MA, Figlioli, G, Bogliolo, M, Catucci, I, Caleca, L, Viz Lasheras, S, Pujol, R, Kiiski, J, Muranen, TA, Barnes, DR, Dennis, J, Michailidou, K, Bolla, MK, Leslie, G, Aalfs, CM, Adank, MA, Adlard, J, Agata, S, Cadoo, K, Agnarsson, BA, Ahearn, T, Aittomaki, K, Ambrosone, CB, Andrews, L, Anton-Culver, H, Antonenkova, NN, Arndt, V, Arnold, N, Aronson, KJ, Arun, BK, Asseryanis, E, Auber, B, Auvinen, P, Azzollini, J, Balmana, J, Barkardottir, RB, Barrowdale, D, Barwell, J, Freeman, LEB, Beauparlant, CJ, Beckmann, MW, Behrens, S, Benitez, J, Berger, R, Bermisheva, M, Blanco, AM, Blomqvist, C, Bogdanova, N, Bojesen, A, Bojesen, SE, Bonanni, B, Borg, A, Brady, AF, Brauch, H, Brenner, H, Bruening, T, Burwinkel, B, Buys, SS, Caldes, T, Caliebe, A, Caligo, MA, Campa, D, Campbell, IG, Canzian, F, Castelao, JE, Chang-Claude, J, Chanock, SJ, Claes, KBM, Clarke, CL, Collavoli, A, Conner, TA, Cox, DG, Cybulski, C, Czene, K, Daly, MB, de la Hoya, M, Devilee, P, Diez, O, Ding, YC, Dite, GS, Ditsch, N, Domchek, SM, Dorfling, CM, dos-Santos-Silva, I, Durda, K, Dwek, M, Eccles, DM, Ekici, AB, Eliassen, AH, Ellberg, C, Eriksson, M, Evans, DG, Fasching, PA, Figueroa, J, Flyger, H, Foulkes, WD, Friebel, TM, Friedman, E, Gabrielson, M, Gaddam, P, Gago-Dominguez, M, Gao, C, Gapstur, SM, Garber, J, Garcia-Closas, M, Garcia-Saenz, JA, Gaudet, MM, Gayther, SA, Giles, GG, Glendon, G, Godwin, AK, Goldberg, MS, Goldgar, DE, Guenel, P, Gutierrez-Barrera, AM, Haeberle, L, Haiman, CA, Hakansson, N, Hall, P, Hamann, U, Harrington, PA, Hein, A, Heyworth, J, Hillemanns, P, Hollestelle, A, Hopper, JL, Hosgood, HD, Howell, A, Hu, C, Hulick, PJ, Hunter, DJ, Imyanitov, EN, Isaacs, C, Jakimovska, M, Jakubowska, A, James, P, Janavicius, R, Janni, W, John, EM, Jones, ME, Jung, A, Kaaks, R, Karlan, BY, Khusnutdinova, E, Kitahara, CM, Konstantopoulou, I, Koutros, S, Kraft, P, Lambrechts, D, Lazaro, C, Le Marchand, L, Lester, J, Lesueur, F, Lilyquist, J, Loud, JT, Lu, KH, Luben, RN, Lubinski, J, Mannermaa, A, Manoochehri, M, Manoukian, S, Margolin, S, Martens, JWM, Maurer, T, Mavroudis, D, Mebirouk, N, Meindl, A, Menon, U, Miller, A, Montagna, M, Nathanson, KL, Neuhausen, SL, Newman, WG, Nguyen-Dumont, T, Nielsen, FC, Nielsen, S, Nikitina-Zake, L, Offit, K, Olah, E, Olopade, O, Olshan, AF, Olson, JE, Olsson, H, Osorio, A, Ottini, L, Peissel, B, Peixoto, A, Peto, J, Plaseska-Karanfilska, D, Pocza, T, Presneau, N, Angel Pujana, M, Punie, K, Rack, B, Rantala, J, Rashid, MU, Rau-Murthy, R, Rennert, G, Lejbkowicz, F, Rhenius, V, Romero, A, Rookus, MA, Ross, EA, Rossing, M, Rudaitis, V, Ruebner, M, Saloustros, E, Sanden, K, Santamarina, M, Scheuner, MT, Schmutzler, RK, Schneider, M, Scott, C, Senter, L, Shah, M, Sharma, P, Shu, X-O, Simard, J, Singer, CF, Sohn, C, Soucy, P, Southey, MC, Spinelli, JJ, Steele, L, Stoppa-Lyonnet, D, Tapper, WJ, Teixeira, MR, Terry, MB, Thomassen, M, Thompson, J, Thull, DL, Tischkowitz, M, Tollenaar, RAEM, Torres, D, Troester, MA, Truong, T, Tung, N, Untch, M, Vachon, CM, van Rensburg, EJ, van Veen, EM, Vega, A, Viel, A, Wappenschmidt, B, Weitzel, JN, Wendt, C, Wieme, G, Wolk, A, Yang, XR, Zheng, W, Ziogas, A, Zorn, KK, Dunning, AM, Lush, M, Wang, Q, McGuffog, L, Parsons, MT, Pharoah, PDP, Fostira, F, Toland, AE, Andrulis, IL, Ramus, SJ, Swerdlow, AJ, Greene, MH, Chung, WK, Milne, RL, Chenevix-Trench, G, Doerk, T, Schmidt, MK, Easton, DF, Radice, P, Hahnen, E, Antoniou, AC, Couch, FJ, Nevanlinna, H, Surralles, J, Peterlongo, P, Balleine, R, Baxter, R, Braye, S, Carpenter, J, Dahlstrom, J, Forbes, J, Lee, CS, Marsh, D, Morey, A, Pathmanathan, N, Scott, R, Simpson, P, Spigelman, A, Wilcken, N, Yip, D, Zeps, N, Belotti, M, Bertrand, O, Birot, A-M, Buecher, B, Caputo, S, Dupre, A, Fourme, E, Gauthier-Villars, M, Golmard, L, Le Mentec, M, Moncoutier, V, de Pauw, A, Saule, C, Boutry-Kryza, N, Calender, A, Giraud, S, Leone, M, Bressac-de-Paillerets, B, Caron, O, Guillaud-Bataille, M, Bignon, Y-J, Uhrhammer, N, Bonadona, V, Lasset, C, Berthet, P, Castera, L, Vaur, D, Bourdon, V, Nogues, C, Noguchi, T, Popovici, C, Remenieras, A, Sobol, H, Coupier, I, Pujol, P, Adenis, C, Dumont, A, Revillion, F, Muller, D, Barouk-Simonet, E, Bonnet, F, Bubien, V, Longy, M, Sevenet, N, Gladieff, L, Guimbaud, R, Feillel, V, Toulas, C, Dreyfus, H, Leroux, CD, Peysselon, M, Rebischung, C, Legrand, C, Baurand, A, Bertolone, G, Coron, F, Faivre, L, Jacquot, C, Lizard, S, Kientz, C, Lebrun, M, Prieur, F, Fert-Ferrer, S, Mari, V, Venat-Bouvet, L, Bezieau, S, Delnatte, C, Mortemousque, I, Colas, C, Coulet, F, Soubrier, F, Warcoin, M, Bronner, M, Sokolowska, J, Collonge-Rame, M-A, Damette, A, Gesta, P, Lallaoui, H, Chiesa, J, Molina-Gomes, D, Ingster, O, Manouvrier-Hanu, S, Lejeune, S, Aghmesheh, M, Greening, S, Amor, D, Gattas, M, Botes, L, Buckley, M, Friedlander, M, Koehler, J, Meiser, B, Saleh, M, Salisbury, E, Trainer, A, Tucker, K, Antill, Y, Dobrovic, A, Fellows, A, Fox, S, Harris, M, Nightingale, S, Phillips, K, Sambrook, J, Thorne, H, Armitage, S, Arnold, L, Kefford, R, Kirk, J, Rickard, E, Bastick, P, Beesley, J, Hayward, N, Spurdle, A, Walker, L, Beilby, J, Saunders, C, Bennett, I, Blackburn, A, Bogwitz, M, Gaff, C, Lindeman, G, Pachter, N, Sexton, A, Visvader, J, Taylor, J, Winship, I, Brennan, M, Brown, M, French, J, Edwards, S, Burgess, M, Burke, J, Patterson, B, Butow, P, Culling, B, Caldon, L, Callen, D, Chauhan, D, Eisenbruch, M, Heiniger, L, Chauhan, M, Christian, A, Dixon, J, Kidd, A, Cohen, P, Colley, A, Fenton, G, Crook, A, Dickson, R, Field, M, Cui, J, Cummings, M, Dawson, S-J, DeFazio, A, Delatycki, M, Dudding, T, Edkins, T, Farshid, G, Flanagan, J, Fong, P, Forrest, L, Gallego-Ortega, D, George, P, Gill, G, Kollias, J, Haan, E, Hart, S, Jenkins, M, Hunt, C, Lakhani, S, Lipton, L, Lobb, L, Mann, G, McLachlan, SA, O'Connell, S, O'Sullivan, S, Pieper, E, Robinson, B, Saunus, J, Scott, E, Shelling, A, Williams, R, and Young, MA
Abstract: Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1, BRCA2, PALB2, ATM, and CHEK2 are associated with breast cancer risk. FANCM, which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants FANCM:p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of BRCA1 or BRCA2. These three variants were also studied functionally by measuring survival and chromosome fragility in FANCM−/− patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that FANCM:p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44, P = 0.034 and OR = 3.79; P = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for FANCM:p.Arg658* and found that also FANCM:p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96; P = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with FANCM:p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare FANCM deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat FANCM-associated tumors.
Published: 2019

42. Two truncating variants in FANCC and breast cancer risk

Author: Dork, T, Peterlongo, P, Mannermaa, A, Bolla, MK, Wang, Q, Dennis, J, Ahearn, T, Andrulis, IL, Anton-Culver, H, Arndt, V, Aronson, KJ, Augustinsson, A, Freeman, LEB, Beckmann, MW, Beeghly-Fadiel, A, Behrens, S, Bermisheva, M, Blomqvist, C, Bogdanova, N, Bojesen, SE, Brauch, H, Brenner, H, Burwinkel, B, Canzian, F, Chan, TL, Chang-Claude, J, Chanock, SJ, Choi, J-Y, Christiansen, H, Clarke, CL, Couch, FJ, Czene, K, Daly, MB, dos-Santos-Silva, I, Dwek, M, Eccles, DM, Ekici, AB, Eriksson, M, Evans, DG, Fasching, PA, Figueroa, J, Flyger, H, Fritschisl, L, Gabrielson, M, Gago-Dominguez, M, Gao, C, Gapstur, SM, Garcia-Closas, M, Garcia-Saenz, JA, Gaudet, MM, Giles, GG, Goldberg, MS, Goldgar, DE, Guenel, P, Haeberle, L, Haiman, CA, Hakansson, N, Hall, P, Hamann, U, Hartman, M, Hauke, J, Hein, A, Hillemanns, P, Hogervorst, FBL, Hooning, MJ, Hopper, JL, Howell, T, Huo, D, Ito, H, Iwasaki, M, Jakubowska, A, Janni, W, John, EM, Jung, A, Kaaks, R, Kang, D, Kapoor, PM, Khusnutdinova, E, Kim, S-W, Kitahara, CM, Koutros, S, Kraft, P, Kristensen, VN, Kwon, A, Lambrechts, D, Le Marchand, L, Li, J, Lindstrom, S, Linet, M, Lo, W-Y, Long, J, Lophatananon, A, Lubinski, J, Manoochehri, M, Manoukian, S, Margolin, S, Martinez, E, Matsuo, K, Mavroudis, D, Meindl, A, Menon, U, Milne, RL, Taib, NAM, Muir, K, Mulligan, AM, Neuhausen, SL, Nevanlinna, H, Neven, P, Newman, WG, Offit, K, Olopade, O, Olshan, AF, Olson, JE, Olsson, H, Park, SK, Park-Simon, T-W, Peto, J, Plaseska-Karanfilska, D, Pohl-Rescigno, E, Presneau, N, Rack, B, Radice, P, Rashid, MU, Rennert, G, Rennert, HS, Romero, A, Ruebner, M, Saloustros, E, Schmidt, MK, Schmutzler, RK, Schneider, MO, Schoemaker, MJ, Scott, C, Shen, C-Y, Shu, X-O, Simard, J, Slager, S, Smichkoska, S, Southey, MC, Spinelli, JJ, Stone, J, Surowy, H, Swerdlow, AJ, Tamimi, RM, Tapper, WJ, Teo, SH, Terry, MB, Toland, AE, Tollenaar, RAEM, Torres, D, Torres-Mejia, G, Troester, MA, Truong, T, Tsugane, S, Untch, M, Vachon, CM, van den Ouweland, AMW, van Veen, EM, Vijai, J, Wendt, C, Wolk, A, Yu, J-C, Zheng, W, Ziogas, A, Ziv, E, Dunning, AM, Pharoah, PDP, Schindler, D, Devilee, P, Easton, DF, Balleine, R, Baxter, R, Braye, S, Carpenter, J, Dahlstrom, J, Forbes, J, Lee, CS, Marsh, D, Morey, A, Pathmanathan, N, Scott, R, Simpson, P, Spigelman, A, Wilcken, N, Yip, D, Zeps, N, Borresen-Dale, A-L, Alnaes, GIG, Sahlberg, KK, Ottestad, L, Karesen, R, Schlichting, E, Holmen, MM, Sauer, T, Haakensen, V, Engebraten, O, Naume, B, Fossa, A, Kiserud, CE, Reinertsen, K, Helland, A, Riis, M, Geisler, J, Dork, T, Peterlongo, P, Mannermaa, A, Bolla, MK, Wang, Q, Dennis, J, Ahearn, T, Andrulis, IL, Anton-Culver, H, Arndt, V, Aronson, KJ, Augustinsson, A, Freeman, LEB, Beckmann, MW, Beeghly-Fadiel, A, Behrens, S, Bermisheva, M, Blomqvist, C, Bogdanova, N, Bojesen, SE, Brauch, H, Brenner, H, Burwinkel, B, Canzian, F, Chan, TL, Chang-Claude, J, Chanock, SJ, Choi, J-Y, Christiansen, H, Clarke, CL, Couch, FJ, Czene, K, Daly, MB, dos-Santos-Silva, I, Dwek, M, Eccles, DM, Ekici, AB, Eriksson, M, Evans, DG, Fasching, PA, Figueroa, J, Flyger, H, Fritschisl, L, Gabrielson, M, Gago-Dominguez, M, Gao, C, Gapstur, SM, Garcia-Closas, M, Garcia-Saenz, JA, Gaudet, MM, Giles, GG, Goldberg, MS, Goldgar, DE, Guenel, P, Haeberle, L, Haiman, CA, Hakansson, N, Hall, P, Hamann, U, Hartman, M, Hauke, J, Hein, A, Hillemanns, P, Hogervorst, FBL, Hooning, MJ, Hopper, JL, Howell, T, Huo, D, Ito, H, Iwasaki, M, Jakubowska, A, Janni, W, John, EM, Jung, A, Kaaks, R, Kang, D, Kapoor, PM, Khusnutdinova, E, Kim, S-W, Kitahara, CM, Koutros, S, Kraft, P, Kristensen, VN, Kwon, A, Lambrechts, D, Le Marchand, L, Li, J, Lindstrom, S, Linet, M, Lo, W-Y, Long, J, Lophatananon, A, Lubinski, J, Manoochehri, M, Manoukian, S, Margolin, S, Martinez, E, Matsuo, K, Mavroudis, D, Meindl, A, Menon, U, Milne, RL, Taib, NAM, Muir, K, Mulligan, AM, Neuhausen, SL, Nevanlinna, H, Neven, P, Newman, WG, Offit, K, Olopade, O, Olshan, AF, Olson, JE, Olsson, H, Park, SK, Park-Simon, T-W, Peto, J, Plaseska-Karanfilska, D, Pohl-Rescigno, E, Presneau, N, Rack, B, Radice, P, Rashid, MU, Rennert, G, Rennert, HS, Romero, A, Ruebner, M, Saloustros, E, Schmidt, MK, Schmutzler, RK, Schneider, MO, Schoemaker, MJ, Scott, C, Shen, C-Y, Shu, X-O, Simard, J, Slager, S, Smichkoska, S, Southey, MC, Spinelli, JJ, Stone, J, Surowy, H, Swerdlow, AJ, Tamimi, RM, Tapper, WJ, Teo, SH, Terry, MB, Toland, AE, Tollenaar, RAEM, Torres, D, Torres-Mejia, G, Troester, MA, Truong, T, Tsugane, S, Untch, M, Vachon, CM, van den Ouweland, AMW, van Veen, EM, Vijai, J, Wendt, C, Wolk, A, Yu, J-C, Zheng, W, Ziogas, A, Ziv, E, Dunning, AM, Pharoah, PDP, Schindler, D, Devilee, P, Easton, DF, Balleine, R, Baxter, R, Braye, S, Carpenter, J, Dahlstrom, J, Forbes, J, Lee, CS, Marsh, D, Morey, A, Pathmanathan, N, Scott, R, Simpson, P, Spigelman, A, Wilcken, N, Yip, D, Zeps, N, Borresen-Dale, A-L, Alnaes, GIG, Sahlberg, KK, Ottestad, L, Karesen, R, Schlichting, E, Holmen, MM, Sauer, T, Haakensen, V, Engebraten, O, Naume, B, Fossa, A, Kiserud, CE, Reinertsen, K, Helland, A, Riis, M, and Geisler, J
Abstract: Fanconi anemia (FA) is a genetically heterogeneous disorder with 22 disease-causing genes reported to date. In some FA genes, monoallelic mutations have been found to be associated with breast cancer risk, while the risk associations of others remain unknown. The gene for FA type C, FANCC, has been proposed as a breast cancer susceptibility gene based on epidemiological and sequencing studies. We used the Oncoarray project to genotype two truncating FANCC variants (p.R185X and p.R548X) in 64,760 breast cancer cases and 49,793 controls of European descent. FANCC mutations were observed in 25 cases (14 with p.R185X, 11 with p.R548X) and 26 controls (18 with p.R185X, 8 with p.R548X). There was no evidence of an association with the risk of breast cancer, neither overall (odds ratio 0.77, 95%CI 0.44-1.33, p = 0.4) nor by histology, hormone receptor status, age or family history. We conclude that the breast cancer risk association of these two FANCC variants, if any, is much smaller than for BRCA1, BRCA2 or PALB2 mutations. If this applies to all truncating variants in FANCC it would suggest there are differences between FA genes in their roles on breast cancer risk and demonstrates the merit of large consortia for clarifying risk associations of rare variants.
Published: 2019

43. Mendelian randomisation study of height and body mass index as modifiers of ovarian cancer risk in 22,588 BRCA1 and BRCA2 mutation carriers

Author: Qian, F, Rookus, MA, Leslie, G, Risch, HA, Greene, MH, Aalfs, CM, Adank, MA, Adlard, J, Agnarsson, BA, Ahmed, M, Aittomaki, K, Andrulis, IL, Arnold, N, Arun, BK, Ausems, MGEM, Azzollini, J, Barrowdale, D, Barwell, J, Benitez, J, Bialkowska, K, Bonadona, V, Borde, J, Borg, A, Bradbury, AR, Brunet, J, Buys, SS, Caldes, T, Caligo, MA, Campbell, I, Carter, J, Chiquette, J, Chung, WK, Claes, KBM, Collee, JM, Collonge-Rame, M-A, Couch, FJ, Daly, MB, Delnatte, C, Diez, O, Domchek, SM, Dorfling, CM, Eason, J, Easton, DF, Eeles, R, Engel, C, Evans, DG, Faivre, L, Feliubado, L, Foretova, L, Friedman, E, Frost, D, Ganz, PA, Garber, J, Garcia-Barberan, V, Gehrig, A, Glendon, G, Godwin, AK, Garcia, EBG, Hamann, U, Hauke, J, Hopper, JL, Hulick, PJ, Imyanitov, EN, Isaacs, C, Izatt, L, Jakubowska, A, Janavicius, R, John, EM, Karlan, BY, Kets, CM, Laitman, Y, Lazaro, C, Leroux, D, Lester, J, Lesueur, F, Loud, JT, Lubinski, J, Lukomska, A, McGuffog, L, Mebirouk, N, Meijers-Heijboer, HEJ, Meindl, A, Miller, A, Montagna, M, Mooij, TM, Mouret-Fourme, E, Nathanson, KL, Nehoray, B, Neuhausen, SL, Nevanlinna, H, Nielsen, FC, Offit, K, Olah, E, Ong, K-R, Oosterwijk, JC, Ottini, L, Parsons, MT, Peterlongo, P, Pfeiler, G, Pradhan, N, Radice, P, Ramus, SJ, Rantala, J, Rennert, G, Robson, M, Rodriguez, GC, Salani, R, Scheuner, MT, Schmutzler, RK, Shah, PD, Side, LE, Simard, J, Singer, CF, Steinemann, D, Stoppa-Lyonnet, D, Tan, YY, Teixeira, MR, Terry, MB, Thomassen, M, Tischkowitz, M, Tognazzo, S, Toland, AE, Tung, N, van Asperen, CJ, van Engelen, K, van Rensburg, EJ, Venat-Bouvet, L, Vierstraete, J, Wagner, G, Walker, L, Weitze, JN, Yannoukakos, D, Antoniou, AC, Goldgar, DE, Olopade, O, Chenevix-Trench, G, Rebbeck, TR, Huo, D, Qian, F, Rookus, MA, Leslie, G, Risch, HA, Greene, MH, Aalfs, CM, Adank, MA, Adlard, J, Agnarsson, BA, Ahmed, M, Aittomaki, K, Andrulis, IL, Arnold, N, Arun, BK, Ausems, MGEM, Azzollini, J, Barrowdale, D, Barwell, J, Benitez, J, Bialkowska, K, Bonadona, V, Borde, J, Borg, A, Bradbury, AR, Brunet, J, Buys, SS, Caldes, T, Caligo, MA, Campbell, I, Carter, J, Chiquette, J, Chung, WK, Claes, KBM, Collee, JM, Collonge-Rame, M-A, Couch, FJ, Daly, MB, Delnatte, C, Diez, O, Domchek, SM, Dorfling, CM, Eason, J, Easton, DF, Eeles, R, Engel, C, Evans, DG, Faivre, L, Feliubado, L, Foretova, L, Friedman, E, Frost, D, Ganz, PA, Garber, J, Garcia-Barberan, V, Gehrig, A, Glendon, G, Godwin, AK, Garcia, EBG, Hamann, U, Hauke, J, Hopper, JL, Hulick, PJ, Imyanitov, EN, Isaacs, C, Izatt, L, Jakubowska, A, Janavicius, R, John, EM, Karlan, BY, Kets, CM, Laitman, Y, Lazaro, C, Leroux, D, Lester, J, Lesueur, F, Loud, JT, Lubinski, J, Lukomska, A, McGuffog, L, Mebirouk, N, Meijers-Heijboer, HEJ, Meindl, A, Miller, A, Montagna, M, Mooij, TM, Mouret-Fourme, E, Nathanson, KL, Nehoray, B, Neuhausen, SL, Nevanlinna, H, Nielsen, FC, Offit, K, Olah, E, Ong, K-R, Oosterwijk, JC, Ottini, L, Parsons, MT, Peterlongo, P, Pfeiler, G, Pradhan, N, Radice, P, Ramus, SJ, Rantala, J, Rennert, G, Robson, M, Rodriguez, GC, Salani, R, Scheuner, MT, Schmutzler, RK, Shah, PD, Side, LE, Simard, J, Singer, CF, Steinemann, D, Stoppa-Lyonnet, D, Tan, YY, Teixeira, MR, Terry, MB, Thomassen, M, Tischkowitz, M, Tognazzo, S, Toland, AE, Tung, N, van Asperen, CJ, van Engelen, K, van Rensburg, EJ, Venat-Bouvet, L, Vierstraete, J, Wagner, G, Walker, L, Weitze, JN, Yannoukakos, D, Antoniou, AC, Goldgar, DE, Olopade, O, Chenevix-Trench, G, Rebbeck, TR, and Huo, D
Abstract: BACKGROUND: Height and body mass index (BMI) are associated with higher ovarian cancer risk in the general population, but whether such associations exist among BRCA1/2 mutation carriers is unknown. METHODS: We applied a Mendelian randomisation approach to examine height/BMI with ovarian cancer risk using the Consortium of Investigators for the Modifiers of BRCA1/2 (CIMBA) data set, comprising 14,676 BRCA1 and 7912 BRCA2 mutation carriers, with 2923 ovarian cancer cases. We created a height genetic score (height-GS) using 586 height-associated variants and a BMI genetic score (BMI-GS) using 93 BMI-associated variants. Associations were assessed using weighted Cox models. RESULTS: Observed height was not associated with ovarian cancer risk (hazard ratio [HR]: 1.07 per 10-cm increase in height, 95% confidence interval [CI]: 0.94-1.23). Height-GS showed similar results (HR = 1.02, 95% CI: 0.85-1.23). Higher BMI was significantly associated with increased risk in premenopausal women with HR = 1.25 (95% CI: 1.06-1.48) and HR = 1.59 (95% CI: 1.08-2.33) per 5-kg/m2 increase in observed and genetically determined BMI, respectively. No association was found for postmenopausal women. Interaction between menopausal status and BMI was significant (Pinteraction < 0.05). CONCLUSION: Our observation of a positive association between BMI and ovarian cancer risk in premenopausal BRCA1/2 mutation carriers is consistent with findings in the general population.
Published: 2019

44. Benign breast disease increases breast cancer risk independent of underlying familial risk profile: Findings from a Prospective Family Study Cohort

Author: Zeinomar, N, Phillips, K-A, Daly, MB, Milne, RL, Dite, GS, MacInnis, RJ, Liao, Y, Kehm, RD, Knight, JA, Southey, MC, Chung, WK, Giles, GG, McLachlan, S-A, Friedlander, ML, Weideman, PC, Glendon, G, Nesci, S, Andrulis, IL, Buys, SS, John, EM, Hopper, JL, Terry, MB, Zeinomar, N, Phillips, K-A, Daly, MB, Milne, RL, Dite, GS, MacInnis, RJ, Liao, Y, Kehm, RD, Knight, JA, Southey, MC, Chung, WK, Giles, GG, McLachlan, S-A, Friedlander, ML, Weideman, PC, Glendon, G, Nesci, S, Andrulis, IL, Buys, SS, John, EM, Hopper, JL, and Terry, MB
Abstract: Benign breast disease (BBD) is an established breast cancer (BC) risk factor, but it is unclear whether the magnitude of the association applies to women at familial or genetic risk. This information is needed to improve BC risk assessment in clinical settings. Using the Prospective Family Study Cohort, we used Cox proportional hazards models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the association of BBD with BC risk. We also examined whether the association with BBD differed by underlying familial risk profile (FRP), calculated using absolute risk estimates from the Breast Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA) model. During 176,756 person-years of follow-up (median: 10.9 years, maximum: 23.7) of 17,154 women unaffected with BC at baseline, we observed 968 incident cases of BC. A total of 4,704 (27%) women reported a history of BBD diagnosis at baseline. A history of BBD was associated with a greater risk of BC: HR = 1.31 (95% CI: 1.14-1.50), and did not differ by underlying FRP, with HRs of 1.35 (95% CI: 1.11-1.65), 1.26 (95% CI: 1.00-1.60), and 1.40 (95% CI: 1.01-1.93), for categories of full-lifetime BOADICEA score <20%, 20 to <35%, ≥35%, respectively. There was no difference in the association for women with BRCA1 mutations (HR: 1.64; 95% CI: 1.04-2.58), women with BRCA2 mutations (HR: 1.34; 95% CI: 0.78-2.3) or for women without a known BRCA1 or BRCA2 mutation (HR: 1.31; 95% CI: 1.13-1.53) (pinteraction = 0.95). Women with a history of BBD have an increased risk of BC that is independent of, and multiplies, their underlying familial and genetic risk.
Published: 2019

45. Genome-wide association and transcriptome studies identify target genes and risk loci for breast cancer

Author: Ferreira, MA, Gamazon, ER, Al-Ejeh, F, Aittomaki, K, Andrulis, IL, Anton-Culver, H, Arason, A, Arndt, V, Aronson, KJ, Arun, BK, Asseryanis, E, Azzollini, J, Balmana, J, Barnes, DR, Barrowdale, D, Beckmann, MW, Behrens, S, Benitez, J, Bermisheva, M, Bialkowska, K, Blomqvist, C, Bogdanova, N, Bojesen, SE, Bolla, MK, Borg, A, Brauch, H, Brenner, H, Broeks, A, Burwinkel, B, Caldes, T, Caligo, MA, Campa, D, Campbell, I, Canzian, F, Carter, J, Carter, BD, Castelao, JE, Chang-Claude, J, Chanock, SJ, Christiansen, H, Chung, WK, Claes, KBM, Clarke, CL, Couch, FJ, Cox, A, Cross, SS, Czene, K, Daly, MB, de la Hoya, M, Dennis, J, Devilee, P, Diez, O, Doerk, T, Dunning, AM, Dwek, M, Eccles, DM, Ejlertsen, B, Ellberg, C, Engel, C, Eriksson, M, Fasching, PA, Fletcher, O, Flyger, H, Friedman, E, Frost, D, Gabrielson, M, Gago-Dominguez, M, Ganz, PA, Gapstur, SM, Garber, J, Garcia-Closas, M, Garcia-Saenz, JA, Gaudet, MM, Giles, GG, Glendon, G, Godwin, AK, Goldberg, MS, Goldgar, DE, Gonzalez-Neira, A, Greene, MH, Gronwald, J, Guenel, P, Haiman, CA, Hall, P, Hamann, U, He, W, Heyworth, J, Hogervorst, FBL, Hollestelle, A, Hoover, RN, Hopper, JL, Hulick, PJ, Humphreys, K, Imyanitov, EN, Isaacs, C, Jakimovska, M, Jakubowska, A, James, PA, Janavicius, R, Jankowitz, RC, John, EM, Johnson, N, Joseph, V, Karlan, BY, Khusnutdinova, E, Kiiski, J, Ko, Y-D, Jones, ME, Konstantopoulou, I, Kristensen, VN, Laitman, Y, Lambrechts, D, Lazaro, C, Leslie, G, Lester, J, Lesueur, F, Lindstrom, S, Long, J, Loud, JT, Lubinski, J, Makalic, E, Mannermaa, A, Manoochehri, M, Margolin, S, Maurer, T, Mavroudis, D, McGuffog, L, Meindl, A, Menon, U, Michailidou, K, Miller, A, Montagna, M, Moreno, F, Moserle, L, Mulligan, AM, Nathanson, KL, Neuhausen, SL, Nevanlinna, H, Nevelsteen, I, Nielsen, FC, Nikitina-Zake, L, Nussbaum, RL, Offit, K, Olah, E, Olopade, O, Olsson, H, Osorio, A, Papp, J, Park-Simon, T-W, Parsons, MT, Pedersen, IS, Peixoto, A, Peterlongo, P, Pharoah, PDP, Plaseska-Karanfilska, D, Poppe, B, Presneau, N, Radice, P, Rantala, J, Rennert, G, Risch, HA, Saloustros, E, Sanden, K, Sawyer, EJ, Schmidt, MK, Schmutzler, RK, Sharma, P, Shu, X-O, Simard, J, Singer, CF, Soucy, P, Southey, MC, Spinelli, JJ, Spurdle, AB, Stone, J, Swerdlow, AJ, Tapper, WJ, Taylor, JA, Teixeira, MR, Terry, MB, Teule, A, Thomassen, M, Thoene, K, Thull, DL, Tischkowitz, M, Toland, AE, Torres, D, Truong, T, Tung, N, Vachon, CM, van Asperen, CJ, van den Ouweland, AMW, van Rensburg, EJ, Vega, A, Viel, A, Wang, Q, Wappenschmidt, B, Weitzel, JN, Wendt, C, Winqvist, R, Yang, XR, Yannoukakos, D, Ziogas, A, Kraft, P, Antoniou, AC, Zheng, W, Easton, DF, Milne, RL, Beesley, J, Chenevix-Trench, G, Arnold, N, Auber, B, Bogdanova-Markov, N, Borde, J, Caliebe, A, Ditsch, N, Dworniczak, B, Engert, S, Faust, U, Gehrig, A, Hahnen, E, Hauke, J, Hentschel, J, Herold, N, Honisch, E, Just, W, Kast, K, Larsen, M, Lemke, J, Huu, PN, Niederacher, D, Ott, C-E, Platzer, K, Pohl-Rescigno, E, Ramser, J, Rhiem, K, Steinemann, D, Sutter, C, Varon-Mateeva, R, Wang-Gohrke, S, Weber, BHF, Prieur, F, Pujol, P, Sagne, C, Sevenet, N, Sobol, H, Sokolowska, J, Stoppa-Lyonnet, D, Venat-Bouvet, L, Adlard, J, Ahmed, M, Barwell, J, Brady, A, Brewer, C, Cook, J, Davidson, R, Donaldson, A, Eason, J, Eeles, R, Evans, DG, Gregory, H, Hanson, H, Henderson, A, Hodgson, S, Izatt, L, Kennedy, MJ, Lalloo, F, Miller, C, Morrison, PJ, Ong, K-R, Perkins, J, Porteous, ME, Rogers, MT, Side, LE, Snape, K, Walker, L, Harrington, PA, Heemskerk-Gerritsen, BAM, Rookus, MA, Seynaeve, CM, van der Baan, FH, van der Hout, AH, van der Kolk, LE, van der Luijt, RB, van Deurzen, CHM, van Doorn, HC, van Engelen, K, van Hest, L, van Os, TAM, Verhoef, S, Vogel, MJ, Wijnen, JT, Miron, A, Kapuscinski, M, Bane, A, Ross, E, Buys, SS, Conner, TA, Balleine, R, Baxter, R, Braye, S, Carpenter, J, Dahlstrom, J, Forbes, J, Lee, SC, Marsh, D, Morey, A, Pathmanathan, N, Simpson, P, Spigelman, A, Wilcken, N, Yip, D, Ferreira, MA, Gamazon, ER, Al-Ejeh, F, Aittomaki, K, Andrulis, IL, Anton-Culver, H, Arason, A, Arndt, V, Aronson, KJ, Arun, BK, Asseryanis, E, Azzollini, J, Balmana, J, Barnes, DR, Barrowdale, D, Beckmann, MW, Behrens, S, Benitez, J, Bermisheva, M, Bialkowska, K, Blomqvist, C, Bogdanova, N, Bojesen, SE, Bolla, MK, Borg, A, Brauch, H, Brenner, H, Broeks, A, Burwinkel, B, Caldes, T, Caligo, MA, Campa, D, Campbell, I, Canzian, F, Carter, J, Carter, BD, Castelao, JE, Chang-Claude, J, Chanock, SJ, Christiansen, H, Chung, WK, Claes, KBM, Clarke, CL, Couch, FJ, Cox, A, Cross, SS, Czene, K, Daly, MB, de la Hoya, M, Dennis, J, Devilee, P, Diez, O, Doerk, T, Dunning, AM, Dwek, M, Eccles, DM, Ejlertsen, B, Ellberg, C, Engel, C, Eriksson, M, Fasching, PA, Fletcher, O, Flyger, H, Friedman, E, Frost, D, Gabrielson, M, Gago-Dominguez, M, Ganz, PA, Gapstur, SM, Garber, J, Garcia-Closas, M, Garcia-Saenz, JA, Gaudet, MM, Giles, GG, Glendon, G, Godwin, AK, Goldberg, MS, Goldgar, DE, Gonzalez-Neira, A, Greene, MH, Gronwald, J, Guenel, P, Haiman, CA, Hall, P, Hamann, U, He, W, Heyworth, J, Hogervorst, FBL, Hollestelle, A, Hoover, RN, Hopper, JL, Hulick, PJ, Humphreys, K, Imyanitov, EN, Isaacs, C, Jakimovska, M, Jakubowska, A, James, PA, Janavicius, R, Jankowitz, RC, John, EM, Johnson, N, Joseph, V, Karlan, BY, Khusnutdinova, E, Kiiski, J, Ko, Y-D, Jones, ME, Konstantopoulou, I, Kristensen, VN, Laitman, Y, Lambrechts, D, Lazaro, C, Leslie, G, Lester, J, Lesueur, F, Lindstrom, S, Long, J, Loud, JT, Lubinski, J, Makalic, E, Mannermaa, A, Manoochehri, M, Margolin, S, Maurer, T, Mavroudis, D, McGuffog, L, Meindl, A, Menon, U, Michailidou, K, Miller, A, Montagna, M, Moreno, F, Moserle, L, Mulligan, AM, Nathanson, KL, Neuhausen, SL, Nevanlinna, H, Nevelsteen, I, Nielsen, FC, Nikitina-Zake, L, Nussbaum, RL, Offit, K, Olah, E, Olopade, O, Olsson, H, Osorio, A, Papp, J, Park-Simon, T-W, Parsons, MT, Pedersen, IS, Peixoto, A, Peterlongo, P, Pharoah, PDP, Plaseska-Karanfilska, D, Poppe, B, Presneau, N, Radice, P, Rantala, J, Rennert, G, Risch, HA, Saloustros, E, Sanden, K, Sawyer, EJ, Schmidt, MK, Schmutzler, RK, Sharma, P, Shu, X-O, Simard, J, Singer, CF, Soucy, P, Southey, MC, Spinelli, JJ, Spurdle, AB, Stone, J, Swerdlow, AJ, Tapper, WJ, Taylor, JA, Teixeira, MR, Terry, MB, Teule, A, Thomassen, M, Thoene, K, Thull, DL, Tischkowitz, M, Toland, AE, Torres, D, Truong, T, Tung, N, Vachon, CM, van Asperen, CJ, van den Ouweland, AMW, van Rensburg, EJ, Vega, A, Viel, A, Wang, Q, Wappenschmidt, B, Weitzel, JN, Wendt, C, Winqvist, R, Yang, XR, Yannoukakos, D, Ziogas, A, Kraft, P, Antoniou, AC, Zheng, W, Easton, DF, Milne, RL, Beesley, J, Chenevix-Trench, G, Arnold, N, Auber, B, Bogdanova-Markov, N, Borde, J, Caliebe, A, Ditsch, N, Dworniczak, B, Engert, S, Faust, U, Gehrig, A, Hahnen, E, Hauke, J, Hentschel, J, Herold, N, Honisch, E, Just, W, Kast, K, Larsen, M, Lemke, J, Huu, PN, Niederacher, D, Ott, C-E, Platzer, K, Pohl-Rescigno, E, Ramser, J, Rhiem, K, Steinemann, D, Sutter, C, Varon-Mateeva, R, Wang-Gohrke, S, Weber, BHF, Prieur, F, Pujol, P, Sagne, C, Sevenet, N, Sobol, H, Sokolowska, J, Stoppa-Lyonnet, D, Venat-Bouvet, L, Adlard, J, Ahmed, M, Barwell, J, Brady, A, Brewer, C, Cook, J, Davidson, R, Donaldson, A, Eason, J, Eeles, R, Evans, DG, Gregory, H, Hanson, H, Henderson, A, Hodgson, S, Izatt, L, Kennedy, MJ, Lalloo, F, Miller, C, Morrison, PJ, Ong, K-R, Perkins, J, Porteous, ME, Rogers, MT, Side, LE, Snape, K, Walker, L, Harrington, PA, Heemskerk-Gerritsen, BAM, Rookus, MA, Seynaeve, CM, van der Baan, FH, van der Hout, AH, van der Kolk, LE, van der Luijt, RB, van Deurzen, CHM, van Doorn, HC, van Engelen, K, van Hest, L, van Os, TAM, Verhoef, S, Vogel, MJ, Wijnen, JT, Miron, A, Kapuscinski, M, Bane, A, Ross, E, Buys, SS, Conner, TA, Balleine, R, Baxter, R, Braye, S, Carpenter, J, Dahlstrom, J, Forbes, J, Lee, SC, Marsh, D, Morey, A, Pathmanathan, N, Simpson, P, Spigelman, A, Wilcken, N, and Yip, D
Abstract: Genome-wide association studies (GWAS) have identified more than 170 breast cancer susceptibility loci. Here we hypothesize that some risk-associated variants might act in non-breast tissues, specifically adipose tissue and immune cells from blood and spleen. Using expression quantitative trait loci (eQTL) reported in these tissues, we identify 26 previously unreported, likely target genes of overall breast cancer risk variants, and 17 for estrogen receptor (ER)-negative breast cancer, several with a known immune function. We determine the directional effect of gene expression on disease risk measured based on single and multiple eQTL. In addition, using a gene-based test of association that considers eQTL from multiple tissues, we identify seven (and four) regions with variants associated with overall (and ER-negative) breast cancer risk, which were not reported in previous GWAS. Further investigation of the function of the implicated genes in breast and immune cells may provide insights into the etiology of breast cancer.
Published: 2019

46. Shared heritability and functional enrichment across six solid cancers (vol 10, 431, 2019)

Author: Jiang, X, Finucane, HK, Schumacher, FR, Schmit, SL, Tyrer, JP, Han, Y, Michailidou, K, Lesseur, C, Kuchenbaecker, KB, Dennis, J, Conti, DV, Casey, G, Gaudet, MM, Huyghe, JR, Albanes, D, Aldrich, MC, Andrew, AS, Andrulis, IL, Anton-Culver, H, Antoniou, AC, Antonenkova, NN, Arnold, SM, Aronson, KJ, Arun, BK, Bandera, EV, Barkardottir, RB, Barnes, DR, Batra, J, Beckmann, MW, Benitez, J, Benlloch, S, Berchuck, A, Berndt, SI, Bickeboller, H, Bien, SA, Blomqvist, C, Boccia, S, Bogdanova, NV, Bojesen, SE, Bolla, MK, Brauch, H, Brenner, H, Brenton, JD, Brook, MN, Brunet, J, Brunnstrom, H, Buchanan, DD, Burwinkel, B, Butzow, R, Cadoni, G, Caldes, T, Caligo, MA, Campbell, I, Campbell, PT, Cancel-Tassin, G, Cannon-Albright, L, Campa, D, Caporaso, N, Carvalho, AL, Chan, AT, Chang-Claude, J, Chanock, SJ, Chen, C, Christiani, DC, Claes, KBM, Claessens, F, Clements, J, Collee, JM, Correa, MC, Couch, FJ, Cox, A, Cunningham, JM, Cybulski, C, Czene, K, Daly, MB, deFazio, A, Devilee, P, Diez, O, Gago-Dominguez, M, Donovan, JL, Dork, T, Duell, EJ, Dunning, AM, Dwek, M, Eccles, DM, Edlund, CK, Edwards, DRV, Ellberg, C, Evans, DG, Fasching, PA, Ferris, RL, Liloglou, T, Figueiredo, JC, Fletcher, O, Fortner, RT, Fostira, F, Franceschi, S, Friedman, E, Gallinger, SJ, Ganz, PA, Garber, J, Garcia-Saenz, JA, Gayther, SA, Giles, GG, Godwin, AK, Goldberg, MS, Goldgar, DE, Goode, EL, Goodman, MT, Goodman, G, Grankvist, K, Greene, MH, Gronberg, H, Gronwald, J, Guenel, P, Hakansson, N, Hall, P, Hamann, U, Hamdy, FC, Hamilton, RJ, Hampe, J, Haugen, A, Heitz, F, Herrero, R, Hillemanns, P, Hoffmeister, M, Hogdall, E, Hong, Y-C, Hopper, JL, Houlston, R, Hulick, PJ, Hunter, DJ, Huntsman, DG, Idos, G, Imyanitov, EN, Ingles, SA, Isaacs, C, Jakubowska, A, James, P, Jenkins, MA, Johansson, M, John, EM, Joshi, AD, Kaneva, R, Karlan, BY, Kelemen, LE, Kuehl, T, Khaw, K-T, Khusnutdinova, E, Kibel, AS, Kiemeney, LA, Kim, J, Kjaer, SK, Knight, JA, Kogevinas, M, Kote-Jarai, Z, Koutros, S, Kristensen, VN, Kupryjanczyk, J, Lacko, M, Lam, S, Lambrechts, D, Landi, MT, Lazarus, P, Le, ND, Lee, E, Lejbkowicz, F, Lenz, H-J, Leslie, G, Lessel, D, Lester, J, Levine, DA, Li, L, Li, CI, Lindblom, A, Lindor, NM, Liu, G, Loupakis, F, Lubinski, J, Maehle, L, Maier, C, Mannermaa, A, Le Marchand, L, Margolin, S, May, T, McGuffog, L, Meindl, A, Middha, P, Miller, A, Milne, RL, MacInnis, RJ, Modugno, F, Montagna, M, Moreno, V, Moysich, KB, Mucci, L, Muir, K, Mulligan, AM, Nathanson, KL, Neal, DE, Ness, AR, Neuhausen, SL, Nevanlinna, H, Newcomb, PA, Newcomb, LF, Nielsen, FC, Nikitina-Zake, L, Nordestgaard, BG, Nussbaum, RL, Offit, K, Olah, E, Al Olama, AA, Olopade, OI, Olshan, AF, Olsson, H, Osorio, A, Pandha, H, Park, JY, Pashayan, N, Parsons, MT, Pejovic, T, Penney, KL, Peters, WHM, Phelan, CM, Phipps, AI, Plaseska-Karanfilska, D, Pring, M, Prokofyeva, D, Radice, P, Stefansson, K, Ramus, SJ, Raskin, L, Rennert, G, Rennert, HS, van Rensburg, EJ, Riggan, MJ, Risch, HA, Risch, A, Roobol, MJ, Rosenstein, BS, Rossing, MA, De Ruyck, K, Saloustros, E, Sandler, DP, Sawyer, EJ, Schabath, MB, Schleutker, J, Schmidt, MK, Setiawan, VW, Shen, H, Siegel, EM, Sieh, W, Singer, CF, Slattery, ML, Sorensen, KD, Southey, MC, Spurdle, AB, Stanford, JL, Stevens, VL, Stintzing, S, Stone, J, Sundfeldt, K, Sutphen, R, Swerdlow, AJ, Tajara, EH, Tangen, CM, Tardon, A, Taylor, JA, Teare, MD, Teixeira, MR, Terry, MB, Terry, KL, Thibodeau, SN, Thomassen, M, Bjorge, L, Tischkowitz, M, Toland, AE, Torres, D, Townsend, PA, Travis, RC, Tung, N, Tworoger, SS, Ulrich, CM, Usmani, N, Vachon, CM, Van Nieuwenhuysen, E, Vega, A, Elias Aguado-Barrera, M, Wang, Q, Webb, PM, Weinberg, CR, Weinstein, S, Weissler, MC, Weitzel, JN, West, CML, White, E, Whittemore, AS, Wichmann, H-E, Wiklund, F, Winqvist, R, Wolk, A, Woll, P, Woods, M, Wu, AH, Wu, X, Yannoukakos, D, Zheng, W, Zienolddiny, S, Ziogas, A, Zorn, KK, Lane, JM, Saxena, R, Thomas, D, Hung, RJ, Diergaarde, B, McKay, J, Peters, U, Hsu, L, Garcia-Closas, M, Eeles, RA, Chenevix-Trench, G, Brennan, PJ, Haiman, CA, Simard, J, Easton, DF, Gruber, SB, Pharoah, PDP, Price, AL, Pasaniuc, B, Amos, CI, Kraft, P, Lindstrom, S, Jiang, X, Finucane, HK, Schumacher, FR, Schmit, SL, Tyrer, JP, Han, Y, Michailidou, K, Lesseur, C, Kuchenbaecker, KB, Dennis, J, Conti, DV, Casey, G, Gaudet, MM, Huyghe, JR, Albanes, D, Aldrich, MC, Andrew, AS, Andrulis, IL, Anton-Culver, H, Antoniou, AC, Antonenkova, NN, Arnold, SM, Aronson, KJ, Arun, BK, Bandera, EV, Barkardottir, RB, Barnes, DR, Batra, J, Beckmann, MW, Benitez, J, Benlloch, S, Berchuck, A, Berndt, SI, Bickeboller, H, Bien, SA, Blomqvist, C, Boccia, S, Bogdanova, NV, Bojesen, SE, Bolla, MK, Brauch, H, Brenner, H, Brenton, JD, Brook, MN, Brunet, J, Brunnstrom, H, Buchanan, DD, Burwinkel, B, Butzow, R, Cadoni, G, Caldes, T, Caligo, MA, Campbell, I, Campbell, PT, Cancel-Tassin, G, Cannon-Albright, L, Campa, D, Caporaso, N, Carvalho, AL, Chan, AT, Chang-Claude, J, Chanock, SJ, Chen, C, Christiani, DC, Claes, KBM, Claessens, F, Clements, J, Collee, JM, Correa, MC, Couch, FJ, Cox, A, Cunningham, JM, Cybulski, C, Czene, K, Daly, MB, deFazio, A, Devilee, P, Diez, O, Gago-Dominguez, M, Donovan, JL, Dork, T, Duell, EJ, Dunning, AM, Dwek, M, Eccles, DM, Edlund, CK, Edwards, DRV, Ellberg, C, Evans, DG, Fasching, PA, Ferris, RL, Liloglou, T, Figueiredo, JC, Fletcher, O, Fortner, RT, Fostira, F, Franceschi, S, Friedman, E, Gallinger, SJ, Ganz, PA, Garber, J, Garcia-Saenz, JA, Gayther, SA, Giles, GG, Godwin, AK, Goldberg, MS, Goldgar, DE, Goode, EL, Goodman, MT, Goodman, G, Grankvist, K, Greene, MH, Gronberg, H, Gronwald, J, Guenel, P, Hakansson, N, Hall, P, Hamann, U, Hamdy, FC, Hamilton, RJ, Hampe, J, Haugen, A, Heitz, F, Herrero, R, Hillemanns, P, Hoffmeister, M, Hogdall, E, Hong, Y-C, Hopper, JL, Houlston, R, Hulick, PJ, Hunter, DJ, Huntsman, DG, Idos, G, Imyanitov, EN, Ingles, SA, Isaacs, C, Jakubowska, A, James, P, Jenkins, MA, Johansson, M, John, EM, Joshi, AD, Kaneva, R, Karlan, BY, Kelemen, LE, Kuehl, T, Khaw, K-T, Khusnutdinova, E, Kibel, AS, Kiemeney, LA, Kim, J, Kjaer, SK, Knight, JA, Kogevinas, M, Kote-Jarai, Z, Koutros, S, Kristensen, VN, Kupryjanczyk, J, Lacko, M, Lam, S, Lambrechts, D, Landi, MT, Lazarus, P, Le, ND, Lee, E, Lejbkowicz, F, Lenz, H-J, Leslie, G, Lessel, D, Lester, J, Levine, DA, Li, L, Li, CI, Lindblom, A, Lindor, NM, Liu, G, Loupakis, F, Lubinski, J, Maehle, L, Maier, C, Mannermaa, A, Le Marchand, L, Margolin, S, May, T, McGuffog, L, Meindl, A, Middha, P, Miller, A, Milne, RL, MacInnis, RJ, Modugno, F, Montagna, M, Moreno, V, Moysich, KB, Mucci, L, Muir, K, Mulligan, AM, Nathanson, KL, Neal, DE, Ness, AR, Neuhausen, SL, Nevanlinna, H, Newcomb, PA, Newcomb, LF, Nielsen, FC, Nikitina-Zake, L, Nordestgaard, BG, Nussbaum, RL, Offit, K, Olah, E, Al Olama, AA, Olopade, OI, Olshan, AF, Olsson, H, Osorio, A, Pandha, H, Park, JY, Pashayan, N, Parsons, MT, Pejovic, T, Penney, KL, Peters, WHM, Phelan, CM, Phipps, AI, Plaseska-Karanfilska, D, Pring, M, Prokofyeva, D, Radice, P, Stefansson, K, Ramus, SJ, Raskin, L, Rennert, G, Rennert, HS, van Rensburg, EJ, Riggan, MJ, Risch, HA, Risch, A, Roobol, MJ, Rosenstein, BS, Rossing, MA, De Ruyck, K, Saloustros, E, Sandler, DP, Sawyer, EJ, Schabath, MB, Schleutker, J, Schmidt, MK, Setiawan, VW, Shen, H, Siegel, EM, Sieh, W, Singer, CF, Slattery, ML, Sorensen, KD, Southey, MC, Spurdle, AB, Stanford, JL, Stevens, VL, Stintzing, S, Stone, J, Sundfeldt, K, Sutphen, R, Swerdlow, AJ, Tajara, EH, Tangen, CM, Tardon, A, Taylor, JA, Teare, MD, Teixeira, MR, Terry, MB, Terry, KL, Thibodeau, SN, Thomassen, M, Bjorge, L, Tischkowitz, M, Toland, AE, Torres, D, Townsend, PA, Travis, RC, Tung, N, Tworoger, SS, Ulrich, CM, Usmani, N, Vachon, CM, Van Nieuwenhuysen, E, Vega, A, Elias Aguado-Barrera, M, Wang, Q, Webb, PM, Weinberg, CR, Weinstein, S, Weissler, MC, Weitzel, JN, West, CML, White, E, Whittemore, AS, Wichmann, H-E, Wiklund, F, Winqvist, R, Wolk, A, Woll, P, Woods, M, Wu, AH, Wu, X, Yannoukakos, D, Zheng, W, Zienolddiny, S, Ziogas, A, Zorn, KK, Lane, JM, Saxena, R, Thomas, D, Hung, RJ, Diergaarde, B, McKay, J, Peters, U, Hsu, L, Garcia-Closas, M, Eeles, RA, Chenevix-Trench, G, Brennan, PJ, Haiman, CA, Simard, J, Easton, DF, Gruber, SB, Pharoah, PDP, Price, AL, Pasaniuc, B, Amos, CI, Kraft, P, and Lindstrom, S
Abstract: An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Published: 2019

47. Mortality after breast cancer as a function of time since diagnosis by estrogen receptor status and age at diagnosis

Author: Jayasekara, H, MacInnis, RJ, Chamberlain, JA, Dite, GS, Leoce, NM, Dowty, JG, Bickerstaffe, A, Win, AK, Milne, RL, Giles, GG, Terry, MB, Eccles, DM, Southey, MC, Hopper, JL, Jayasekara, H, MacInnis, RJ, Chamberlain, JA, Dite, GS, Leoce, NM, Dowty, JG, Bickerstaffe, A, Win, AK, Milne, RL, Giles, GG, Terry, MB, Eccles, DM, Southey, MC, and Hopper, JL
Abstract: Our aim was to estimate how long-term mortality following breast cancer diagnosis depends on age at diagnosis, tumor estrogen receptor (ER) status, and the time already survived. We used the population-based Australian Breast Cancer Family Study which followed-up 1,196 women enrolled during 1992-1999 when aged <60 years at diagnosis with a first primary invasive breast cancer, over-sampled for younger ages at diagnosis, for whom tumor pathology features and ER status were measured. There were 375 deaths (median follow-up = 15.7; range = 0.8-21.4, years). We estimated the mortality hazard as a function of time since diagnosis using a flexible parametric survival analysis with ER status a time-dependent covariate. For women with ER-negative tumors compared with those with ER-positive tumors, 5-year mortality was initially higher (p < 0.001), similar if they survived to 5 years (p = 0.4), and lower if they survived to 10 years (p = 0.02). The estimated mortality hazard for ER-negative disease peaked at ~3 years post-diagnosis, thereafter declined with time, and at 7 years post-diagnosis became lower than that for ER-positive disease. This pattern was more pronounced for women diagnosed at younger ages. Mortality was also associated with lymph node count (hazard ratio (HR) per 10 nodes = 2.52 [95% CI:2.11-3.01]) and tumor grade (HR per grade = 1.62 [95% CI:1.34-1.96]). The risk of death following a breast cancer diagnosis differs substantially and qualitatively with diagnosis age, ER status and time survived. For women who survive >7 years, those with ER-negative disease will on average live longer, and more so if younger at diagnosis.
Published: 2019

48. Risk-Reducing Oophorectomy and Breast Cancer Risk Across the Spectrum of Familial Risk

Author: Terry, MB, Daly, MB, Phillips, KA, Ma, X, Zeinomar, N, Leoce, N, Dite, GS, MacInnis, RJ, Chung, WK, Knight, JA, Southey, MC, Milne, RL, Goldgar, D, Giles, GG, Weideman, PC, Glendon, G, Buchsbaum, R, Andrulis, IL, John, EM, Buys, SS, Hopper, JL, Terry, MB, Daly, MB, Phillips, KA, Ma, X, Zeinomar, N, Leoce, N, Dite, GS, MacInnis, RJ, Chung, WK, Knight, JA, Southey, MC, Milne, RL, Goldgar, D, Giles, GG, Weideman, PC, Glendon, G, Buchsbaum, R, Andrulis, IL, John, EM, Buys, SS, and Hopper, JL
Abstract: There remains debate about whether risk-reducing salpingo-oophorectomy (RRSO), which reduces ovarian cancer risk, also reduces breast cancer risk. We examined the association between RRSO and breast cancer risk using a prospective cohort of 17 917 women unaffected with breast cancer at baseline (7.2% known carriers of BRCA1 or BRCA2 mutations). During a median follow-up of 10.7 years, 1046 women were diagnosed with incident breast cancer. Modeling RRSO as a time-varying exposure, there was no association with breast cancer risk overall (hazard ratio [HR] = 1.04, 95% confidence interval [CI] = 0.87 to 1.24) or by tertiles of predicted absolute risk based on family history (HR = 0.68, 95% CI = 0.32 to 1.47, HR = 0.94, 95% CI = 0.70 to 1.26, and HR = 1.10, 95% CI = 0.88 to 1.39, for lowest, middle, and highest tertile of risk, respectively) or for BRCA1 and BRCA2 mutation carriers when examined separately. There was also no association after accounting for hormone therapy use after RRSO. These findings suggest that RRSO should not be considered efficacious for reducing breast cancer risk.
Published: 2019

49. Genome-wide association study of germline variants and breast cancer-specific mortality

Author: Escala-Garcia, M, Guo, Q, Doerk, T, Canisius, S, Keeman, R, Dennis, J, Beesley, J, Lecarpentier, J, Bolla, MK, Wang, Q, Abraham, J, Andrulis, IL, Anton-Culver, H, Arndt, V, Auer, PL, Beckmann, MW, Behrens, S, Benitez, J, Bermisheva, M, Bernstein, L, Blomqvist, C, Boeckx, B, Bojesen, SE, Bonanni, B, Borresen-Dale, A-L, Brauch, H, Brenner, H, Brentnall, A, Brinton, L, Broberg, P, Brock, IW, Brucker, SY, Burwinkel, B, Caldas, C, Caldes, T, Campa, D, Canzian, F, Carracedo, A, Carter, BD, Castelao, JE, Chang-Claude, J, Chanock, SJ, Chenevix-Trench, G, Cheng, T-YD, Chin, S-F, Clarke, CL, Cordina-Duverger, E, Couch, FJ, Cox, DG, Cox, A, Cross, SS, Czene, K, Daly, MB, Devilee, P, Dunn, JA, Dunning, AM, Durcan, L, Dwek, M, Earl, HM, Ekici, AB, Eliassen, AH, Ellberg, C, Engel, C, Eriksson, M, Evans, DG, Figueroa, J, Flesch-Janys, D, Flyger, H, Gabrielson, M, Gago-Dominguez, M, Galle, E, Gapstur, SM, Garcia-Closas, M, Garcia-Saenz, JA, Gaudet, MM, George, A, Georgoulias, V, Giles, GG, Glendon, G, Goldgar, DE, Gonzalez-Neira, A, Alnaes, GIG, Grip, M, Guenel, P, Haeberle, L, Hahnen, E, Haiman, CA, Hakansson, N, Hall, P, Hamann, U, Hankinson, S, Harkness, EF, Harrington, PA, Hart, SN, Hartikainen, JM, Hein, A, Hillemanns, P, Hiller, L, Holleczek, B, Hollestelle, A, Hooning, MJ, Hoover, RN, Hopper, JL, Howell, A, Huang, G, Humphreys, K, Hunter, DJ, Janni, W, John, EM, Jones, ME, Jukkola-Vuorinen, A, Jung, A, Kaaks, R, Kabisch, M, Kaczmarek, K, Kerin, MJ, Khan, S, Khusnutdinova, E, Kiiski, J, Kitahara, CM, Knight, JA, Ko, Y-D, Koppert, LB, Kosma, V-M, Kraft, P, Kristensen, VN, Kruger, U, Kuehl, T, Lambrechts, D, Le Marchand, L, Lee, E, Lejbkowicz, F, Li, L, Lindblom, A, Lindstrom, S, Linet, M, Lissowska, J, Lo, W-Y, Loibl, S, Lubinski, J, Lux, MP, MacInnis, RJ, Maierthaler, M, Maishman, T, Makalic, E, Mannermaa, A, Manoochehri, M, Manoukian, S, Margolin, S, Martinez, ME, Mavroudis, D, McLean, C, Meindl, A, Middha, P, Miller, N, Milne, RL, Moreno, F, Mulligan, AM, Mulot, C, Nassir, R, Neuhausen, SL, Newman, WT, Nielsen, SF, Nordestgaard, BG, Norman, A, Olsson, H, Orr, N, Pankratz, VS, Park-Simon, T-W, Perez, JIA, Perez-Barrios, C, Peterlongo, P, Petridis, C, Pinchev, M, Prajzendanc, K, Prentice, R, Presneau, N, Prokofieva, D, Pylkas, K, Rack, B, Radice, P, Ramachandran, D, Rennert, G, Rennert, HS, Rhenius, V, Romero, A, Roylance, R, Saloustros, E, Sawyer, EJ, Schmidt, DF, Schmutzler, RK, Schneeweiss, A, Schoemaker, MJ, Schumacher, F, Schwentner, L, Scott, RJ, Scott, C, Seynaeve, C, Shah, M, Simard, J, Smeets, A, Sohn, C, Southey, MC, Swerdlow, AJ, Talhouk, A, Tamimi, RM, Tapper, WJ, Teixeira, MR, Tengstrom, M, Terry, MB, Thoene, K, Tollenaar, RAEM, Tomlinson, I, Torres, D, Truong, T, Turman, C, Turnbull, C, Ulmer, H-U, Untch, M, Vachon, C, van Asperen, CJ, van den Ouweland, AMW, van Veen, EM, Wendt, C, Whittemore, AS, Willett, W, Winqvist, R, Wolk, A, Yang, XR, Zhang, Y, Easton, DF, Fasching, PA, Nevanlinna, H, Eccles, DM, Pharoah, PDP, Schmidt, MK, Escala-Garcia, M, Guo, Q, Doerk, T, Canisius, S, Keeman, R, Dennis, J, Beesley, J, Lecarpentier, J, Bolla, MK, Wang, Q, Abraham, J, Andrulis, IL, Anton-Culver, H, Arndt, V, Auer, PL, Beckmann, MW, Behrens, S, Benitez, J, Bermisheva, M, Bernstein, L, Blomqvist, C, Boeckx, B, Bojesen, SE, Bonanni, B, Borresen-Dale, A-L, Brauch, H, Brenner, H, Brentnall, A, Brinton, L, Broberg, P, Brock, IW, Brucker, SY, Burwinkel, B, Caldas, C, Caldes, T, Campa, D, Canzian, F, Carracedo, A, Carter, BD, Castelao, JE, Chang-Claude, J, Chanock, SJ, Chenevix-Trench, G, Cheng, T-YD, Chin, S-F, Clarke, CL, Cordina-Duverger, E, Couch, FJ, Cox, DG, Cox, A, Cross, SS, Czene, K, Daly, MB, Devilee, P, Dunn, JA, Dunning, AM, Durcan, L, Dwek, M, Earl, HM, Ekici, AB, Eliassen, AH, Ellberg, C, Engel, C, Eriksson, M, Evans, DG, Figueroa, J, Flesch-Janys, D, Flyger, H, Gabrielson, M, Gago-Dominguez, M, Galle, E, Gapstur, SM, Garcia-Closas, M, Garcia-Saenz, JA, Gaudet, MM, George, A, Georgoulias, V, Giles, GG, Glendon, G, Goldgar, DE, Gonzalez-Neira, A, Alnaes, GIG, Grip, M, Guenel, P, Haeberle, L, Hahnen, E, Haiman, CA, Hakansson, N, Hall, P, Hamann, U, Hankinson, S, Harkness, EF, Harrington, PA, Hart, SN, Hartikainen, JM, Hein, A, Hillemanns, P, Hiller, L, Holleczek, B, Hollestelle, A, Hooning, MJ, Hoover, RN, Hopper, JL, Howell, A, Huang, G, Humphreys, K, Hunter, DJ, Janni, W, John, EM, Jones, ME, Jukkola-Vuorinen, A, Jung, A, Kaaks, R, Kabisch, M, Kaczmarek, K, Kerin, MJ, Khan, S, Khusnutdinova, E, Kiiski, J, Kitahara, CM, Knight, JA, Ko, Y-D, Koppert, LB, Kosma, V-M, Kraft, P, Kristensen, VN, Kruger, U, Kuehl, T, Lambrechts, D, Le Marchand, L, Lee, E, Lejbkowicz, F, Li, L, Lindblom, A, Lindstrom, S, Linet, M, Lissowska, J, Lo, W-Y, Loibl, S, Lubinski, J, Lux, MP, MacInnis, RJ, Maierthaler, M, Maishman, T, Makalic, E, Mannermaa, A, Manoochehri, M, Manoukian, S, Margolin, S, Martinez, ME, Mavroudis, D, McLean, C, Meindl, A, Middha, P, Miller, N, Milne, RL, Moreno, F, Mulligan, AM, Mulot, C, Nassir, R, Neuhausen, SL, Newman, WT, Nielsen, SF, Nordestgaard, BG, Norman, A, Olsson, H, Orr, N, Pankratz, VS, Park-Simon, T-W, Perez, JIA, Perez-Barrios, C, Peterlongo, P, Petridis, C, Pinchev, M, Prajzendanc, K, Prentice, R, Presneau, N, Prokofieva, D, Pylkas, K, Rack, B, Radice, P, Ramachandran, D, Rennert, G, Rennert, HS, Rhenius, V, Romero, A, Roylance, R, Saloustros, E, Sawyer, EJ, Schmidt, DF, Schmutzler, RK, Schneeweiss, A, Schoemaker, MJ, Schumacher, F, Schwentner, L, Scott, RJ, Scott, C, Seynaeve, C, Shah, M, Simard, J, Smeets, A, Sohn, C, Southey, MC, Swerdlow, AJ, Talhouk, A, Tamimi, RM, Tapper, WJ, Teixeira, MR, Tengstrom, M, Terry, MB, Thoene, K, Tollenaar, RAEM, Tomlinson, I, Torres, D, Truong, T, Turman, C, Turnbull, C, Ulmer, H-U, Untch, M, Vachon, C, van Asperen, CJ, van den Ouweland, AMW, van Veen, EM, Wendt, C, Whittemore, AS, Willett, W, Winqvist, R, Wolk, A, Yang, XR, Zhang, Y, Easton, DF, Fasching, PA, Nevanlinna, H, Eccles, DM, Pharoah, PDP, and Schmidt, MK
Abstract: BACKGROUND: We examined the associations between germline variants and breast cancer mortality using a large meta-analysis of women of European ancestry. METHODS: Meta-analyses included summary estimates based on Cox models of twelve datasets using ~10.4 million variants for 96,661 women with breast cancer and 7697 events (breast cancer-specific deaths). Oestrogen receptor (ER)-specific analyses were based on 64,171 ER-positive (4116) and 16,172 ER-negative (2125) patients. We evaluated the probability of a signal to be a true positive using the Bayesian false discovery probability (BFDP). RESULTS: We did not find any variant associated with breast cancer-specific mortality at P < 5 × 10-8. For ER-positive disease, the most significantly associated variant was chr7:rs4717568 (BFDP = 7%, P = 1.28 × 10-7, hazard ratio [HR] = 0.88, 95% confidence interval [CI] = 0.84-0.92); the closest gene is AUTS2. For ER-negative disease, the most significant variant was chr7:rs67918676 (BFDP = 11%, P = 1.38 × 10-7, HR = 1.27, 95% CI = 1.16-1.39); located within a long intergenic non-coding RNA gene (AC004009.3), close to the HOXA gene cluster. CONCLUSIONS: We uncovered germline variants on chromosome 7 at BFDP < 15% close to genes for which there is biological evidence related to breast cancer outcome. However, the paucity of variants associated with mortality at genome-wide significance underpins the challenge in providing genetic-based individualised prognostic information for breast cancer patients.
Published: 2019

50. Polygenic Risk Scores for Prediction of Breast Cancer and Breast Cancer Subtypes

Author: Mavaddat, N, Michailidou, K, Dennis, J, Lush, M, Fachal, L, Lee, A, Tyrer, JP, Chen, T-H, Wang, Q, Bolla, MK, Yang, X, Adank, MA, Ahearn, T, Aittomaki, K, Allen, J, Andrulis, IL, Anton-Culver, H, Antonenkova, NN, Arndt, V, Aronson, KJ, Auer, PL, Auvinen, P, Barrdahl, M, Freeman, LEB, Beckmann, MW, Behrens, S, Benitez, J, Bermisheva, M, Bernstein, L, Blomqvist, C, Bogdanova, N, Bojesen, SE, Bonanni, B, Borresen-Dale, A-L, Brauch, H, Bremer, M, Brenner, H, Brentnall, A, Brock, IW, Brooks-Wilson, A, Brucker, SY, Bruening, T, Burwinkel, B, Campa, D, Carter, BD, Castelao, JE, Chanock, SJ, Chlebowski, R, Christiansen, H, Clarke, CL, Collee, JM, Cordina-Duverger, E, Cornelissen, S, Couch, FJ, Cox, A, Cross, SS, Czene, K, Daly, MB, Devilee, P, Doerk, T, dos-Santos-Silva, I, Dumont, M, Durcan, L, Dwek, M, Eccles, DM, Ekici, AB, Eliassen, AH, Ellberg, C, Engel, C, Eriksson, M, Evans, DG, Fasching, PA, Figueroa, J, Fletcher, O, Flyger, H, Foersti, A, Fritschi, L, Gabrielson, M, Gago-Dominguez, M, Gapstur, SM, Garcia-Saenz, JA, Gaudet, MM, Georgoulias, V, Giles, GG, Gilyazova, IR, Glendon, G, Goldberg, MS, Goldgar, DE, Gonzalez-Neira, A, Alnaes, GIG, Grip, M, Gronwald, J, Grundy, A, Guenel, P, Haeberle, L, Hahnen, E, Haiman, CA, Hakansson, N, Hamann, U, Hankinson, SE, Harkness, EF, Hart, SN, He, W, Hein, A, Heyworth, J, Hillemanns, P, Hollestelle, A, Hooning, MJ, Hoover, RN, Hopper, JL, Howell, A, Huang, G, Humphreys, K, Hunter, DJ, Jakimovska, M, Jakubowska, A, Janni, W, John, EM, Johnson, N, Jones, ME, Jukkola-Vuorinen, A, Jung, A, Kaaks, R, Kaczmarek, K, Kataja, V, Keeman, R, Kerin, MJ, Khusnutdinova, E, Kiiski, J, Knight, JA, Ko, Y-D, Kosma, V-M, Koutros, S, Kristensen, VN, Kruger, U, Kuehl, T, Lambrechts, D, Le Marchand, L, Lee, E, Lejbkowicz, F, Lilyquist, J, Lindblom, A, Lindstrom, S, Lissowska, J, Lo, W-Y, Loibl, S, Long, J, Lubinski, J, Lux, MP, MacInnis, RJ, Maishman, T, Makalic, E, Kostovska, IM, Mannermaa, A, Manoukian, S, Margolin, S, Martens, JWM, Martinez, ME, Mavroudis, D, McLean, C, Meindl, A, Menon, U, Middha, P, Miller, N, Moreno, F, Mulligan, AM, Mulot, C, Munoz-Garzon, VM, Neuhausen, SL, Nevanlinna, H, Neven, P, Newman, WG, Nielsen, SF, Nordestgaard, BG, Norman, A, Offit, K, Olson, JE, Olsson, H, Orr, N, Pankratz, VS, Park-Simon, T-W, Perez, JIA, Perez-Barrios, C, Peterlongo, P, Peto, J, Pinchev, M, Plaseska-Karanfilska, D, Polley, EC, Prentice, R, Presneau, N, Prokofyeva, D, Purrington, K, Pylkas, K, Rack, B, Radice, P, Rau-Murthy, R, Rennert, G, Rennert, HS, Rhenius, V, Robson, M, Romero, A, Ruddy, KJ, Ruebner, M, Saloustros, E, Sandler, DP, Sawyer, EJ, Schmidt, DF, Schmutzler, RK, Schneeweiss, A, Schoemaker, MJ, Schumacher, F, Schuermann, P, Schwentner, L, Scott, C, Scott, RJ, Seynaeve, C, Shah, M, Sherman, ME, Shrubsole, MJ, Shu, X-O, Slager, S, Smeets, A, Sohn, C, Soucy, P, Southey, MC, Spinelli, JJ, Stegmaier, C, Stone, J, Swerdlow, AJ, Tamimi, RM, Tapper, WJ, Taylor, JA, Terry, MB, Thoene, K, Tollenaar, RAEM, Tomlinson, I, Truong, T, Tzardi, M, Ulmer, H-U, Untch, M, Vachon, CM, van Veen, EM, Vijai, J, Weinberg, CR, Wendt, C, Whittemore, AS, Wildiers, H, Willett, W, Winqvist, R, Wolk, A, Yang, XR, Yannoukakos, D, Zhang, Y, Zheng, W, Ziogas, A, Clarke, C, Balleine, R, Baxter, R, Braye, S, Carpenter, J, Dahlstrom, J, Forbes, J, Lee, CS, Marsh, D, Morey, A, Pathmanathan, N, Scott, R, Simpson, P, Spigelman, A, Wilcken, N, Yip, D, Zeps, N, Sexton, A, Dobrovic, A, Christian, A, Trainer, A, Fellows, A, Shelling, A, De Fazio, A, Blackburn, A, Crook, A, Meiser, B, Patterson, B, Saunders, C, Hunt, C, Amor, D, Ortega, DG, Edkins, E, Salisbury, E, Haan, E, Macrea, F, Farshid, G, Lindeman, G, Trench, G, Mann, G, Giles, G, Gill, G, Thorne, H, Campbell, I, Hickie, I, Caldon, L, Winship, I, Cui, J, Flanagan, J, Kollias, J, Visvader, J, Taylor, J, Burke, J, Saunus, J, Forbs, J, Hopper, J, Beesley, J, Kirk, J, French, J, Tucker, K, Wu, K, Phillips, K, Forrest, L, Lipton, L, Andrews, L, Lobb, L, Walker, L, Kentwell, M, Spurdle, M, Cummings, M, Gleeson, M, Harris, M, Jenkins, M, Young, MA, Delatycki, M, Wallis, M, Burgess, M, Brown, M, Southey, M, Bogwitz, M, Field, M, Friedlander, M, Gattas, M, Saleh, M, Aghmesheh, M, Hayward, N, Pachter, N, Cohen, P, Duijf, P, James, P, Fong, P, Butow, P, Williams, R, Kefford, R, Simard, J, Balleine, R-M, Dawson, S-J, Lok, S, O'connell, S, Greening, S, Nightingale, S, Edwards, S, Fox, S, McLachlan, S-A, Lakhani, S, Dudding, T, Antill, Y, Sahlberg, KK, Ottestad, L, Karesen, R, Schlichting, E, Holmen, MM, Sauer, T, Haakensen, V, Engebraten, O, Naume, B, Fossa, A, Kiserud, CE, Reinertsen, K, Helland, A, Riis, M, Geisler, J, Dunning, AM, Thompson, DJ, Chenevix-Trench, G, Chang-Claude, J, Schmidt, MK, Hall, P, Milne, RL, Pharoah, PDP, Antoniou, AC, Chatterjee, N, Kraft, P, Garcia-Closas, M, Easton, DF, Mavaddat, N, Michailidou, K, Dennis, J, Lush, M, Fachal, L, Lee, A, Tyrer, JP, Chen, T-H, Wang, Q, Bolla, MK, Yang, X, Adank, MA, Ahearn, T, Aittomaki, K, Allen, J, Andrulis, IL, Anton-Culver, H, Antonenkova, NN, Arndt, V, Aronson, KJ, Auer, PL, Auvinen, P, Barrdahl, M, Freeman, LEB, Beckmann, MW, Behrens, S, Benitez, J, Bermisheva, M, Bernstein, L, Blomqvist, C, Bogdanova, N, Bojesen, SE, Bonanni, B, Borresen-Dale, A-L, Brauch, H, Bremer, M, Brenner, H, Brentnall, A, Brock, IW, Brooks-Wilson, A, Brucker, SY, Bruening, T, Burwinkel, B, Campa, D, Carter, BD, Castelao, JE, Chanock, SJ, Chlebowski, R, Christiansen, H, Clarke, CL, Collee, JM, Cordina-Duverger, E, Cornelissen, S, Couch, FJ, Cox, A, Cross, SS, Czene, K, Daly, MB, Devilee, P, Doerk, T, dos-Santos-Silva, I, Dumont, M, Durcan, L, Dwek, M, Eccles, DM, Ekici, AB, Eliassen, AH, Ellberg, C, Engel, C, Eriksson, M, Evans, DG, Fasching, PA, Figueroa, J, Fletcher, O, Flyger, H, Foersti, A, Fritschi, L, Gabrielson, M, Gago-Dominguez, M, Gapstur, SM, Garcia-Saenz, JA, Gaudet, MM, Georgoulias, V, Giles, GG, Gilyazova, IR, Glendon, G, Goldberg, MS, Goldgar, DE, Gonzalez-Neira, A, Alnaes, GIG, Grip, M, Gronwald, J, Grundy, A, Guenel, P, Haeberle, L, Hahnen, E, Haiman, CA, Hakansson, N, Hamann, U, Hankinson, SE, Harkness, EF, Hart, SN, He, W, Hein, A, Heyworth, J, Hillemanns, P, Hollestelle, A, Hooning, MJ, Hoover, RN, Hopper, JL, Howell, A, Huang, G, Humphreys, K, Hunter, DJ, Jakimovska, M, Jakubowska, A, Janni, W, John, EM, Johnson, N, Jones, ME, Jukkola-Vuorinen, A, Jung, A, Kaaks, R, Kaczmarek, K, Kataja, V, Keeman, R, Kerin, MJ, Khusnutdinova, E, Kiiski, J, Knight, JA, Ko, Y-D, Kosma, V-M, Koutros, S, Kristensen, VN, Kruger, U, Kuehl, T, Lambrechts, D, Le Marchand, L, Lee, E, Lejbkowicz, F, Lilyquist, J, Lindblom, A, Lindstrom, S, Lissowska, J, Lo, W-Y, Loibl, S, Long, J, Lubinski, J, Lux, MP, MacInnis, RJ, Maishman, T, Makalic, E, Kostovska, IM, Mannermaa, A, Manoukian, S, Margolin, S, Martens, JWM, Martinez, ME, Mavroudis, D, McLean, C, Meindl, A, Menon, U, Middha, P, Miller, N, Moreno, F, Mulligan, AM, Mulot, C, Munoz-Garzon, VM, Neuhausen, SL, Nevanlinna, H, Neven, P, Newman, WG, Nielsen, SF, Nordestgaard, BG, Norman, A, Offit, K, Olson, JE, Olsson, H, Orr, N, Pankratz, VS, Park-Simon, T-W, Perez, JIA, Perez-Barrios, C, Peterlongo, P, Peto, J, Pinchev, M, Plaseska-Karanfilska, D, Polley, EC, Prentice, R, Presneau, N, Prokofyeva, D, Purrington, K, Pylkas, K, Rack, B, Radice, P, Rau-Murthy, R, Rennert, G, Rennert, HS, Rhenius, V, Robson, M, Romero, A, Ruddy, KJ, Ruebner, M, Saloustros, E, Sandler, DP, Sawyer, EJ, Schmidt, DF, Schmutzler, RK, Schneeweiss, A, Schoemaker, MJ, Schumacher, F, Schuermann, P, Schwentner, L, Scott, C, Scott, RJ, Seynaeve, C, Shah, M, Sherman, ME, Shrubsole, MJ, Shu, X-O, Slager, S, Smeets, A, Sohn, C, Soucy, P, Southey, MC, Spinelli, JJ, Stegmaier, C, Stone, J, Swerdlow, AJ, Tamimi, RM, Tapper, WJ, Taylor, JA, Terry, MB, Thoene, K, Tollenaar, RAEM, Tomlinson, I, Truong, T, Tzardi, M, Ulmer, H-U, Untch, M, Vachon, CM, van Veen, EM, Vijai, J, Weinberg, CR, Wendt, C, Whittemore, AS, Wildiers, H, Willett, W, Winqvist, R, Wolk, A, Yang, XR, Yannoukakos, D, Zhang, Y, Zheng, W, Ziogas, A, Clarke, C, Balleine, R, Baxter, R, Braye, S, Carpenter, J, Dahlstrom, J, Forbes, J, Lee, CS, Marsh, D, Morey, A, Pathmanathan, N, Scott, R, Simpson, P, Spigelman, A, Wilcken, N, Yip, D, Zeps, N, Sexton, A, Dobrovic, A, Christian, A, Trainer, A, Fellows, A, Shelling, A, De Fazio, A, Blackburn, A, Crook, A, Meiser, B, Patterson, B, Saunders, C, Hunt, C, Amor, D, Ortega, DG, Edkins, E, Salisbury, E, Haan, E, Macrea, F, Farshid, G, Lindeman, G, Trench, G, Mann, G, Giles, G, Gill, G, Thorne, H, Campbell, I, Hickie, I, Caldon, L, Winship, I, Cui, J, Flanagan, J, Kollias, J, Visvader, J, Taylor, J, Burke, J, Saunus, J, Forbs, J, Hopper, J, Beesley, J, Kirk, J, French, J, Tucker, K, Wu, K, Phillips, K, Forrest, L, Lipton, L, Andrews, L, Lobb, L, Walker, L, Kentwell, M, Spurdle, M, Cummings, M, Gleeson, M, Harris, M, Jenkins, M, Young, MA, Delatycki, M, Wallis, M, Burgess, M, Brown, M, Southey, M, Bogwitz, M, Field, M, Friedlander, M, Gattas, M, Saleh, M, Aghmesheh, M, Hayward, N, Pachter, N, Cohen, P, Duijf, P, James, P, Fong, P, Butow, P, Williams, R, Kefford, R, Simard, J, Balleine, R-M, Dawson, S-J, Lok, S, O'connell, S, Greening, S, Nightingale, S, Edwards, S, Fox, S, McLachlan, S-A, Lakhani, S, Dudding, T, Antill, Y, Sahlberg, KK, Ottestad, L, Karesen, R, Schlichting, E, Holmen, MM, Sauer, T, Haakensen, V, Engebraten, O, Naume, B, Fossa, A, Kiserud, CE, Reinertsen, K, Helland, A, Riis, M, Geisler, J, Dunning, AM, Thompson, DJ, Chenevix-Trench, G, Chang-Claude, J, Schmidt, MK, Hall, P, Milne, RL, Pharoah, PDP, Antoniou, AC, Chatterjee, N, Kraft, P, Garcia-Closas, M, and Easton, DF
Abstract: Stratification of women according to their risk of breast cancer based on polygenic risk scores (PRSs) could improve screening and prevention strategies. Our aim was to develop PRSs, optimized for prediction of estrogen receptor (ER)-specific disease, from the largest available genome-wide association dataset and to empirically validate the PRSs in prospective studies. The development dataset comprised 94,075 case subjects and 75,017 control subjects of European ancestry from 69 studies, divided into training and validation sets. Samples were genotyped using genome-wide arrays, and single-nucleotide polymorphisms (SNPs) were selected by stepwise regression or lasso penalized regression. The best performing PRSs were validated in an independent test set comprising 11,428 case subjects and 18,323 control subjects from 10 prospective studies and 190,040 women from UK Biobank (3,215 incident breast cancers). For the best PRSs (313 SNPs), the odds ratio for overall disease per 1 standard deviation in ten prospective studies was 1.61 (95%CI: 1.57-1.65) with area under receiver-operator curve (AUC) = 0.630 (95%CI: 0.628-0.651). The lifetime risk of overall breast cancer in the top centile of the PRSs was 32.6%. Compared with women in the middle quintile, those in the highest 1% of risk had 4.37- and 2.78-fold risks, and those in the lowest 1% of risk had 0.16- and 0.27-fold risks, of developing ER-positive and ER-negative disease, respectively. Goodness-of-fit tests indicated that this PRS was well calibrated and predicts disease risk accurately in the tails of the distribution. This PRS is a powerful and reliable predictor of breast cancer risk that may improve breast cancer prevention programs.
Published: 2019

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