Article | Published:


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



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.


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.


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).


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.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.


  1. 1.

    Salehi, F., Dunfield, L., Phillips, K. P., Krewski, D. Vanderhyden, B. C. Risk factors for ovarian cancer: an overview with emphasis on hormonal factors. J. Toxicol. Environ. Health B Crit. Rev. 11, 301–321 (2008).

  2. 2.

    Wentzensen, N., Poole, E. M., Trabert, B., White, E., Arslan, A. A., Patel, A. V. et al. Ovarian cancer risk factors by histologic subtype: an analysis from the Ovarian Cancer Cohort Consortium. J. Clin. Oncol. 34, 2888–2898 (2016).

  3. 3.

    Rauh-Hain, J. A., Krivak, T. C., Del Carmen, M. G., Olawaiye, A. B. Ovarian cancer screening and early detection in the general population. Rev. Obstet. Gynecol. 4, 15–21 (2011).

  4. 4.

    Jacobs, I. J., Menon, U., Ryan, A., Gentry-Maharaj, A., Burnell, M., Kalsi, J. K. et al. Ovarian cancer screening and mortality in the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS): a randomised controlled trial. Lancet 387, 945–956 (2016).

  5. 5.

    Neff, R. T., Senter, L. Salani, R. BRCA mutation in ovarian cancer: testing, implications and treatment considerations. Ther. Adv. Med. Oncol. 9, 519–531 (2017).

  6. 6.

    King, M. C., Marks, J. H., Mandell, J. B. & New York Breast Cancer Study Group. Breast and ovarian cancer risks due to inherited mutations in BRCA1 and BRCA2. Science 302, 643–646 (2003).

  7. 7.

    Kuchenbaecker, K. B., Hopper, J. L., Barnes, D. R., Phillips, K. A., Mooij, T. M., Roos-Blom, M. J. et al. Risks of breast, ovarian, and contralateral breast cancer for BRCA1 and BRCA2 mutation carriers. JAMA 317, 2402–2416 (2017).

  8. 8.

    Friebel, T. M., Domchek, S. M. & Rebbeck, T. R. Modifiers of cancer risk in BRCA1 and BRCA2 mutation carriers: systematic review and meta-analysis. J. Natl Cancer Inst. 106, (2014).

  9. 9.

    Gayther, S. A., Russell, P., Harrington, P., Antoniou, A. C., Easton, D. F. Ponder, B. A. The contribution of germline BRCA1 and BRCA2 mutations to familial ovarian cancer: no evidence for other ovarian cancer-susceptibility genes. Am. J. Hum. Genet. 65, 1021–1029 (1999).

  10. 10.

    Lango Allen, H., Estrada, K., Lettre, G., Berndt, S. I., Weedon, M. N., Rivadeneira, F. et al. Hundreds of variants clustered in genomic loci and biological pathways affect human height. Nature 467, 832–838 (2010).

  11. 11.

    Locke, A. E., Kahali, B., Berndt, S. I., Justice, A. E., Pers, T. H., Day, F. R. et al. Genetic studies of body mass index yield new insights for obesity biology. Nature 518, 197–206 (2015).

  12. 12.

    Collaborative Group on Epidemiological Studies of Ovarian Cancer. Ovarian cancer and body size: individual participant meta-analysis including 25,157 women with ovarian cancer from 47 epidemiological studies. PLoS Med. 9, e1001200 (2012).

  13. 13.

    Beehler, G. P., Sekhon, M., Baker, J. A., Teter, B. E., McCann, S. E., Rodabaugh, K. J. et al. Risk of ovarian cancer associated with BMI varies by menopausal status. J. Nutr. 136, 2881–2886 (2006).

  14. 14.

    Dixon, S. C., Nagle, C. M., Thrift, A. P., Pharoah, P. D., Pearce, C. L., Zheng, W. et al. Adult body mass index and risk of ovarian cancer by subtype: a Mendelian randomization study. Int. J. Epidemiol. 45, 884–895 (2016).

  15. 15.

    Bhaskaran, K., Douglas, I., Forbes, H., dos-Santos-Silva, I., Leon, D. A. Smeeth, L. Body-mass index and risk of 22 specific cancers: a population-based cohort study of 5.24 million UK adults. Lancet 384, 755–765 (2014).

  16. 16.

    Olsen, C. M., Nagle, C. M., Whiteman, D. C., Ness, R., Pearce, C. L., Pike, M. C. et al. Obesity and risk of ovarian cancer subtypes: evidence from the Ovarian Cancer Association Consortium. Endocr. Relat. Cancer 20, 251–262 (2013).

  17. 17.

    Cunningham, J. M., Cicek, M. S., Larson, N. B., Davila, J., Wang, C., Larson, M. C. et al. Clinical characteristics of ovarian cancer classified by BRCA1, BRCA2, and RAD51C status. Sci. Rep. 4, 4026 (2014).

  18. 18.

    McGee, J., Kotsopoulos, J., Lubinski, J., Lynch, H. T., Rosen, B., Tung, N. et al. Anthropometric measures and risk of ovarian cancer among BRCA1 and BRCA2 mutation carriers. Obesity (Silver Spring) 20, 1288–1292 (2012).

  19. 19.

    Burgess, S., Butterworth, A. Thompson, S. G. Mendelian randomization analysis with multiple genetic variants using summarized data. Genet. Epidemiol. 37, 658–665 (2013).

  20. 20.

    Paternoster, L., Tilling, K. Davey Smith, G. Genetic epidemiology and Mendelian randomization for informing disease therapeutics: conceptual and methodological challenges. PLoS Genet. 13, e1006944 (2017).

  21. 21.

    VanderWeele, T. J., Tchetgen Tchetgen, E. J., Cornelis, M. Kraft, P. Methodological challenges in mendelian randomization. Epidemiology 25, 427–435 (2014).

  22. 22.

    Couch, F. J., Wang, X., McGuffog, L., Lee, A., Olswold, C., Kuchenbaecker, K. B. et al. Genome-wide association study in BRCA1 mutation carriers identifies novel loci associated with breast and ovarian cancer risk. PLoS Genet. 9, e1003212 (2013).

  23. 23.

    Rebbeck, T. R., Mitra, N., Wan, F., Sinilnikova, O. M., Healey, S., McGuffog, L. et al. Association of type and location of BRCA1 and BRCA2 mutations with risk of breast and ovarian cancer. JAMA 313, 1347–1361 (2015).

  24. 24.

    Qian, F., Wang, S., Mitchell, J., McGuffog, L., Barrowdale, D., Leslie, G. et al. Height and body mass index as modifiers of breast cancer risk in BRCA1/2 mutation carriers: a Mendelian randomization study. J. Natl Cancer Inst. (2018).

  25. 25.

    Wood, A. R., Esko, T., Yang, J., Vedantam, S., Pers, T. H., Gustafsson, S. et al. Defining the role of common variation in the genomic and biological architecture of adult human height. Nat. Genet. 46, 1173–1186 (2014).

  26. 26.

    Antoniou, A., Pharoah, P. D., Narod, S., Risch, H. A., Eyfjord, J. E., Hopper, J. L. et al. Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case series unselected for family history: a combined analysis of 22 studies. Am. J. Hum. Genet. 72, 1117–1130 (2003).

  27. 27.

    Antoniou, A. C., Goldgar, D. E., Andrieu, N., Chang-Claude, J., Brohet, R., Rookus, M. A. et al. A weighted cohort approach for analysing factors modifying disease risks in carriers of high-risk susceptibility genes. Genet Epidemiol. 29, 1–11 (2005).

  28. 28.

    Bautista, L. E., Smeeth, L., Hingorani, A. D. Casas, J. P. Estimation of bias in nongenetic observational studies using “mendelian triangulation”. Ann. Epidemiol. 16, 675–680 (2006).

  29. 29.

    Bowden, J., Davey Smith, G. Burgess, S. Mendelian randomization with invalid instruments: effect estimation and bias detection through Egger regression. Int. J. Epidemiol. 44, 512–525 (2015).

  30. 30.

    Terza, J. V., Basu, A. Rathouz, P. J. Two-stage residual inclusion estimation: addressing endogeneity in health econometric modeling. J. Health Econ. 27, 531–543 (2008).

  31. 31.

    Ramus, S. J. Gayther, S. A. The contribution of BRCA1 and BRCA2 to ovarian cancer. Mol. Oncol. 3, 138–150 (2009).

  32. 32.

    Jones, M. R., Kamara, D., Karlan, B. Y., Pharoah, P. D. P. Gayther, S. A. Genetic epidemiology of ovarian cancer and prospects for polygenic risk prediction. Gynecol. Oncol. 147, 705–713 (2017).

  33. 33.

    Reeves, G. K., Pirie, K., Beral, V., Green, J., Spencer, E., Bull, D. et al. Cancer incidence and mortality in relation to body mass index in the Million Women Study: cohort study. BMJ 335, 1134 (2007).

  34. 34.

    Gao, C., Patel, C. J., Michailidou, K., Peters, U., Gong, J., Schildkraut, J. et al. Mendelian randomization study of adiposity-related traits and risk of breast, ovarian, prostate, lung and colorectal cancer. Int. J. Epidemiol. 45, 896–908 (2016).

  35. 35.

    Liu, Z., Zhang, T. T., Zhao, J. J., Qi, S. F., Du, P., Liu, D. W. et al. The association between overweight, obesity and ovarian cancer: a meta-analysis. Jpn. J. Clin. Oncol. 45, 1107–1115 (2015).

  36. 36.

    Schouten, L. J., Rivera, C., Hunter, D. J., Spiegelman, D., Adami, H. O., Arslan, A. et al. Height, body mass index, and ovarian cancer: a pooled analysis of 12 cohort studies. Cancer Epidemiol. Biomark. Prev. 17, 902–912 (2008).

  37. 37.

    Lahmann, P. H., Cust, A. E., Friedenreich, C. M., Schulz, M., Lukanova, A., Kaaks, R. et al. Anthropometric measures and epithelial ovarian cancer risk in the European Prospective Investigation into Cancer and Nutrition. Int. J. Cancer 126, 2404–2415 (2010).

  38. 38.

    Cook, L. S., Meisner, A. L. W. & Weiss, N. S. in Cancer Epidemiolgy and Prevention, 4th edn. (eds Thun, M. J., Linet, M. S., Cerhan, J. R., Haiman, C. A., David Schottenfeld, D.) Ch. 47 (Oxford University Press, Oxford, 2018).

  39. 39.

    Dixon-Suen, S. C., Nagle, C. M., Thrift, A. P., Pharoah, P. D. P., Ewing, A., Pearce, C. L. et al. Adult height is associated with increased risk of ovarian cancer: a Mendelian randomisation study. Br. J. Cancer 118, 1123–1129 (2018).

  40. 40.

    Schildkraut, J. M., Schwingl, P. J., Bastos, E., Evanoff, A. Hughes, C. Epithelial ovarian cancer risk among women with polycystic ovary syndrome. Obstet. Gynecol. 88(4 Pt 1), 554–559 (1996).

  41. 41.

    Tworoger, S. S., Fairfield, K. M., Colditz, G. A., Rosner, B. A. Hankinson, S. E. Association of oral contraceptive use, other contraceptive methods, and infertility with ovarian cancer risk. Am. J. Epidemiol. 166, 894–901 (2007).

  42. 42.

    Yin, W., Falconer, H., Yin, L., Xu, L. & Ye, W. Association between polycystic ovary syndrome and cancer risk. JAMA Oncol. (2018).

  43. 43.

    Oktay, K., Kim, J. Y., Barad, D. Babayev, S. N. Association of BRCA1 mutations with occult primary ovarian insufficiency: a possible explanation for the link between infertility and breast/ovarian cancer risks. J. Clin. Oncol. 28, 240–244 (2010).

  44. 44.

    Iyengar, N. M., Gucalp, A., Dannenberg, A. J. Hudis, C. A. Obesity and cancer mechanisms: tumor microenvironment and inflammation. J. Clin. Oncol. 34, 4270–4276 (2016).

  45. 45.

    Eliassen, A. H. Hankinson, S. E. Endogenous hormone levels and risk of breast, endometrial and ovarian cancers: prospective studies. Adv. Exp. Med. Biol. 630, 148–165 (2008).

  46. 46.

    Risch, H. A. Hormonal etiology of epithelial ovarian cancer, with a hypothesis concerning the role of androgens and progesterone. J. Natl Cancer Inst. 90, 1774–1786 (1998).

  47. 47.

    Widschwendter, M., Rosenthal, A. N., Philpott, S., Rizzuto, I., Fraser, L., Hayward, J. et al. The sex hormone system in carriers of BRCA1/2 mutations: a case-control study. Lancet Oncol. 14, 1226–1232 (2013).

  48. 48.

    Jain, A., Polotsky, A. J., Rochester, D., Berga, S. L., Loucks, T., Zeitlian, G. et al. Pulsatile luteinizing hormone amplitude and progesterone metabolite excretion are reduced in obese women. J. Clin. Endocrinol. Metab. 92, 2468–2473 (2007).

  49. 49.

    Bu, S. Z., Yin, D. L., Ren, X. H., Jiang, L. Z., Wu, Z. J., Gao, Q. R. et al. Progesterone induces apoptosis and up-regulation of p53 expression in human ovarian carcinoma cell lines. Cancer 79, 1944–1950 (1997).

  50. 50.

    Schildkraut, J. M., Calingaert, B., Marchbanks, P. A., Moorman, P. G. Rodriguez, G. C. Impact of progestin and estrogen potency in oral contraceptives on ovarian cancer risk. J. Natl Cancer Inst. 94, 32–38 (2002).

  51. 51.

    Rodriguez, G. C., Nagarsheth, N. P., Lee, K. L., Bentley, R. C., Walmer, D. K., Cline, M. et al. Progestin-induced apoptosis in the Macaque ovarian epithelium: differential regulation of transforming growth factor-beta. J. Natl Cancer Inst. 94, 50–60 (2002).

  52. 52.

    Crowe, F. L., Key, T. J., Allen, N. E., Appleby, P. N., Overvad, K., Gronbaek, H. et al. A cross-sectional analysis of the associations between adult height, BMI and serum concentrations of IGF-I and IGFBP-1 -2 and -3 in the European Prospective Investigation into Cancer and Nutrition (EPIC). Ann. Hum. Biol. 38, 194–202 (2011).

  53. 53.

    Beauchamp, M. C., Yasmeen, A., Knafo, A. Gotlieb, W. H. Targeting insulin and insulin-like growth factor pathways in epithelial ovarian cancer. J. Oncol. 2010, 257058 (2010).

  54. 54.

    Pollak, M. The insulin and insulin-like growth factor receptor family in neoplasia: an update. Nat. Rev. Cancer 12, 159–169 (2012).

  55. 55.

    Lukanova, A., Lundin, E., Toniolo, P., Micheli, A., Akhmedkhanov, A., Rinaldi, S. et al. Circulating levels of insulin-like growth factor-I and risk of ovarian cancer. Int. J. Cancer 101, 549–554 (2002).

  56. 56.

    Werner, H. Bruchim, I. IGF-1 and BRCA1 signalling pathways in familial cancer. Lancet Oncol. 13, e537–e544 (2012).

  57. 57.

    Yengo, L., Sidorenko, J., Kemper, K. E., Zheng, Z., Wood, A. R., Weedon, M. N. et al. Meta-analysis of genome-wide association studies for height and body mass index in approximately 700000 individuals of European ancestry. Hum. Mol. Genet. 27, 3641–3649 (2018).

  58. 58.

    Visscher, P. M., Wray, N. R., Zhang, Q., Sklar, P., McCarthy, M. I., Brown, M. A. et al. 10 Years of GWAS discovery: biology, function, and translation. Am. J. Hum. Genet. 101, 5–22 (2017).

Download references


We thank all the families and clinicians who contributed to the studies; Sue Healey, in particular taking on the task of mutation classification with the late Olga Sinilnikova; Maggie Angelakos, Judi Maskiell, Gillian Dite, Helen Tsimiklis; members and participants in the New York site of the Breast Cancer Family Registry; members and participants in the Ontario Familial Breast Cancer Registry; Vilius Rudaitis and Laimonas Griškevičius; Drs Janis Eglitis, Anna Krilova and Aivars Stengrevics; Yuan Chun Ding and Linda Steele for their work in participant enrollment and biospecimen and data management; Bent Ejlertsen and Anne-Marie Gerdes for the recruitment and genetic counseling of participants; Alicia Barroso, Rosario Alonso and Guillermo Pita; Manoukian Siranoush, Bernard Peissel, Cristina Zanzottera, Milena Mariani, Daniela Zaffaroni, Bernardo Bonanni, Monica Barile, Irene Feroce, Mariarosaria Calvello, Alessandra Viel, Riccardo Dolcetti, Giuseppe Giannini, Laura Papi, Gabriele Lorenzo Capone, Liliana Varesco, Viviana Gismondi, Maria Grazia Tibiletti, Daniela Furlan, Antonella Savarese, Aline Martayan, Stefania Tommasi, Brunella Pilato; the personnel of the Cogentech Cancer Genetic Test Laboratory, Milan, Italy; Ms. JoEllen Weaver and Dr. Betsy Bove; Marta Santamariña, Ana Blanco, Miguel Aguado, Uxía Esperón and Belinda Rodríguez. We thank all participants, clinicians, family doctors, researchers, and technicians for their contributions and commitment to the DKFZ study. Genetic Modifiers of Cancer Risk in BRCA1/2 Mutation Carriers (GEMO) study is a study from the National Cancer Genetics Network UNICANCER Genetic Group, France. We wish to pay a tribute to Olga M. Sinilnikova, who with Dominique Stoppa-Lyonnet initiated and coordinated GEMO until she sadly passed away on the 30 June 2014. The team in Lyon (Olga Sinilnikova, Mélanie Léoné, Laure Barjhoux, Carole Verny-Pierre, Sylvie Mazoyer, Francesca Damiola, Valérie Sornin) managed the GEMO samples until the biological resource centre was transferred to Paris in December 2015 (Noura Mebirouk, Fabienne Lesueur, Dominique Stoppa-Lyonnet). We want to thank all the GEMO collaborating groups for their contribution to this study: Coordinating Centre, Service de Génétique, Institut Curie, Paris, France: Muriel Belotti, Ophélie Bertrand, Anne-Marie Birot, Bruno Buecher, Sandrine Caputo, Anaïs Dupré, Emmanuelle Fourme, Marion Gauthier-Villars, Lisa Golmard, Claude Houdayer, Marine Le Mentec, Virginie Moncoutier, Antoine de Pauw, Claire Saule, Dominique Stoppa-Lyonnet, and Inserm U900, Institut Curie, Paris, France: Fabienne Lesueur, Noura Mebirouk. Contributing Centres: Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents, Hospices Civils de Lyon - Centre Léon Bérard, Lyon, France: Nadia Boutry-Kryza, Alain Calender, Sophie Giraud, Mélanie Léone. Institut Gustave Roussy, Villejuif, France: Brigitte Bressac-de-Paillerets, Olivier Caron, Marine Guillaud-Bataille. Centre Jean Perrin, Clermont–Ferrand, France: Yves-Jean Bignon, Nancy Uhrhammer. Centre Léon Bérard, Lyon, France: Valérie Bonadona, Christine Lasset. Centre François Baclesse, Caen, France: Pascaline Berthet, Laurent Castera, Dominique Vaur. Institut Paoli Calmettes, Marseille, France: Violaine Bourdon, Catherine Noguès, Tetsuro Noguchi, Cornel Popovici, Audrey Remenieras, Hagay Sobol. CHU Arnaud-de-Villeneuve, Montpellier, France: Isabelle Coupier, Pascal Pujol. Centre Oscar Lambret, Lille, France: Claude Adenis, Aurélie Dumont, Françoise Révillion. Centre Paul Strauss, Strasbourg, France: Danièle Muller. Institut Bergonié, Bordeaux, France: Emmanuelle Barouk-Simonet, Françoise Bonnet, Virginie Bubien, Michel Longy, Nicolas Sevenet, Institut Claudius Regaud, Toulouse, France: Laurence Gladieff, Rosine Guimbaud, Viviane Feillel, Christine Toulas. CHU Grenoble, France: Hélène Dreyfus, Christine Dominique Leroux, Magalie Peysselon, Rebischung. CHU Dijon, France: Amandine Baurand, Geoffrey Bertolone, Fanny Coron, Laurence Faivre, Caroline Jacquot, Sarab Lizard. CHU St-Etienne, France: Caroline Kientz, Marine Lebrun, Fabienne Prieur. Hôtel Dieu Centre Hospitalier, Chambéry, France: Sandra Fert Ferrer. Centre Antoine Lacassagne, Nice, France: Véronique Mari. CHU Limoges, France: Laurence Vénat-Bouvet. CHU Nantes, France: Stéphane Bézieau, Capucine Delnatte. CHU Bretonneau, Tours and Centre Hospitalier de Bourges France: Isabelle Mortemousque. Groupe Hospitalier Pitié-Salpétrière, Paris, France: Chrystelle Colas, Florence Coulet, Florent Soubrier, Mathilde Warcoin. CHU Vandoeuvre-les-Nancy, France: Myriam Bronner, Johanna Sokolowska. CHU Besançon, France: Marie-Agnès Collonge-Rame, Alexandre Damette. CHU Poitiers, Centre Hospitalier d’Angoulême and Centre Hospitalier de Niort, France: Paul Gesta. Centre Hospitalier de La Rochelle: Hakima Lallaoui. CHU Nîmes Carémeau, France: Jean Chiesa. CHI Poissy, France: Denise Molina-Gomes. CHU Angers, France: Olivier Ingster; Ilse Coene en Brecht Crombez; Ilse Coene and Brecht Crombez; Alicia Tosar and Paula Diaque; Dr. Sofia Khan, Dr. Taru A. Muranen, Dr. Carl Blomqvist, Dr. Irja Erkkilä and Dr. Virpi Palola; The Hereditary Breast and Ovarian Cancer Research Group Netherlands (HEBON) consists of the following Collaborating Centres: Netherlands Cancer Institute (coordinating centre), Amsterdam, NL: M.A. Rookus, F.B.L. Hogervorst, F.E. van Leeuwen, M.A. Adank, M.K. Schmidt, N.S. Russell, D.J. Jenner; Erasmus Medical Center, Rotterdam, NL: J.M. Collée, A.M.W. van den Ouweland, M.J. Hooning, C.M. Seynaeve, C.H.M. van Deurzen, I.M. Obdeijn, I.A. Boere; Leiden University Medical Center, NL: C.J. van Asperen, P. Devilee, T.C.T.E.F. van Cronenburg; Radboud University Nijmegen Medical Center, NL: C.M. Kets, A.R. Mensenkamp; University Medical Center Utrecht, NL: M.G.E.M. Ausems, M.J. Koudijs; Amsterdam Medical Center, NL: C.M. Aalfs, H.E.J. Meijers-Heijboer; VU University Medical Center, Amsterdam, NL: K. van Engelen, J.J.P. Gille; Maastricht University Medical Center, NL: E.B. Gómez-Garcia, M.J. Blok, M. de Boer; University of Groningen, NL: J.C. Oosterwijk, A.H. van der Hout, M.J. Mourits, G.H. de Bock; The Netherlands Comprehensive Cancer Organisation (IKNL): S. Siesling, J.Verloop; The nationwide network and registry of histopathology and cytopathology in The Netherlands (PALGA): A.W. van den Belt-Dusebout. HEBON thanks the study participants and the registration teams of IKNL and PALGA for part of the data collection; Hong Kong Sanatorium and Hospital; the Hungarian Breast and Ovarian Cancer Study Group members (Janos Papp, Aniko Bozsik, Timea Pocza, Zoltan Matrai, Miklos Kasler, Judit Franko, Maria Balogh, Gabriella Domokos, Judit Ferenczi, Department of Molecular Genetics, National Institute of Oncology, Budapest, Hungary) and the clinicians and patients for their contributions to this study; the Oncogenetics Group (VHIO) and the High Risk and Cancer Prevention Unit of the University Hospital Vall d’Hebron, and the Cellex Foundation for providing research facilities and equipment; the ICO Hereditary Cancer Program team led by Dr. Gabriel Capella; the ICO Hereditary Cancer Program team led by Dr. Gabriel Capella; Dr Martine Dumont for sample management and skilful assistance; Ana Peixoto, Catarina Santos and Pedro Pinto; members of the Center of Molecular Diagnosis, Oncogenetics Department and Molecular Oncology Research Center of Barretos Cancer Hospital; Heather Thorne, Eveline Niedermayr, all the kConFab research nurses and staff, the heads and staff of the Family Cancer Clinics, and the Clinical Follow Up Study (which has received funding from the NHMRC, the National Breast Cancer Foundation, Cancer Australia, and the National Institute of Health (USA)) for their contributions to this resource, and the many families who contributed to kConFab; the KOBRA Study Group; Csilla Szabo (National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA); Marie Navratilova, Dita Hanouskova and Eva Machackova (Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute and MF MU, Brno, Czech Republic); and Michal Zikan, and Zdenek Kleibl (Oncogynecologic Center and Department of Biochemistry and Experimental Oncology, First Faculty of Medicine, Charles University, Prague, Czech Republic); Anne Lincoln, Lauren Jacobs; the NICCC National Familial Cancer Consultation Service team led by Sara Dishon, the laboratory team led by Dr. Flavio Lejbkowicz, and the research field operations team led by Dr. Mila Pinchev; the investigators of the Australia New Zealand NRG Oncology group; members and participants in the Ontario Cancer Genetics Network; Leigha Senter, Kevin Sweet, Caroline Craven, Julia Cooper, and Michelle O’Conor; Yip Cheng Har, Nur Aishah Mohd Taib, Phuah Sze Yee, Norhashimah Hassan and all the research nurses, research assistants and doctors involved in the MyBrCa Study for assistance in patient recruitment, data collection and sample preparation, Philip Iau, Sng Jen-Hwei and Sharifah Nor Akmal for contributing samples from the Singapore Breast Cancer Study and the HUKM-HKL Study, respectively; the Meirav Comprehensive breast cancer centre team at the Sheba Medical Center; Christina Selkirk; Åke Borg, Håkan Olsson, Helena Jernström, Karin Henriksson, Katja Harbst, Maria Soller, Ulf Kristoffersson; from Gothenburg Sahlgrenska University Hospital: Anna Öfverholm, Margareta Nordling, Per Karlsson, Zakaria Einbeigi; from Stockholm and Karolinska University Hospital: Anna von Wachenfeldt, Annelie Liljegren, Annika Lindblom, Brita Arver, Gisela Barbany Bustinza, Johanna Rantala; from Umeå University Hospital: Beatrice Melin, Christina Edwinsdotter Ardnor, Monica Emanuelsson; from Uppsala University: Hans Ehrencrona, Maritta Hellström Pigg, Richard Rosenquist; from Linköping University Hospital: Marie Stenmark-Askmalm, Sigrun Liedgren; Cecilia Zvocec, Qun Niu; Joyce Seldon and Lorna Kwan; Dr. Robert Nussbaum, Beth Crawford, Kate Loranger, Julie Mak, Nicola Stewart, Robin Lee, Amie Blanco and Peggy Conrad and Salina Chan; Simon Gayther, Susan Ramus, Paul Pharoah, Carole Pye, Patricia Harrington and Eva Wozniak; Geoffrey Lindeman, Marion Harris, Martin Delatycki, Sarah Sawyer, Rebecca Driessen, and Ella Thompson for performing all DNA amplification.

Author information

Correspondence to Dezheng Huo.

Ethics declarations

Competing interests

G.P. received honoraria and grant from Pfizer, Roche, Novartis, Accord, AstraZeneca, Amgen, Accord and Lilly. R.S. served on advisory board for Tesaro, Clovis, Astra Zeneca, Ethicon and Genmab, and speaker’s bureau for Tesaro and Genentech. The other authors declare no competing interests.

Ethics approval and consent to participate

The current work and all contributing studies in CIMBA received approval from the local institutional review board or ethics committee. Written informed consent was provided by all of the participants participating in each individual CIMBA study. The institutional committees that approved individual studies are listed in Supplemental Materials.


CIMBA: The CIMBA data management and data analysis were supported by Cancer Research – UK grants C12292/A20861, C12292/A11174. ACA is a Cancer Research UK Senior Cancer Research Fellow. G.C.T. and A.B.S. are NHMRC Research Fellows. iCOGS: the European Community’s Seventh Framework Programme under grant agreement No. 223175 (HEALTH-F2-2009-223175) (COGS), Cancer Research UK (C1287/A10118, C1287/A 10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692, C8197/A16565), the National Institutes of Health (CA128978) and Post-Cancer GWAS initiative (1U19 CA148537, 1U19 CA148065 and 1U19 CA148112 - the GAME-ON initiative), the Department of Defence (W81XWH-10-1-0341), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer (CRN-87521), and the Ministry of Economic Development, Innovation and Export Trade (PSR-SIIRI-701), Komen Foundation for the Cure, the Breast Cancer Research Foundation, and the Ovarian Cancer Research Fund. The PERSPECTIVE project was supported by the Government of Canada through Genome Canada and the Canadian Institutes of Health Research, the Ministry of Economy, Science and Innovation through Genome Québec, and The Quebec Breast Cancer Foundation. BCFR: UM1 CA164920 from the National Cancer Institute. The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centres in the Breast Cancer Family Registry (BCFR), nor does mention of trade names, commercial products, or organisations imply endorsement by the US Government or the BCFR. BFBOCC: Lithuania (BFBOCC-LT): Research Council of Lithuania grant SEN-18/2015. BIDMC: Breast Cancer Research Foundation. BMBSA: Cancer Association of South Africa (PI Elizabeth J. van Rensburg). CNIO: Spanish Ministry of Health PI16/00440 supported by FEDER funds, the Spanish Ministry of Economy and Competitiveness (MINECO) SAF2014-57680-R and the Spanish Research Network on Rare diseases (CIBERER). COH-CCGCRN: Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under grant number R25CA112486, and RC4CA153828 (PI: J. Weitzel) from the National Cancer Institute and the Office of the Director, National Institutes of Health. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. CONSIT: Associazione Italiana Ricerca sul Cancro (AIRC; IG2014 no.15547) to P. Radice. Italian Association for Cancer Research (AIRC; grant no.16933) to L. Ottini. Associazione Italiana Ricerca sul Cancro (AIRC; IG2015 no.16732) to P.P. J.A. is supported by funds from Italian citizens who allocated the 5 × 1000 share of their tax payment in support of the Fondazione IRCCS Istituto Nazionale Tumori, according to Italian laws (INT-Institutional strategic projects ‘5 × 1000’). DEMOKRITOS: European Union (European Social Fund – ESF) and Greek national funds through the Operational Program ‘Education and Lifelong Learning’ of the National Strategic Reference Framework (NSRF) - Research Funding Program of the General Secretariat for Research & Technology: SYN11_10_19 NBCA. Investing in knowledge society through the European Social Fund. DFKZ: German Cancer Research Center. EMBRACE: Cancer Research UK Grants C1287/A10118 and C1287/A11990. D.G.E. and F.L. are supported by an NIHR grant to the Biomedical Research Centre, Manchester. The Investigators at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust are supported by an NIHR grant to the Biomedical Research Centre at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust. R.E. and E.B. are supported by Cancer Research UK Grant C5047/A8385. R.E. is also supported by NIHR support to the Biomedical Research Centre at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust. FCCC: The University of Kansas Cancer Center (P30 CA168524) and the Kansas Bioscience Authority Eminent Scholar Program. A.K.G. was funded by R0 1CA140323, R01 CA214545, and by the Chancellors Distinguished Chair in Biomedical Sciences Professorship. FPGMX: FISPI05/2275 and Mutua Madrileña Foundation (FMMA). GC-HBOC: German Cancer Aid (grant no. 110837, R.K.S.). GEMO: Ligue Nationale Contre le Cancer; the Association ‘Le cancer du sein, parlons-en!’ Award, the Canadian Institutes of Health Research for the ‘CIHR Team in Familial Risks of Breast Cancer’ program and the French National Institute of Cancer (INCa grants 2013-1-BCB-01-ICH-1 and SHS-E-SP 18-015). GEORGETOWN: The Non-Therapeutic Subject Registry Shared Resource at Georgetown University (NIH/NCI grant P30-CA051008), the Fisher Center for Hereditary Cancer and Clinical Genomics Research, and Swing Fore the Cure. G-FAST: Bruce Poppe is a senior clinical investigator of FWO. Mattias Van Heetvelde obtained funding from IWT. HCSC: Spanish Ministry of Health PI15/00059, PI16/01292, and CB-161200301 CIBERONC from ISCIII (Spain), partially supported by European Regional Development FEDER funds. HEBCS: Helsinki University Hospital Research Fund, the Finnish Cancer Society and the Sigrid Juselius Foundation. HEBON: the Dutch Cancer Society grants NKI1998-1854, NKI2004-3088, NKI2007-3756, the Netherlands Organisation of Scientific Research grant NWO 91109024, the Pink Ribbon grants 110005 and 2014-187.WO76, the BBMRI grant NWO 184.021.007/CP46 and the Transcan grant JTC 2012 Cancer 12-054. HRBCP: Hong Kong Sanatorium and Hospital, Dr Ellen Li Charitable Foundation, The Kerry Group Kuok Foundation, National Institute of Health1R 03CA130065, and North California Cancer Center. HUNBOCS: Hungarian Research Grants KTIA-OTKA CK-80745 and OTKA K-112228. ICO: The authors would like to particularly acknowledge the support of the Asociación Española Contra el Cáncer (AECC), the Instituto de Salud Carlos III (organismo adscrito al Ministerio de Economía y Competitividad) and “Fondo Europeo de Desarrollo Regional (FEDER), una manera de hacer Europa” (PI10/01422, PI13/00285, PIE13/00022, PI15/00854, PI16/00563 and CIBERONC) and the Institut Català de la Salut and Autonomous Government of Catalonia (2009SGR290, 2014SGR338 and PERIS Project MedPerCan). IHCC: PBZ_KBN_122/P05/2004. ILUH: Icelandic Association ‘Walking for Breast Cancer Research’ and by the Landspitali University Hospital Research Fund. INHERIT: Canadian Institutes of Health Research for the “CIHR Team in Familial Risks of Breast Cancer” program – grant # CRN-87521 and the Ministry of Economic Development, Innovation and Export Trade – grant # PSR-SIIRI-701. IOVHBOCS: Ministero della Salute and ‘5 × 1000’ Istituto Oncologico Veneto grant. IPOBCS: Liga Portuguesa Contra o Cancro. kConFab: The National Breast Cancer Foundation, and previously by the National Health and Medical Research Council (NHMRC), the Queensland Cancer Fund, the Cancer Councils of New South Wales, Victoria, Tasmania and South Australia, and the Cancer Foundation of Western Australia. MAYO: NIH grants CA116167, CA192393 and CA176785, an NCI Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA116201), and a grant from the Breast Cancer Research Foundation. MCGILL: Jewish General Hospital Weekend to End Breast Cancer, Quebec Ministry of Economic Development, Innovation and Export Trade. M.T. is supported by the European Union Seventh Framework Program (2007Y2013)/European Research Council (Grant No. 310018). MODSQUAD: MH CZ - DRO (MMCI, 00209805), MEYS - NPS I - LO1413 to L.F. and by Charles University in Prague project UNCE204024 (to M.Z.). MSKCC: The Breast Cancer Research Foundation, the Robert and Kate Niehaus Clinical Cancer Genetics Initiative, the Andrew Sabin Research Fund and a Cancer Center Support Grant/Core Grant (P30 CA008748). NAROD: 1R01 CA149429-01. NCI: The Intramural Research Program of the US National Cancer Institute, NIH, and by support services contracts NO2-CP-11019-50, N02-CP-21013-63 and N02-CP-65504 with Westat, Inc, Rockville, MD. NICCC: Clalit Health Services in Israel, the Israel Cancer Association and the Breast Cancer Research Foundation (BCRF), NY. NNPIO: the Russian Foundation for Basic Research (grants 17-54-12007, 17-00-00171 and 18-515-12007). NRG Oncology: U10 CA180868, NRG SDMC grant U10 CA180822, NRG Administrative Office and the NRG Tissue Bank (CA 27469), the NRG Statistical and Data Center (CA 37517) and the Intramural Research Program, NCI. OSUCCG: Ohio State University Comprehensive Cancer Center. PBCS: Italian Association of Cancer Research (AIRC) [IG 2013 N.14477] and Tuscany Institute for Tumors (ITT) grant 2014-2015-2016. SEABASS: Ministry of Science, Technology and Innovation, Ministry of Higher Education (UM.C/HlR/MOHE/06) and Cancer Research Initiatives Foundation. SMC: the Israeli Cancer Association. SWE-BRCA: the Swedish Cancer Society. UCHICAGO: NCI Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA125183), R01 CA142996, 1U01CA161032, P20CA233307, R01 CA228198, American Cancer Society (MRSG-13-063-01-TBG, CRP-10-119-01-CCE), Breast Cancer Research Foundation, Susan G. Komen Foundation (SAC110026), and Ralph and Marion Falk Medical Research Trust, the Entertainment Industry Fund National Women’s Cancer Research Alliance. F.Q. was supported by the Alpha Omega Alpha Carolyn L. Cuckein Student Research Fellowship. UCLA: Jonsson Comprehensive Cancer Center Foundation; Breast Cancer Research Foundation. UCSF: UCSF Cancer Risk Program and Helen Diller Family Comprehensive Cancer Center. UKFOCR: Cancer Research UK. UPENN: Breast Cancer Research Foundation; Susan G. Komen Foundation for the cure, Basser Center for BRCA. UPITT/MWH: Hackers for Hope Pittsburgh. VFCTG: Victorian Cancer Agency, Cancer Australia, National Breast Cancer Foundation. WCP: B.Y.K. is funded by the American Cancer Society Early Detection Professorship (SIOP-06-258-01-COUN) and the National Center for Advancing Translational Sciences (NCATS), Grant UL1TR000124. D.G.E. is supported by the Manchester NIHR Biomedical Research Centre (IS-BRC-1215-20007). TOR: H.R. is funed by NCI, R01 CA063682.

Data availability

Owing to the sensitive nature of the data used in this study, data requests by researchers trained in maintaining human subject confidentiality may be directed to the corresponding author of this study.


This work is published under the standard license to publish agreement. After 12 months the work will become freely available and the license terms will switch to a Creative Commons Attribution 4.0 International (CC BY 4.0).

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Supplementary Materials

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark