Heritable DNA methylation marks associated with susceptibility to breast cancer

• DOI: 10.1038/s41467-018-03058-6
• Publication Date: 2018-02-22T11:11:08Z
• Authors: Jihoon E. Joo; James G. Dowty; Roger L. Milne; Ee Ming Wong; Pierre-Antoine Dugué; Dallas English; John L. Hopper; David E. Goldgar; Graham G. Giles; Melissa C. Southey; ; Adrienne Sexton; Alice Christian; Alison Trainer; Allan Spigelman; Andrew Fellows; Andrew Shelling; Anna De Fazio; Anneke Blackburn; Ashley Crook; Bettina Meiser; Briony Patterson; Christine Clarke; Christobel Saunders; Clare Hunt; Clare Scott; David Amor; Deborah Marsh; Edward Edkins; Elizabeth Salisbury; Eric Haan; Eveline Neidermayr; Finlay Macrae; Gelareh Farshid; Geoff Lindeman; Georgia Chenevix-...; Graham Mann; Grantley Gill; Heather Thorne; Ian Campbell; Ian Hickie; Ingrid Winship; Jack Goldblatt; James Flanagan; James Kollias; Jane Visvader; Jennifer Stone; Jessica Taylor; Jo Burke; Jodi Saunus; John Forbes; Jonathan Beesley; Judy Kirk; Juliet French; Kathy Tucker; Kathy Wu; Kelly Phillips; Lara Lipton; Leslie Andrews; Elizabeth Lobb; Logan Walker; Maira Kentwell; Amanda Spurdle; Margaret Cummings; Margaret Gleeson; Marion Harris; Mark Jenkins; Mary Anne Young; Martin Delatycki; Mathew Wallis; Matthew Burgess; Melanie Price; Melissa Brown; Michael Bogwitz; Michael Field; Michael Friedlander; Michael Gattas; Mona Saleh; Nick Hayward; Nick Pachter; Paul Cohen; Pascal Duijf; Paul James; Peter Simpson; Peter Fong; Phyllis Butow; Rachael Williams; Richard Kefford; Rodney Scott; Rosemary Balleine; Sarah-Jane Dawson; Sheau Lok; Shona O’Connell; Sian Greening; Sophie Nightingale; Stacey Edwards; Stephen Fox; Sue-Anne McLachlan; Sunil Lakhani; Susan Thomas; Yoland Antill
• Keywords: 0301 basic medicine; 1300 Biochemistry; Science; General Physics and Astronomy; 610; Genetics and Molecular Biology; Breast Neoplasms; sporadic breast; Article; Epigenesis, Genetic; Cohort Studies; 03 medical and health sciences; breast cancer; 616; Humans; 3100 Physics and Astronomy; Genetic Predisposition to Disease; DNA methylation; Q; Australia; General Chemistry; DNA Methylation; 1600 Chemistry; 3. Good health; Multidisciplinary Sciences; Case-Control Studies; General Biochemistry; germline mutations; CpG Islands; Female

AbstractMendelian-like inheritance of germline DNA methylation in cancer susceptibility genes has been previously reported. We aimed to scan the genome for heritable methylation marks associated with breast cancer susceptibility by studying 25 Australian multiple-case breast cancer families. Here we report genome-wide DNA methylation measured in 210 peripheral blood DNA samples provided by family members using the Infinium HumanMethylation450. We develop and apply a new statistical method to identify heritable methylation marks based on complex segregation analysis. We estimate carrier probabilities for the 1000 most heritable methylation marks based on family structure, and we use Cox proportional hazards survival analysis to identify 24 methylation marks with corresponding carrier probabilities significantly associated with breast cancer. We replicate an association with breast cancer risk for four of the 24 marks using an independent nested case–control study. Here, we report a novel approach for identifying heritable DNA methylation marks associated with breast cancer risk.