Analysis of rare disruptive germline mutations in 2135 enriched BRCA-negative breast cancers excludes additional high-impact susceptibility genes
Chey Loveday, Alice Garrett, Philip Law, Sandra Hanks, Emma Poyastro-Pearson, Julian Adlard, Julian Barwell, J. Berg, Angela F. Brady, C Brewer, C J Chapman, Jackie Cook, R. Davidson, Alan Donaldson, Fiona Douglas, Lynn Greenhalgh, Alex Henderson, Louise Izatt, Ajith Kumar, Fiona Lalloo, Zosia Miedzybrodzka, P. Morrison, J. Paterson, Mary Porteous, Mark T. Rogers, Lyndon Walker, A. Ardern-Jones, Julian Adlard, Madiha Ahmed, Gerhardt Attard, Kent R. Bailey, Elizabeth Bancroft, Cathryn Bardsley, Desmond P.J. Barton, Madelaine Bartlett, Julian Barwell, Laura Baxter, Rachel Belk, J. Berg, Birgitta Bernhard, D. Timothy Bishop, Laura Boyes, N. Bradshaw, A.F. Brady, Steven R. Brant, C. Brewer, Glen Brice, G. Bromilow, Corinne Brooks, Amanda S. Bruce, Barbara Bulman, Lucy Burgess, Joyce Campbell, Natalie Canham, B. Castle, Roseanne Cetnarskyj, C J Chapman, Oonagh Claber, Nathan Coates, T Cole, Andrew Collins, Jackie Cook, Susan Coulson, Gillian Crawford, D. G. Crüger, Chad Cummings, Lucia D’Mello, R. Davidson, Lauren Day, Brad Dell, CHS Dolling, Alan Donaldson, Huw Dorkins, F. Douglas, Sean R. Downing, Sean C. Drummond, C. Dubras, J Dunlop, S. Durrell, Diana Eccles, Clare M. Eddy, Melissa Edwards, Emma Edwards, J.A. Edwardson, Rosalind A. Eeles, Ian O. Ellis, Frances Elmslie, D. Gareth Evans, Barbara Gibbons, C. Gardiner, Neeti Ghali, Clare Giblin, S. L. Gibson, Sheila Goff, Selina Goodman, David Goudie, Lynn Greenhalgh, J. A. Grier, Helen Gregory, Sophia R. Halliday
Abstract
BACKGROUND: Breast cancer has a significant heritable basis, of which ∼60% remains unexplained. Testing for BRCA1/BRCA2 offers useful discrimination of breast cancer risk within families, and identification of additional breast cancer susceptibility genes could offer clinical utility. PATIENTS AND METHODS: We included 2135 invasive breast cancer cases recruited via the Breast and Ovarian Cancer Susceptibility study, a retrospective UK study of familial breast cancer. ELIGIBILITY CRITERIA: female, BRCA-negative, white European ethnicity, and one of: (i) breast cancer family history, (ii) bilateral disease, (iii) young age of onset (<30 years), and (iv) concomitant ovarian cancer. We undertook exome sequencing of cases and carried out gene-level burden testing of rare damaging variants against those from 51 377 ethnicity-matched population controls from gnomAD. RESULTS: (1 in 1779, less than half that of PALB2). Power was lower for identification of novel moderate penetrance genes (OR = 2-3) like CHEK2 and ATM. CONCLUSIONS: This is the largest case-control whole-exome analysis of enriched breast cancer published to date. Whilst additional breast cancer susceptibility genes likely exist, those of high penetrance are likely to be of very low mutational frequency. Contention exists regarding the clinical utility of such genes.