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Analysis of rare disruptive germline mutations in 2135 enriched BRCA-negative breast cancers excludes additional high-impact susceptibility genes

2022; Elsevier BV; Volume: 33; Issue: 12 Linguagem: Inglês

10.1016/j.annonc.2022.09.152

1569-8041

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. J. Morrison, J. Paterson, Mary Porteous, Mark T. Rogers, Lyndon Walker, Diana Eccles, D. Gareth Evans, Katie Snape, Helen Hanson, Richard S. Houlston, Clare Turnbull, 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, Angela 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, Fiona Douglas, Sean R. Downing, S. Drummond, C. Dubras, Jackie 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, Rebecca Hardy, Celia Hartigan, Tricia Heaton, Alex Henderson, Christopher F. Higgins, Shirley Hodgson, Tessa Homfray, D. Horrigan, Catherine Houghton, Richard S. Houlston, Louise Hughes, Victoria Hunt, Lisa Irvine, Louise Izatt, Chris Jacobs, Steven James, Mattie R. James, Lisa Jeffers, Irene Jobson, Wanda K. Jones, Esther M. John, Susan Kenwrick, Catherine Kightley, C W Kirk, Edwin P. Kirk, Emma Kivuva, Kelly Kohut, Monika Kosicka‐Slawinska, A. Kulkarni, Ajith Kumar, Fiona Lalloo, N. Lambord, Craig B. Langman, Paul Leonard, S Levene, Sigurd Locker, Philip C. Logan, Mark Longmuir, Anneke Lucassen, V. Lyus, Alex Magee, Alison Male, Sahar Mansour, Deborah McBride, Emily P. McCann, Vivienne McConnell, Meriel McEntagart, C. McKeown, L. McLeish, Deborah McLeod, Andrew Melville, L J Mercer, Catherine Mercer, Zosia Miedzybrodzka, Anita Mitra, P. J. Morrison, V Murday, Anne R. Murray, Kathryn Myhill, Jessica Myring, Emily A. O’Hara, J. Paterson, Pauline Pearson, Gabriella Pichert, Kaye Platt, Mary Porteous, Carrie Pottinger, Sue Price, L. Protheroe, S. Pugh, Oliver Quarrell, Karen Randhawa, Caitlin Riddick, Lisa Robertson, A. Robinson, V. Roffey-Johnson, Mark Rogers, Stephen Rose, Sarah J. Rowe, Andrew Craig Schofield, Nazneen Rahman, Sibel Saya, Gillian Scott, Julia S. Scott, Angela Searle, Susan Shanley, S. Sharif, A. Shaw, Jacqui Shaw, J Shea-Simonds, Lucy Side, Julie Sillibourne, Kelly Claire Simon, Sarah Simpson, Susanna Slater, Susan V. Smalley, Katherine R. Smith, Lesley Snadden, Katie Snape, Judith Soloway, Y. Stait, Barbara Stayner, Mike Steel, Christopher Steel, Helen Stewart, D. Stirling, Mathew Thomas, Susan N. Thomas, Susannah Tomkins, Helen Turner, Anthony Vandersteen, Emma Wakeling, F. Waldrup, Lyndon Walker, Catherine Watt, Sarah Watts, Andrea L. Webber, Catriona Whyte, Jennifer Wiggins, Ebony Williams, Laura Winchester,

Genetic Associations and Epidemiology

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.We included 2135 invasive breast cancer cases recruited via the Breast and Ovarian Cancer Susceptibility study, a retrospective UK study of familial breast cancer.female, BRCA-negative, white European ethnicity, and one of: (i) breast cancer family history, (ii) bilateral disease, (iii) young age of onset ( 80%) to detect a gene of BRCA1-like risk [odds ratio (OR) = 10.6] down to a population minor allele frequency of 4.6 × 10-5 (1 in 10 799, less than one-tenth that of BRCA1)and of PALB2-like risk (OR = 5.0) down to a population minor allele frequency of 2.8 × 10-4 (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.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.