The impact of coding germline variants on contralateral breast cancer risk and survival

• DOI: 10.1016/j.ajhg.2023.02.003
• Publication Date: 2023-02-23T15:30:37Z
• Authors: Anna Morra; Nasim Mavaddat; Taru A. Muranen; Thomas U. Ahearn; Jamie Allen; Irene L. Andrulis; Päivi Auvinen; Heiko Becher; Sabine Behrens; Carl Blomqvist; Stig E. Bojesen; Manjeet K. Bolla; Hiltrud Brauch; Nicola J. Camp; Sara Carvalho; Jose E. Castelao; Melissa H. Cessna; Jenny Chang-Claude; Georgia Chenevix-...; Kamila Czene; Brennan Decker; Joe Dennis; Thilo Dörk; Leila Dorling; Alison M. Dunning; Arif B. Ekici; Mikael Eriksson; D. Gareth Evans; Peter A. Fasching; Jonine D. Figueroa; Henrik Flyger; Manuela Gago-Domi...; Montserrat García...; Willemina R.R. Ge...; Graham G. Giles; Pascal Guénel; Melanie Gündert; Eric Hahnen; Per Hall; Ute Hamann; Patricia A. Harri...; Wei He; Päivi Heikkilä; Maartje J. Hooning; Reiner Hoppe; Anthony Howell; Keith Humphreys; Anna Jakubowska; Audrey Y. Jung; Renske Keeman; Vessela N. Kriste...; Jan Lubiński; Arto Mannermaa; Mehdi Manoochehri; Siranoush Manoukian; Sara Margolin; Dimitrios Mavroudis; Roger L. Milne; Anna Marie Mulligan; William G. Newman; Tjoung-Won Park-S...; Paolo Peterlongo; Paul D.P. Pharoah; Valerie Rhenius; Emmanouil Saloustros; Elinor J. Sawyer; Rita K. Schmutzler; Mitul Shah; Amanda B. Spurdle; Ian Tomlinson; Thérèse Truong; Elke M. van Veen; Maaike P.G. Vrees...; Qin Wang; Camilla Wendt; Xiaohong R. Yang; Heli Nevanlinna; Peter Devilee; Douglas F. Easton; Marjanka K. Schmidt; Kristine K. Sahlberg; Anne-Lise Børrese...; Inger Torhild Gram; Karina Standahl O...; Olav Engebråten; Bjørn Naume; Jürgen Geisler; OSBREAC; Grethe I. Grenake...; David Amor; Lesley Andrews; Yoland Antill; Rosemary Balleine; Jonathan Beesley; Ian Bennett; Michael Bogwitz; Leon Botes; Meagan Brennan; Melissa Brown; Michael Buckley; Jo Burke; Phyllis Butow; Liz Caldon; Ian Campbell; Michelle Cao; Anannya Chakrabarti; Deepa Chauhan; Manisha Chauhan; Georgia Chenevix-...; Alice Christian; Paul Cohen; Alison Colley; Ashley Crook; James Cui; Eliza Courtney; Margaret Cummings; Sarah-Jane Dawson; Anna DeFazio; Martin Delatycki; Rebecca Dickson; Joanne Dixon; Ted Edkins; Stacey Edwards; Gelareh Farshid; Andrew Fellows; Georgina Fenton; Michael Field; James Flanagan; Peter Fong; Laura Forrest; Stephen Fox; Juliet French; Michael Friedlander; Clara Gaff; Mike Gattas; Peter George; Sian Greening; Marion Harris; Stewart Hart; Nick Hayward; John Hopper; Cass Hoskins; Clare Hunt; Paul James; Mark Jenkins; Alexa Kidd; Judy Kirk; Jessica Koehler; James Kollias; Sunil Lakhani; Mitchell Lawrence; Jason Lee; Shuai Li; Geoff Lindeman; Lara Lipton; Liz Lobb; Sherene Loi; Graham Mann; Deborah Marsh; Sue Anne McLachlan; Bettina Meiser; Roger Milne; Sophie Nightingale; Shona O'Connell; Sarah O'Sullivan; David Gallego Ortega; Nick Pachter; Jia-Min Pang; Gargi Pathak; Briony Patterson; Amy Pearn; Kelly Phillips; Ellen Pieper; Susan Ramus; Edwina Rickard; Bridget Robinson; Mona Saleh; Anita Skandarajah; Elizabeth Salisbury; Christobel Saunders; Jodi Saunus; Rodney Scott; Clare Scott; Adrienne Sexton; Andrew Shelling; Peter Simpson; Melissa Southey; Amanda Spurdle; Jessica Taylor; Renea Taylor; Heather Thorne; Alison Trainer; Kathy Tucker; Jane Visvader; Logan Walker; Rachael Williams; Ingrid Winship; Mary Ann Young; Milita Zaheed
• Keywords: Genes, BRCA2; 610; Breast Neoplasms; Outcomes; survival; Article; 03 medical and health sciences; Age; 0302 clinical medicine; SDG 3 - Good Health and Well-being; 616; Humans; Women; Genetic Predisposition to Disease; contralateral breast cancer risk; Germ-Line Mutation; Prophylactic mastectomy; Index event bias; BRCA2; ResearchInstitutes_Networks_Beacons/mcrc; name=Manchester Cancer Research Centre; 3. Good health; Germ Cells; Genes; Ovarian; breast cancer susceptibility genes; Genetics, developmental biology, physiology; Mutation; Female; coding germline variants

Evidence linking coding germline variants in breast cancer (BC)-susceptibility genes other than BRCA1, BRCA2, and CHEK2 with contralateral breast cancer (CBC) risk and breast cancer-specific survival (BCSS) is scarce. The aim of this study was to assess the association of protein-truncating variants (PTVs) and rare missense variants (MSVs) in nine known (ATM, BARD1, BRCA1, BRCA2, CHEK2, PALB2, RAD51C, RAD51D, and TP53) and 25 suspected BC-susceptibility genes with CBC risk and BCSS. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated with Cox regression models. Analyses included 34,401 women of European ancestry diagnosed with BC, including 676 CBCs and 3,449 BC deaths; the median follow-up was 10.9 years. Subtype analyses were based on estrogen receptor (ER) status of the first BC. Combined PTVs and pathogenic/likely pathogenic MSVs in BRCA1, BRCA2, and TP53 and PTVs in CHEK2 and PALB2 were associated with increased CBC risk [HRs (95% CIs): 2.88 (1.70-4.87), 2.31 (1.39-3.85), 8.29 (2.53-27.21), 2.25 (1.55-3.27), and 2.67 (1.33-5.35), respectively]. The strongest evidence of association with BCSS was for PTVs and pathogenic/likely pathogenic MSVs in BRCA2 (ER-positive BC) and TP53 and PTVs in CHEK2 [HRs (95% CIs): 1.53 (1.13-2.07), 2.08 (0.95-4.57), and 1.39 (1.13-1.72), respectively, after adjusting for tumor characteristics and treatment]. HRs were essentially unchanged when censoring for CBC, suggesting that these associations are not completely explained by increased CBC risk, tumor characteristics, or treatment. There was limited evidence of associations of PTVs and/or rare MSVs with CBC risk or BCSS for the 25 suspected BC genes. The CBC findings are relevant to treatment decisions, follow-up, and screening after BC diagnosis.