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

2023; Elsevier BV; Volume: 110; Issue: 3 Linguagem: Inglês

10.1016/j.ajhg.2023.02.003

1537-6605

Anna Morra, Nasim Mavaddat, Taru 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‐Trench, 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‐Dominguez, Montserrat García‐Closas, Willemina R.R. Geurts-Giele, Graham G. Giles, Pascal Guénel, Melanie Gündert, Eric Hahnen, Per Hall, Ute Hamann, Patricia Harrington, Wei He, Päivi Heikkilä, Maartje J. Hooning, Reiner Hoppe, Sacha J. Howell, Keith Humphreys, Anna Jakubowska, Audrey Jung, Renske Keeman, Vessela N. Kristensen, Jan Lubiński, Graham J. Mann, Mehdi Manoochehri, Siranoush Manoukian, Sara Margolin, Dimitrios Mavroudis, Roger L. Milne, Anna Marie Mulligan, William G. Newman, Tjoung‐Won Park‐Simon, 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. Vreeswijk, Qin Wang, Camilla Wendt, Xiaohong R. Yang, Heli Nevanlinna, Peter Devilee, Douglas F. Easton, Marjanka K. Schmidt, Kristine Kleivi Sahlberg, Anne‐Lise Børresen‐Dale, Inger Torhild Gram, Karina Standahl Olsen, Olav Engebråten, Bjørn Naume, Jürgen Geisler, OSBREAC, Grethe I.G. Alnæs, David J. Amor, Lesley Andrews, Yoland Antill, Rosemary L. Balleine, Jonathan Beesley, Ian Bennett, Michael Bogwitz, Leon Botes, Meagan Brennan, Melissa A. Brown, Michael F. Buckley, Jo Burke, Phyllis Butow, Liz Caldon, Ian Campbell, Michelle Cao, Anannya Chakrabarti, Deepa Chauhan, Manisha Chauhan, Georgia Chenevix‐Trench, Alice Christian, Paul A. Cohen, Alison Colley, Ashley Crook, James Cui, Eliza Courtney, Margaret C. Cummings, Sarah‐Jane Dawson, Anna deFazio, Martin Delatycki, Rebecca Dickson, Joanne Dixon, Ted Edkins, Stacey L. Edwards, Gelareh Farshid, Andrew Fellows, Georgina Fenton, Michael Field, James M. Flanagan, Peter C.C. Fong, Laura Forrest, Stephen B. Fox, Juliet D. French, Michael Friedlander, Clara Gaff, Mike Gattas, Peter George, Sian Greening, Marion Harris, Stewart Hart, Nicholas K. Hayward, John L. Hopper, Cass Hoskins, Clare Hunt, Paul A. James, Mark A. Jenkins, Alexa Kidd, Judy Kirk, Jessica Koehler, James Kollias, Sunil R. Lakhani, Mitchell Lawrence, Jason Lee, Shuai Li, Geoffrey J. Lindeman, Lara Lipton, Liz Lobb, Sherene Loi, Graham J. Mann, Deborah J. Marsh, Sue Anne McLachlan, Bettina Meiser, Roger L. Milne, Sophie Nightingale, Shona O’Connell, Sarah O’Sullivan, David Gallego‐Ortega, Nick Pachter, Jia‐Min Pang, Gargi Pathak, Briony Patterson, Amy Pearn, Kelly‐Anne Phillips, Ellen Pieper, Susan J. Ramus, Edwina Rickard, Bridget A. Robinson, Mona Saleh, Anita Skandarajah, Elizabeth Salisbury, Christobel Saunders, Jodi M. Saunus, Rodney J. Scott, Clare L. Scott, Adrienne Sexton, Andrew N. Shelling, Peter T. Simpson, Melissa C. Southey, Amanda B. Spurdle, Jessica Taylor, Renea A. Taylor, Heather Thorne, Alison H. Trainer, Kathy Tucker, Jane E. Visvader, Logan C. Walker, Rachael Williams, Ingrid Winship, Mary Ann Young, Milita Zaheed,

Genomic variations and chromosomal abnormalities

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.