TY - JOUR

T1 - The impact of coding germline variants on contralateral breast cancer risk and survival

AU - Morra, Anna

AU - Mavaddat, Nasim

AU - Muranen, Taru A.

AU - Ahearn, Thomas U.

AU - Allen, Jamie

AU - Andrulis, Irene L.

AU - Auvinen, Päivi

AU - Becher, Heiko

AU - Behrens, Sabine

AU - Blomqvist, Carl

AU - Bojesen, Stig E.

AU - Bolla, Manjeet K.

AU - Brauch, Hiltrud

AU - Camp, Nicola J.

AU - Carvalho, Sara

AU - Castelao, Jose E.

AU - Cessna, Melissa H.

AU - Chang-Claude, Jenny

AU - Chenevix-Trench, Georgia

AU - Sahlberg, Kristine K.

AU - Børresen-Dale, Anne Lise

AU - Gram, Inger Torhild

AU - Olsen, Karina Standahl

AU - Engebråten, Olav

AU - Naume, Bjørn

AU - Geisler, Jürgen

AU - OSBREAC, null

AU - Grenaker Alnæs, Grethe I.

AU - Czene, Kamila

AU - Decker, Brennan

AU - Dennis, Joe

AU - Dörk, Thilo

AU - Dorling, Leila

AU - Dunning, Alison M.

AU - Ekici, Arif B.

AU - Eriksson, Mikael

AU - Evans, D. Gareth

AU - Fasching, Peter A.

AU - Figueroa, Jonine D.

AU - Flyger, Henrik

AU - Gago-Dominguez, Manuela

AU - García-Closas, Montserrat

AU - Geurts-Giele, Willemina R.R.

AU - Giles, Graham G.

AU - Guénel, Pascal

AU - Gündert, Melanie

AU - Hahnen, Eric

AU - Hall, Per

AU - NBCS Collaborators

AU - kConFab Investigators

N1 - Publisher Copyright: © 2023 The Authors

PY - 2023

Y1 - 2023

N2 - 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.

AB - 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.

KW - breast cancer susceptibility genes

KW - coding germline variants

KW - contralateral breast cancer risk

KW - survival

U2 - 10.1016/j.ajhg.2023.02.003

DO - 10.1016/j.ajhg.2023.02.003

M3 - Journal article

C2 - 36827971

AN - SCOPUS:85149226266

VL - 110

SP - 475

EP - 486

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

SN - 0002-9297

IS - 3

ER -