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

Morra A, Mavaddat N, Muranen TA, Ahearn TU, Allen J, Andrulis IL, Auvinen P, Becher H, Behrens S, Blomqvist C, Bojesen SE, Bolla MK, Brauch H, Camp NJ, Carvalho S, Castelao JE, Cessna MH, Chang-Claude J, Chenevix-Trench G, Sahlberg KK, Børresen-Dale AL, Gram IT, Olsen KS, Engebråten O, Naume B, Geisler J, OSBREAC , Grenaker Alnæs GI, Czene K, Decker B, Dennis J, Dörk T, Dorling L, Dunning AM, Ekici AB, Eriksson M, Evans DG, Fasching P, Figueroa JD, Flyger H, Gago-Dominguez M, García-Closas M, Geurts-Giele WR, Giles GG, Guénel P, Gündert M, Hahnen E, Hall P, Hamann U, Harrington PA, He W, Heikkilä P, Hooning MJ, Hoppe R, Howell A, Humphreys K, Amor D, Andrews L, Antill Y, Balleine R, Beesley J, Bennett I, Bogwitz M, Botes L, Brennan M, Brown M, Buckley M, Burke J, Butow P, Caldon L, Campbell I, Cao M, Chakrabarti A, Chauhan D, Chauhan M, Christian A, Cohen P, Colley A, Crook A, Cui J, Courtney E, Cummings M, Dawson SJ, DeFazio A, Delatycki M, Dickson R, Dixon J, Edkins T, Edwards S, Farshid G, Fellows A, Fenton G, Field M, Flanagan J, Fong P, Forrest L, Fox S, French J, Friedlander M, Gaff C, Gattas M, George P, Greening S, Harris M, Hart S, Hayward N, Hopper J, Hoskins C, Hunt C, James P, Jenkins M, Kidd A, Kirk J, Koehler J, Kollias J, Lakhani S, Lawrence M, Lee J, Li S, Lindeman G, Lipton L, Lobb L, Loi S, Mann G, Marsh D, McLachlan SA, Meiser B, Milne R, Nightingale S, O'Connell S, O'Sullivan S, Ortega DG, Pachter N, Pang JM, Pathak G, Patterson B, Pearn A, Phillips K, Pieper E, Ramus S, Rickard E, Robinson B, Saleh M, Skandarajah A, Salisbury E, Saunders C, Saunus J, Scott R, Scott C, Sexton A, Shelling A, Simpson P, Southey M, Spurdle A, Taylor J, Taylor R, Thorne H, Trainer A, Tucker K, Visvader J, Walker L, Williams R, Winship I, Young MA, Zaheed M, Jakubowska A, Jung AY, Keeman R, Kristensen VN, Lubiński J, Mannermaa A, Manoochehri M, Manoukian S, Margolin S, Mavroudis D, Milne RL, Mulligan AM, Newman WG, Park-Simon TW, Peterlongo P, Pharoah PD, Rhenius V, Saloustros E, Sawyer EJ, Schmutzler RK, Shah M, Spurdle AB, Tomlinson I, Truong T, van Veen EM, Vreeswijk MP, Wang Q, Wendt C, Yang XR, Nevanlinna H, Devilee P, Easton DF, Schmidt MK (2023)

Publication Type: Journal article

Publication year: 2023

Journal

Book Volume: 110

Pages Range: 475-486

Journal Issue: 3

DOI: 10.1016/j.ajhg.2023.02.003

Abstract

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.

Authors with CRIS profile

Involved external institutions

Fondazione IRCCS: Istituto Nazionale dei Tumori Italy (IT) University of Manchester United Kingdom (GB) Intermountain Healthcare United States (USA) (US) University of Cambridge United Kingdom (GB) University of Birmingham United Kingdom (GB) Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital (NKI / NKI-AVL) Netherlands (NL) Mount Sinai Hospital (MSH) Canada (CA) Deutsches Krebsforschungszentrum (DKFZ) Germany (DE) King’s College London United Kingdom (GB) Medizinische Hochschule Hannover (MHH) / Hannover Medical School Germany (DE) Research Center in Epidemiology and Population Health / Centre de recherche en Epidémiologie et Santé des Populations (CESP) France (FR) General University Hospital of Larissa Greece (GR) University of Toronto Canada (CA) Complejo Hospitalario Universitario de Santiago de Compostela Spain (ES) Universitätsklinikum Köln Germany (DE) Copenhagen University Hospital Denmark (DK) Karolinska Institute Sweden (SE) Erasmus University Medical Center (MC) Netherlands (NL) Helsingin yliopisto / University of Helsinki Finland (FI) University General Hospital of Heraklion Greece (GR) University of Eastern Finland Finland (FI) Dr. Margarete Fischer-Bosch-Institut für Klinische Pharmakologie Germany (DE) Pomeranian Medical University / Pomorski Uniwersytet Medyczny w Szczecinie (PMU) Poland (PL) Cancer Council Victoria Australia (AU) National Cancer Institute (NCI) United States (USA) (US) University of Oslo Norway (NO) Leiden University Medical Center Netherlands (NL) Universitätsklinikum Hamburg-Eppendorf (UKE) Germany (DE) IFOM - FIRC Institute of Molecular Oncology Italy (IT) QIMR Berghofer Medical Research Institute (früher: the Queensland Institute of Medical Research) Australia (AU) Södersjukhuset Sweden (SE) Huntsman Cancer Institute United States (USA) (US) Instituto de Investigación Sanitaria Galicia Sur Spain (ES)

How to cite

APA:

Morra, A., Mavaddat, N., Muranen, T.A., Ahearn, T.U., Allen, J., Andrulis, I.L.,... Schmidt, M.K. (2023). The impact of coding germline variants on contralateral breast cancer risk and survival. American Journal of Human Genetics, 110(3), 475-486. https://doi.org/10.1016/j.ajhg.2023.02.003

MLA:

Morra, Anna, et al. "The impact of coding germline variants on contralateral breast cancer risk and survival." American Journal of Human Genetics 110.3 (2023): 475-486.

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