Breast cancer risks associated with missense variants in breast cancer susceptibility genes

Dorling L, Carvalho S, Allen J, Parsons MT, Fortuno C, Gonzalez-Neira A, Heijl SM, Adank MA, Ahearn TU, Andrulis IL, Auvinen P, Becher H, Beckmann M, Behrens S, Bermisheva M, Bogdanova NV, Bojesen SE, Bolla MK, Bremer M, Briceno I, Camp NJ, Campbell A, Castelao JE, Chang-Claude J, Chanock SJ, Chenevix-Trench G, Collee JM, Czene K, Dennis J, Dork T, Eriksson M, Evans DG, Fasching P, Figueroa J, Flyger H, Gabrielson M, Gago-Dominguez M, Garcia-Closas M, Giles GG, Glendon G, Guenel P, Gundert M, Hadjisavvas A, Hahnen E, Hall P, Hamann U, Harkness EF, Hartman M, Hogervorst FBL, Hollestelle A, Hoppe R, Howell A, Jakubowska A, Jung A, Khusnutdinova E, Kim SW, Ko YD, Kristensen VN, Lakeman IMM, Li J, Lindblom A, Loizidou MA, Lophatananon A, Lubinski J, Luccarini C, Madsen MJ, Mannermaa A, Manoochehri M, Margolin S, Mavroudis D, Milne RL, Mohd Taib NA, Muir K, Nevanlinna H, Newman WG, Oosterwijk JC, Park SK, Peterlongo P, Radice P, Saloustros E, Sawyer EJ, Schmutzler RK, Shah M, Sim X, Southey MC, Surowy H, Suvanto M, Tomlinson I, Torres D, Truong T, Van Asperen CJ, Waltes R, Wang Q, Yang XR, Pharoah PDP, Schmidt MK, Benitez J, Vroling B, Dunning AM, Teo SH, Kvist A, De La Hoya M, Devilee P, Spurdle AB, Vreeswijk MPG, Easton DF (2022)

Publication Type: Journal article

Publication year: 2022

Journal

Book Volume: 14

Journal Issue: 1

DOI: 10.1186/s13073-022-01052-8

Abstract

Background Protein truncating variants in ATM, BRCA1, BRCA2, CHEK2, and PALB2 are associated with increased breast cancer risk, but risks associated with missense variants in these genes are uncertain. Methods We analyzed data on 59,639 breast cancer cases and 53,165 controls from studies participating in the Breast Cancer Association Consortium BRIDGES project. We sampled training (80%) and validation (20%) sets to analyze rare missense variants in ATM (1146 training variants), BRCA1 (644), BRCA2 (1425), CHEK2 (325), and PALB2 (472). We evaluated breast cancer risks according to five in silico prediction-of-deleteriousness algorithms, functional protein domain, and frequency, using logistic regression models and also mixture models in which a subset of variants was assumed to be risk-associated. Results The most predictive in silico algorithms were Helix (BRCA1, BRCA2 and CHEK2) and CADD (ATM). Increased risks appeared restricted to functional protein domains for ATM (FAT and PIK domains) and BRCA1 (RING and BRCT domains). For ATM, BRCA1, and BRCA2, data were compatible with small subsets (approximately 7%, 2%, and 0.6%, respectively) of rare missense variants giving similar risk to those of protein truncating variants in the same gene. For CHEK2, data were more consistent with a large fraction (approximately 60%) of rare missense variants giving a lower risk (OR 1.75, 95% CI (1.47-2.08)) than CHEK2 protein truncating variants. There was little evidence for an association with risk for missense variants in PALB2. The best fitting models were well calibrated in the validation set. Conclusions These results will inform risk prediction models and the selection of candidate variants for functional assays and could contribute to the clinical reporting of gene panel testing for breast cancer susceptibility.

Authors with CRIS profile

Involved external institutions

Helsingin yliopisto / University of Helsinki Finland (FI) University of Groningen / Rijksuniversiteit Groningen Netherlands (NL) Seoul National University (SNU) / 서울대학교 Korea, Republic of (KR) IFOM - FIRC Institute of Molecular Oncology Italy (IT) Fondazione IRCCS: Istituto Nazionale dei Tumori Italy (IT) General University Hospital of Larissa Greece (GR) King’s College London United Kingdom (GB) Universität zu Köln Germany (DE) University of Cambridge United Kingdom (GB) National University of Singapore (NUS) Singapore (SG) Cancer Council Victoria Australia (AU) Deutsches Krebsforschungszentrum (DKFZ) Germany (DE) University of Birmingham United Kingdom (GB) École Polytechnique - Université Paris-Saclay France (FR) Medizinische Hochschule Hannover (MHH) / Hannover Medical School Germany (DE) National Cancer Institute (NCI) United States (USA) (US) Antoni van Leeuwenhoek Netherlands (NL) Spanish National Cancer Research Centre / Centro Nacional de Investigaciones Oncológicas (CNIO) Spain (ES) Bio-Prodict BV Netherlands (NL) University of Malaya (UM) / Universiti Malaya Malaysia (MY) Lund University / Lunds universitet Sweden (SE) Leiden University Netherlands (NL) QIMR Berghofer Medical Research Institute (früher: the Queensland Institute of Medical Research) Australia (AU) Netherlands Cancer Institute (NKI) Netherlands (NL) Mount Sinai Hospital (MSH) Canada (CA) Universitätsklinikum Hamburg-Eppendorf (UKE) Germany (DE) Russian Academy of Sciences / Росси́йская акаде́мия нау́к (RAS) Russian Federation (RU) Universidad de La Sabana Colombia (CO) University of Edinburgh United Kingdom (GB) Erasmus University Rotterdam (EUR) / Erasmus Universiteit Rotterdam Netherlands (NL) University of Manchester United Kingdom (GB) Copenhagen University Hospital Denmark (DK) Karolinska Institute Sweden (SE) Complejo Hospitalario Universitario de Santiago de Compostela Spain (ES) Manchester University NHS Foundation Trust (MFT) United Kingdom (GB) Erasmus University Medical Center (MC) Netherlands (NL) Robert-Bosch-Krankenhaus Germany (DE) Johanniter-Krankenhaus Bonn Germany (DE) National University Health System (NUHS) Singapore (SG) Cyprus Institute of Neurology and Genetics Cyprus (CY) Pomeranian Medical University / Pomorski Uniwersytet Medyczny w Szczecinie (PMU) Poland (PL) University of Utah United States (USA) (US) University of Eastern Finland Finland (FI) Servizo Galego de Saúde Spain (ES) Daelim Saint Mary's Hospital Korea, Republic of (KR) University of Oslo Norway (NO) Hospital Clínico San Carlos Spain (ES) Södersjukhuset Sweden (SE) University General Hospital of Heraklion Greece (GR)

How to cite

APA:

Dorling, L., Carvalho, S., Allen, J., Parsons, M.T., Fortuno, C., Gonzalez-Neira, A.,... Easton, D.F. (2022). Breast cancer risks associated with missense variants in breast cancer susceptibility genes. Genome Medicine, 14(1). https://doi.org/10.1186/s13073-022-01052-8

MLA:

Dorling, Leila, et al. "Breast cancer risks associated with missense variants in breast cancer susceptibility genes." Genome Medicine 14.1 (2022).

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