FANCM missense variants and breast cancer risk: a case-control association study of 75,156 European women

Figlioli G, Billaud A, Ahearn TU, Antonenkova NN, Becher H, Beckmann M, Behrens S, Benitez J, Bermisheva M, Blok MJ, Bogdanova N, Bonanni B, Burwinkel B, Camp NJ, Campbell A, Castelao JE, Cessna MH, Chanock SJ, Czene K, Devilee P, Doerk T, Engel C, Eriksson M, Fasching P, Figueroa JD, Gabrielson M, Gago-Dominguez M, Garcia-Closas M, Gonzalez-Neira A, Grassmann F, Guenel P, Gundert M, Hadjisavvas A, Hahnen E, Hall P, Hamann U, Harrington PA, He W, Hillemanns P, Hollestelle A, Hooning MJ, Hoppe R, Howell A, Humphreys K, Jager A, Jakubowska A, Khusnutdinova EK, Ko YD, Kristensen VN, Lindblom A, Lissowska J, Lubinski J, Mannermaa A, Manoukian S, Margolin S, Mavroudis D, Newman WG, Obi N, Panayiotidis M, Rashid MU, Rhenius V, Rookus MA, Saloustros E, Sawyer EJ, Schmutzler RK, Shah M, Sironen R, Southey MC, Suvanto M, Tollenaar RAEM, Tomlinson I, Truong T, Van Der Kolk LE, Van Veen EM, Wappenschmidt B, Yang XR, Bolla MK, Dennis J, Dunning AM, Easton DF, Lush M, Michailidou K, Pharoah PDP, Wang Q, Adank MA, Schmidt MK, Andrulis IL, Chang-Claude J, Nevanlinna H, Chenevix-Trench G, Evans DG, Milne RL, Radice P, Peterlongo P (2023)

Publication Type: Journal article

Publication year: 2023

Journal

DOI: 10.1038/s41431-022-01257-w

Abstract

Evidence from literature, including the BRIDGES study, indicates that germline protein truncating variants (PTVs) in FANCM confer moderately increased risk of ER-negative and triple-negative breast cancer (TNBC), especially for women with a family history of the disease. Association between FANCM missense variants (MVs) and breast cancer risk has been postulated. In this study, we further used the BRIDGES study to test 689 FANCM MVs for association with breast cancer risk, overall and in ER-negative and TNBC subtypes, in 39,885 cases (7566 selected for family history) and 35,271 controls of European ancestry. Sixteen common MVs were tested individually; the remaining rare 673 MVs were tested by burden analyses considering their position and pathogenicity score. We also conducted a meta-analysis of our results and those from published studies. We did not find evidence for association for any of the 16 variants individually tested. The rare MVs were significantly associated with increased risk of ER-negative breast cancer by burden analysis comparing familial cases to controls (OR = 1.48; 95% CI 1.07-2.04; P = 0.017). Higher ORs were found for the subgroup of MVs located in functional domains or predicted to be pathogenic. The meta-analysis indicated that FANCM MVs overall are associated with breast cancer risk (OR = 1.22; 95% CI 1.08-1.38; P = 0.002). Our results support the definition from previous analyses of FANCM as a moderate-risk breast cancer gene and provide evidence that FANCM MVs could be low/moderate risk factors for ER-negative and TNBC subtypes. Further genetic and functional analyses are necessary to clarify better the increased risks due to FANCM MVs.

Authors with CRIS profile

Involved external institutions

European Institute of Oncology / Istituto Europeo di Oncologia (IEO) Italy (IT) University of Edinburgh United Kingdom (GB) Karolinska Institute Sweden (SE) Universität Leipzig Germany (DE) Spanish National Cancer Research Centre / Centro Nacional de Investigaciones Oncológicas (CNIO) Spain (ES) École Polytechnique - Université Paris-Saclay France (FR) Deutsches Krebsforschungszentrum (DKFZ) Germany (DE) Medizinische Hochschule Hannover (MHH) / Hannover Medical School Germany (DE) Erasmus University Medical Center (MC) Netherlands (NL) Oslo University Hospital / Oslo Universitetssykehus Rikshospitalet Norway (NO) Antoni van Leeuwenhoek Netherlands (NL) 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) University of Eastern Finland Finland (FI) IFOM - FIRC Institute of Molecular Oncology Italy (IT) National Cancer Institute (NCI) United States (USA) (US) N.N. Alexandrov National Cancer Centre of Belarus for Oncology and Medical Radiology Belarus (BY) Universitätsklinikum Hamburg-Eppendorf (UKE) Germany (DE) Russian Academy of Sciences / Росси́йская акаде́мия нау́к (RAS) Russian Federation (RU) University of Utah United States (USA) (US) Servizo Galego de Saúde Spain (ES) Maastricht University Netherlands (NL) Intermountain Healthcare United States (USA) (US) Leiden University Netherlands (NL) Complejo Hospitalario Universitario de Santiago de Compostela Spain (ES) Cyprus Institute of Neurology and Genetics Cyprus (CY) Robert-Bosch-Krankenhaus Germany (DE) University of Manchester United Kingdom (GB) Pomeranian Medical University / Pomorski Uniwersytet Medyczny w Szczecinie (PMU) Poland (PL) Johanniter GmbH Germany (DE) Maria Skłodowska-Curie Institute of Oncology / Centrum Onkologii–Instytut im. Marii Skłodowskiej-Curie w Warszawie Poland (PL) Fondazione IRCCS: Istituto Nazionale dei Tumori Italy (IT) Södersjukhuset Sweden (SE) University General Hospital of Heraklion Greece (GR) Helsingin yliopisto / University of Helsinki Finland (FI) Mount Sinai Hospital (MSH) Canada (CA) QIMR Berghofer Medical Research Institute (früher: the Queensland Institute of Medical Research) Australia (AU) Monash University Australia (AU)

How to cite

APA:

Figlioli, G., Billaud, A., Ahearn, T.U., Antonenkova, N.N., Becher, H., Beckmann, M.,... Peterlongo, P. (2023). FANCM missense variants and breast cancer risk: a case-control association study of 75,156 European women. European Journal of Human Genetics. https://doi.org/10.1038/s41431-022-01257-w

MLA:

Figlioli, Gisella, et al. "FANCM missense variants and breast cancer risk: a case-control association study of 75,156 European women." European Journal of Human Genetics (2023).

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