Population-based germline breast cancer gene association studies and meta-analysis to inform wider mainstream testing

C F Rowlands; S Allen; J Balmaña; S M Domchek; D G Evans; H Hanson; N Hoogerbrugge; P A James; K L Nathanson; M Robson; M Tischkowitz; W D Foulkes; C Turnbull

doi:10.1016/j.annonc.2024.07.244

Population-based germline breast cancer gene association studies and meta-analysis to inform wider mainstream testing

Ann Oncol. 2024 Oct;35(10):892-901. doi: 10.1016/j.annonc.2024.07.244. Epub 2024 Jul 8.

Authors

C F Rowlands¹, S Allen¹, J Balmaña², S M Domchek³, D G Evans⁴, H Hanson⁵, N Hoogerbrugge⁶, P A James⁷, K L Nathanson⁸, M Robson⁹, M Tischkowitz¹⁰, W D Foulkes¹¹, C Turnbull¹²

Affiliations

¹ Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.
² Hereditary Cancer Genetics Group, Vall d'Hebron Institute of Oncology (VHIO), Barcelona; Medical Oncology Department, Hospital Universitari Vall d'Hebron, Vall d'Hebron Hospital Campus, Barcelona, Spain.
³ Basser Center for BRCA, Abramson Cancer Center, University of Pennsylvania, Philadelphia, USA.
⁴ Manchester Academic Health Science Centre, Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester.
⁵ Department of Clinical and Biomedical Sciences, University of Exeter Medical School, Exeter; Peninsula Regional Genetics Service, Royal Devon University Healthcare NHS Foundation Trust, Exeter, UK.
⁶ Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
⁷ Parkville Familial Cancer Centre, The Royal Melbourne Hospital and Peter MacCallum Cancer Centre, Melbourne, Australia.
⁸ Division of Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia; Abramson Cancer Center, Perelman School of Medicine, Philadelphia.
⁹ Department of Medicine, Memorial Sloan Kettering Cancer Center, New York; Weill Cornell Medical College, New York, USA.
¹⁰ Department of Medical Genetics, National Institute for Health Research Cambridge Biomedical Research Centre, University of Cambridge, Cambridge, UK.
¹¹ Department of Human Genetics, McGill University, Montréal, Canada; Department of Oncology, McGill University, Montréal, Canada; Department of Medicine, McGill University, Montréal, Canada.
¹² Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK. Electronic address: Turnbull.lab@icr.ac.uk.

PMID: 38986768
DOI: 10.1016/j.annonc.2024.07.244

Abstract

Background: Germline genetic testing, previously restricted to familial and young-onset breast cancer, is now offered increasingly broadly to patients with 'population-type' breast cancer in mainstream oncology clinics, with wide variation in the genes included.

Patients and methods: Weighted meta-analysis was carried out for three population-based case-control studies (BRIDGES, CARRIERS and UK Biobank) comprising in total 101 397 women with breast cancer and 312 944 women without breast cancer, to quantify 37 putative breast cancer susceptibility genes (BCSGs) for the frequency of pathogenic variants (PVs) in unselected, 'population-type' breast cancer cases and their association with breast cancer and its subtypes.

Results: Meta-analysed odds ratios (ORs) and frequencies of PVs in 'population-type' breast cancer cases were generated for BRCA1 (OR 8.73, 95% confidence interval (CI) 7.47-10.20; 1 in 101), BRCA2 (OR 5.68, 95% CI 5.13-6.30; 1 in 68) and PALB2 (OR 4.30, 95% CI 3.68-5.03; 1 in 187). For both CHEK2 (OR 2.40, 95% CI 2.21-2.62; 1 in 73) and ATM (OR 2.16, 95% CI 1.93-2.41; 1 in 132) subgroup analysis showed a stronger association with oestrogen receptor-positive disease. The magnitude of association and frequency of PVs were low for RAD51C (OR 1.53, 95% CI 1.29-2.04; 1 in 913), RAD51D (OR 1.76, 95% CI 1.29-2.41; 1 in 1079) and BARD1 (OR 2.34, 95% CI 1.85-2.97; 1 in 672); frequencies and associations were higher when the analysis was restricted to triple-negative breast cancers. The PV frequency in 'population-type' breast cancer cases was very low for 'syndromic' BCSGs TP53 (1 in 1844), STK11 (1 in 11 525), CDH1 (1 in 2668), PTEN (1 in 3755) and NF1 (1 in 1470), with metrics of association also modest ranging from OR 3.62 (95% CI 1.98-6.61) for TP53 down to OR 1.60 (95% CI 0.48-5.30) for STK11.

Conclusions: These metrics reflecting 'population-type' breast cancer will be informative in defining the appropriate gene set as we continue to expand to germline testing to an increasingly unselected group of breast cancer cases.

Keywords: breast cancer; case–control; mainstream genetic testing; meta-analysis; multigene panel testing.

Publication types

Meta-Analysis

MeSH terms

Ataxia Telangiectasia Mutated Proteins / genetics
BRCA1 Protein / genetics
BRCA2 Protein / genetics
Breast Neoplasms* / epidemiology
Breast Neoplasms* / genetics
Breast Neoplasms* / pathology
Case-Control Studies
Checkpoint Kinase 2 / genetics
DNA-Binding Proteins / genetics
Fanconi Anemia Complementation Group N Protein / genetics
Female
Genetic Association Studies
Genetic Predisposition to Disease*
Genetic Testing* / methods
Germ-Line Mutation*
Humans
Tumor Suppressor Proteins
Ubiquitin-Protein Ligases / genetics

Substances

Fanconi Anemia Complementation Group N Protein
BRCA1 Protein
PALB2 protein, human
BRCA2 Protein
BRCA1 protein, human
Checkpoint Kinase 2
BRCA2 protein, human
CHEK2 protein, human
Ataxia Telangiectasia Mutated Proteins
BARD1 protein, human
Ubiquitin-Protein Ligases
DNA-Binding Proteins
ATM protein, human
RAD51D protein, human
Tumor Suppressor Proteins