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Population-based germline breast cancer gene association studies and meta-analysis to inform wider mainstream testing.
- Source :
-
Annals of oncology : official journal of the European Society for Medical Oncology [Ann Oncol] 2024 Oct; Vol. 35 (10), pp. 892-901. Date of Electronic Publication: 2024 Jul 08. - Publication Year :
- 2024
-
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.<br />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.<br />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.<br />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.<br /> (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)
- Subjects :
- Humans
Female
Case-Control Studies
Fanconi Anemia Complementation Group N Protein genetics
BRCA1 Protein genetics
BRCA2 Protein genetics
Checkpoint Kinase 2 genetics
Genetic Association Studies
Ataxia Telangiectasia Mutated Proteins genetics
Ubiquitin-Protein Ligases genetics
DNA-Binding Proteins genetics
Tumor Suppressor Proteins
Breast Neoplasms genetics
Breast Neoplasms epidemiology
Breast Neoplasms pathology
Genetic Predisposition to Disease
Germ-Line Mutation
Genetic Testing methods
Subjects
Details
- Language :
- English
- ISSN :
- 1569-8041
- Volume :
- 35
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- Annals of oncology : official journal of the European Society for Medical Oncology
- Publication Type :
- Academic Journal
- Accession number :
- 38986768
- Full Text :
- https://doi.org/10.1016/j.annonc.2024.07.244