| 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. © 2024 The Authors |
| Keywords: |
controlled study; dna binding protein; major clinical study; case control study; genetics; case-control studies; dna-binding proteins; genetic analysis; genetic predisposition to disease; breast cancer; ubiquitin protein ligase; genetic variation; pathology; mutational analysis; breast neoplasms; brca1 protein; brca2 protein; protein p53; uvomorulin; oncogene; tumor suppressor gene; cancer center; breast tumor; tumor suppressor proteins; phosphatidylinositol 3,4,5 trisphosphate 3 phosphatase; atm protein; neurofibromin; checkpoint kinase 2; mutation rate; cancer classification; epidemiology; tumor suppressor protein; tumor gene; genetic predisposition; genetic screening; breast carcinogenesis; ubiquitin-protein ligases; brca1 protein, human; meta analysis; germ-line mutation; genetic testing; penetrance; population based case control study; meta-analysis; pten gene; atm gene; triple negative breast cancer; brca1 associated ring domain protein 1; protein kinase lkb1; germline mutation; procedures; chek2 gene; tp53 gene; genetic association studies; nf1 gene; estrogen receptor positive breast cancer; palb2 gene; rad51c gene; brca2 protein, human; humans; human; female; article; palb2 protein, human; ataxia telangiectasia mutated proteins; cdh1 gene; rad51d gene; stk11 gene; genetic association study; chek2 protein, human; partner and localizer of brca2; multigene panel testing; bard1 gene; atm protein, human; fanconi anemia complementation group n protein; rad51d protein, human; case–control; mainstream genetic testing; bard1 protein, human; breast cancer susceptibility gene; germline genetic testing
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