Population-based germline breast cancer gene association studies and meta-analysis to inform wider mainstream testing.
Level 3 - non-randomized controlled study
Meta-analysis of population-based case-control studies
PubMed 38986768 · doi:10.1016/j.annonc.2024.07.244
What was done
Weighted meta-analysis was carried out for three population-based case-control studies (BRIDGES, CARRIERS, and UK Biobank) comprising 101,397 women with breast cancer and 312,944 women without breast cancer. The authors quantified pathogenic variant (PV) frequencies and disease associations across 37 putative breast cancer susceptibility genes in unselected, population-type breast cancer cases and subtypes.
What was found
Pathogenic variant frequencies in cases and pooled odds ratios (ORs) were: - BRCA1: OR 8.73 (95% CI 7.47-10.20), carrier frequency 1 in 101 - BRCA2: OR 5.68 (95% CI 5.13-6.30), carrier frequency 1 in 68 - PALB2: OR 4.30 (95% CI 3.68-5.03), carrier frequency 1 in 187 - CHEK2: OR 2.40 (95% CI 2.21-2.62), carrier frequency 1 in 73 (stronger in estrogen receptor-positive disease) - ATM: OR 2.16 (95% CI 1.93-2.41), carrier frequency 1 in 132 (stronger in estrogen receptor-positive disease) - RAD51C: OR 1.53 (95% CI 1.29-2.04), carrier frequency 1 in 913 - RAD51D: OR 1.76 (95% CI 1.29-2.41), carrier frequency 1 in 1079 - BARD1: OR 2.34 (95% CI 1.85-2.97), carrier frequency 1 in 672 (higher in triple-negative cases) Syndromic genes showed very low PV frequencies in cases: TP53 (1 in 1844; OR 3.62, 95% CI 1.98-6.61), STK11 (1 in 11,525; OR 1.60, 95% CI 0.48-5.30), CDH1 (1 in 2668), PTEN (1 in 3755), and NF1 (1 in 1470).
Why it matters
As germline genetic testing expands to unselected breast cancer patients in mainstream oncology clinics, these population-level metrics help define which genes provide sufficient diagnostic yield and clinical validity to include on routine testing panels.
Limits
The abstract does not report the racial or ancestral breakdown of the pooled cohorts, which are historically heavily European-predominant. Due to extremely low mutation rates, several syndromic genes (such as STK11) had wide confidence intervals crossing unity. Specific effect estimates were not provided in the abstract for all 37 evaluated genes.
Cited by
- supports Fewer than 5% of women who get breast cancer carry an identified cancer-causing genetic mutation.