Association of gene variant type and location with breast cancer risk in the general population

Abstract

Background: Pathogenic variants (PVs) in ATM, BRCA1, BRCA2, CHEK2, and PALB2 are associated with increased breast cancer risk. It is unknown, however, whether this risk differs by PV type or location in carriers ascertained from the general population.

Patients and methods: To evaluate breast cancer risks associated with PV type and location in ATM, BRCA1, BRCA2, CHEK2, and PALB2, we carried out age-adjusted case-control association analysis in 32 247 women with and 32 544 age-matched women without breast cancer from the CARRIERS Consortium. PVs were grouped by type and location within genes and assessed for risks of breast cancer [odds ratios (OR), 95% confidence intervals (CI), and P values] using logistic regression.

Results: Compared with women carrying BRCA2 exon 11 protein truncating variants (PTVs) in the CARRIERS population-based study, women with BRCA2 ex1-10 PTVs (OR = 13.5, 95% CI 6.0-38.7, P < 0.001) and ex13-27 PTVs (OR = 9.0, 95% CI 4.9-18.5, P < 0.001) had higher breast cancer risks, lower rates of estrogen receptor (ER)-negative breast cancer (ex13-27 OR = 0.5, 95% CI 0.2-0.9, P = 0.035; ex1-10 OR = 0.5, 95% CI 0.1-1.0, P = 0.065), and earlier age at breast cancer diagnosis (ex13-27 5.5 years, P < 0.001; ex1-10 2.4 years, P = 0.169). These associations with ER-negative breast cancer and age were replicated in a high-risk clinical cohort from Ambry Genetics and the population-based UK Biobank cohort. No differences in risk by gene region were observed for PTVs in other predisposition genes.

Conclusions: Population-based and clinical high-risk cohorts establish that PTVs in exon 11 of BRCA2 are associated with reduced breast cancer risk, later age at diagnosis, and greater risk of ER-negative disease. These differential risks may improve individualized risk prediction and clinical management for women carrying BRCA2 PTVs.

Keywords: breast cancer risk; pathogenic variant type and location; population-based cohort.

Figure 1:. Age adjusted risk, age at breast cancer diagnosis, and ER-negative breast cancer in BRCA2 variant carriers in CARRIERS, the United Kingdom Biobank and Ambry Genetics clinical testing cohorts.

a) Odds ratios (OR) and 95% confidence intervals (CI) in carriers of BRCA2 pathogenic variants (PV) in CARRIERS by PV location/type. Dotted line is OR = 1. b) Mean age at breast cancer diagnosis ± standard error of mean (SEM) in women from CARRIERS, the United Kingdom Biobank (UKBB) and Ambry Genetics. Dotted line is the mean age at diagnosis in carriers of exon 11 protein truncating variants (PTVs). c) Prevalence and association of BRCA2 PV location/type with estrogen-receptor (ER) negative breast cancer in women from CARRIERS and from Ambry Genetics. ORs were estimated using logistic regression. Non-NMD includes in-frame deletions, missense PVs, and C-terminal PTVs not leading to NMD.

Figure 2:. Age adjusted risk of ATM, BRCA1, BRCA2, CHEK2, and PALB2 variant types and locations.

Odds ratios (OR), P-values and 95% confidence intervals (CI) were estimated using logistic regression in carriers of BRCA2, BRCA1, PALB2, ATM, and CHEK2 pathogenic variants (PVs) in the population-based studies. PTV = protein truncating variant, NMD = nonsense mediated decay, FDR = False Discovery Rate. Non-NMD includes in-frame deletions, missense PVs, and C-terminal PTVs not leading to NMD. Dotted line is OR = 1.