Prevalence and clinical significance of pathogenic germline BRCA1/2 mutations in Chinese non-small cell lung cancer patients

Abstract

Objective: Germline alterations in the breast cancer susceptibility genes type 1 and 2, BRCA1 and BRCA2, predispose individuals to hereditary cancers, including breast, ovarian, prostate, pancreatic, and stomach cancers. Accumulating evidence suggests inherited genetic susceptibility to lung cancer. The present study aimed to survey the prevalence of pathogenic germline BRCA mutations (gBRCAm) and explore the potential association between gBRCAm and disease onset in Chinese advanced non-small cell lung cancer (NSCLC) patients. Methods: A total of 6,220 NSCLC patients were screened using capture-based ultra-deep targeted sequencing to identify patients harboring germline BRCA1/2 mutations. Results: Out of the 6,220 patients screened, 1.03% (64/6,220) of the patients harbored the pathogenic gBRCAm, with BRCA2 mutations being the most predominant mutations (49/64, 76.5%). Patients who developed NSCLC before 50 years of age were more likely to carry gBRCAm (P = 0.036). Among the patients harboring classic lung cancer driver mutations, those with concurrent gBRCAm were significantly younger than those harboring the wild-type gBRCA (P = 0.029). By contrast, the age of patients with or without concurrent gBRCAm was comparable to those of patients without the driver mutations (P = 0.972). In addition, we identified EGFR-mutant patients with concurrent gBRCAm who showed comparable progression-free survival but significantly longer overall survival (P = 0.002) compared to EGFR-mutant patients with wild-type germline BRCA. Conclusions: Overall, our study is the largest survey of the prevalence of pathogenic gBRCAm in advanced Chinese NSCLC patients. Results suggested a lack of association between germline BRCA status and treatment outcome of EGFR-TKI. In addition, results showed a positive correlation between pathogenic gBRCAm and an early onset of NSCLC.

Do Female BRCA2 Pathogenic Variant Carriers Have an Increased Risk of Lung Cancer?

“…3 Recently, an association between BRCA2 and lung cancer was suggested in a large Chinese study with a 0.8% PV prevalence in patients with advanced non–small-cell lung cancer. 4 Furthermore, a recent study concluded that lung cancer occurred significantly earlier in BRCA2 PVs carriers compared with noncarriers by approximately 12 years (95% CI, 2.5 to 20.6). 5 In conclusion, an impact of germline BRCA2 PV on lung cancer risk remains open for discussion.…”

Germline Testing of Patients With Non–small Cell Lung Cancers Demonstrating Incidentally Uncovered BRCA2 Apparent Pathogenic Germline Variants

“…The authors wrote "accumulating evidence suggests inherited genetic susceptibility to lung cancer." 7 As further evidence of BRCA PGVs predisposing to NSCLC, the authors noted in their report that patients with NSCLC and a PGV tended to be younger than those not carrying a PGV. 7 Tian et al reported that among 1764 patients with lung cancer (97% with NSCLC), 67 (3.8%) were found to have a PGV/likely pathogenic variant (LV), with BRCA2 being the most common PGV identified (0.79%).…”

“…7 As further evidence of BRCA PGVs predisposing to NSCLC, the authors noted in their report that patients with NSCLC and a PGV tended to be younger than those not carrying a PGV. 7 Tian et al reported that among 1764 patients with lung cancer (97% with NSCLC), 67 (3.8%) were found to have a PGV/likely pathogenic variant (LV), with BRCA2 being the most common PGV identified (0.79%). 8 Among 1026 NSCLC patients, Liu et al suggested "plausible" susceptibility from germline variants in 4.7%, again with the most common PGV identified being BRCA2.…”

Characterization of lung cancers in patients with BRCA germline variants: A multicenter series

“…Studies other than the two presented in the introduction [7,8] have found an unusually high prevalence of BRA1/2gl variants among LC patients. In a national Chinese multicenter retrospective study conducted in advanced stage (stage III-IV) non-small cell lung cancer (NSCLC), Hu et al [10] found a 1.03% (64 of 6220 participants) prevalence of BRCA1/2glpv which was higher than the estimated frequency in East Asians (0.2%) [11]. In a recent crosssectional study including 7768 LC patients, the prevalence of BRCA2glpv [12] was 0.66%.The SAFIR02-Lung trial [13] is a French multi-center, open-label, randomized, phase II adaptative trial investigating untreated advanced NSCLC wild-type for EGFR and ALK.…”