The contribution of hereditary cancer-related germline mutations to lung cancer susceptibility

Abstract

Background: Germline variations may contribute to lung cancer susceptibility besides environmental factors. The influence of germline mutations on lung cancer susceptibility and their correlation with somatic mutations has not been systematically investigated.Methods: In this study, germline mutations from 1,026 non-small cell lung cancer (NSCLC) patients were analyzed with a 58-gene next-generation sequencing (NGS) panel containing known hereditary cancerrelated genes, and were categorized based on American College of Medical Genetics and Genomics (ACMG) guidelines in pathogenicity, and the corresponding somatic mutations were analyzed using a 605-gene NGS panel containing known cancer-related genes.Results: Plausible genetic susceptibility was found in 4.7% of lung cancer patients, in which 14 patients with pathogenic mutations (P group) and 34 patients with likely-pathogenic mutations (LP group) were identified. The ratio of the first degree relatives with lung cancer history of the P groups was significantly higher than the Non-P group (P=0.009). The ratio of lung cancer patients with history of other cancers was higher in P (P=0.0007) or LP (P=0.017) group than the Non-P group. Pathogenic mutations fell most commonly in BRCA2, followed by CHEK2 and ATM. Likely-pathogenic mutations fell most commonly in NTRK1 and EXT2, followed by BRIP1 and PALB2. These genes are involved in DNA repair, cell cycle regulation and tumor suppression. By comparing the germline mutation frequency from this study with that from the whole population or East Asian population (gnomAD database), we found that the overall odds ratio (OR) for P or LP group was 17.93 and 15.86, respectively, when compared with the whole population, and was 2.88 and 3.80, respectively, when compared with the East Asian population, suggesting the germline mutations of the P and LP groups were risk factors for lung cancer. Somatic mutation analysis revealed no significant difference in tumor mutation burden (TMB) among the groups, although a trend of lower TMB in the pathogenic group was found. The SNV/INDEL mutation frequency of TP53 in the P group was significantly lower than the other two groups, and the copy number variation (CNV) mutation frequency of PIK3CA and MET was significantly higher than the Non-P group. Pathway enrichment analysis found no significant difference in aberrant pathways among the three groups.Conclusions: A proportion of 4.7% of patients carrying germline variants may be potentially linked to increased susceptibility to lung cancer. Patients with pathogenic germline mutations exhibited stronger family history and higher lung cancer risk.

Mutational status of main driver genes influences the prognosis of stage I–III lung adenocarcinoma patients underwent radical surgery

“…If cancers are found at early stages and appropriate therapeutic strategies are implemented, the survival may not be different to those patients with only one primary cancer. Moreover, for those with family history of cancers, screening for germline mutations should be considered, as it has been shown that pathogenic or likely pathogenic germline mutations increased the risk of lung cancer (26). Location appeared to have no influence on patient survival in our study, while it was reported that a small proportion of lung cancer patients have synchronous multiple primary lung cancer (SMPLC) or intrapulmonary metastasis, representing two distinct conditions of multiple lung lesions (27)(28)(29).…”

Characteristics of BRCA1/2 pathogenic germline mutations in chinese NSCLC patients and a comparison with HBOC

“…This incidence was much lower than that reported in Chinese HBOC, in which 5.74 % of breast cancer and 21.79 % of ovarian cancer patients had BRCA1/2 germline mutations, with an overall pathogenic mutation frequency of 69.9 % and 71.1 % for BRCA1 and BRCA2 exons, respectively [ 11 ]. Indeed, studies have suggested that no significant difference was found in the ratio of NSCLC patients with smoking history between those with or without pathogenic germline mutations [ 8 , 10 ], and germline mutations in driver oncogenes and inherited lung cancer risk may be independent of smoking history [ 14 ]. These observations suggested that the influence of BRCA1/2 germline mutations in NSCLC may not be as big as that in HBOC, and factors other than germline variants may play more important roles in sporadic lung cancer patients, most likely environmental factors including smoking [ 10 ].…”

“…An interesting observation in this study is that family history of lung cancer has been seen in 57.14 % (8/14) of lung cancer patients with pathogenic germline mutation, and in 32.35 % (11/34) of patients with likely pathogenic germline mutations [ 10 ]. Therefore, it can be suggested that NSCLC did happen to a family when pathogenic germline mutations were inherited.…”

“…The information on mutations and specific mutation sites were collected from three publications reporting the BRCA1/2 germline mutations in Chinese population [ 8 – 10 ]. Mutation sites were reorganized in protein change format and the carrier frequency was calculated for BRCA1 (Table 1 ) and BRCA2 (Table 2 ).…”

Identification of the Unique Clinical and Genetic Features of Chinese Lung Cancer Patients With EGFR Germline Mutations in a Large-Scale Retrospective Study

“…Epidemiological surveys have further suggested that lung cancer has inherited susceptibility and show familial aggregation (3)(4)(5)(6). That is, genetic factors, such as highfrequency single nucleotide polymorphisms with low penetrance and low-frequency pathogenic germline variants with high penetrance, have been confirmed to be related to lung cancer predisposition (7)(8)(9)(10). Multiple genome-wide association studies confirmed CHRNA5, TERT, BAT2, and FKBPL as candidate genes associated with lung cancer risk (6,7).…”