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 cancer-related 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.

Keywords: BRCA2; EGFR; Lung cancer; germline; pathogenic; susceptibility.

Figure 1

Gene names, variation types and number of variations of all pathogenic (P) and likely pathogenic (LP) germline mutations, and a scheme of the pathogenic germline variants and the position of individual mutations of the pathogenic mutations found in this study. Gene names, the number of mutations and the ratio of mutations of pathogenic germline variations and likely pathogenic variations are shown in (A,B), respectively. Mutation types and the corresponding number of mutations for P and LP groups are shown in (C). The scheme and key functional domains of BRCA2, CHECK2, ATM, BLM, RAD50 and EPCAM are shown as individual panels in (D), and the position of 14 germline mutations are marked on each panel.

Figure 2

The TMB and the gene somatic variation rate for all patients in this study. (A) Comparison of the TMB from nonsynonymous somatic mutations of the P, LP and the Non-P groups. (B) Comparison of the variation rate (mutational frequency) for main genes with somatic SNV and INDEL mutations for P, LP and Non-P group. (C) Comparison of the variation rate (mutational frequency) for main genes with copy number variations (CNVs) for P, LP and Non-P group. TMB, tumor mutation burden; P, pathogenic; LP, likely pathogenic; SNV, single nucleotide variation; INDEL, insertion and deletion.

Figure S1

Full SNV and INDEL somatic mutation spectrum for patients with pathogenic (A), likely pathogenic (B) or non-pathogenic (C) germline mutations. Somatic mutation spectrum for 14 patients with pathogenic germline mutations is shown in (A). Somatic mutation spectrum for 35 patients with likely pathogenic germline mutations is shown in (B). Somatic mutation spectrum for 1041 patients with non-pathogenic germline mutations is shown in (C). Details of germline mutations are labeled beneath the figures for (A,B), and somatic mutated genes are listed in the order of variation rate to the right of the figures. The rightest bars represent the overall number of mutations for each gene. Percentage to the left of the figures represents variation rate for each gene. Y-axis above the figures represents the number of somatic mutations detected for each patient. Colors represent mutation types as indicated by the figure legend.

Figure S2

Full CNV somatic mutation spectrum for patients with pathogenic (A), likely pathogenic (B) or non-pathogenic (C) germline mutations. Gene names with CNVs are shown to the right of the figures. Each column represents one patient, and the corresponding germline mutations are labeled beneath the figures. Colors represent the copy number for each gene, which is visualized based on the calculation of log2ratio-1. Only those patients with CNVs are shown in this figure. CNV, copy number variation.

Figure S3

Results of GO and KEGG enrichment analysis for P, LP and the Non-P groups. The upper panel shows the results of GO enrichment and the lower panel shows the results of KEGG enrichment analysis, respectively. In GO enrichment panel, color represents the degree of significance (adjusted P value) as labeled, and bars represent the number of genes with mutations involved for each function or pathway. In KEGG enrichment panel, color represents the degree of significance (adjusted P value) as labeled, and the size of dots represents the ratio of genes in which the mutations were found for each function or pathway, and bigger dots represent higher ratio. GO, Gene Ontology; KEGG, Kyoto Encyclopedia of Genes and Genomes; P, pathogenic; LP, likely pathogenic.