HaploX Biotechnology Co., Ltd, Beijing, China
Lele Song , Mengyuan Liu , Xinyi Liu , Suo Peisu , Tanxiao Huang , Yaru Chen , Yanqing Zhou , Guifeng Liu , Jianfei Yao , Shifu Chen , Mingyan Xu
Background: Germline variations may contribute to lung cancer susceptibility besides environmental factors. The susceptibility of germline mutations and their correlation with somatic mutations has not been systematically investigated in lung cancer patients. Methods: Germline mutations from 1090 lung cancer patients were analyzed with a 58-gene NGS panel containing known hereditary cancer-related genes, and were categorized based on ACMG guidelines in pathogenicity, and the corresponding somatic mutations were analyzed using a 605-gene NGS panel containing known cancer-related genes. Results: Genetic susceptibility was found in 4.5% of lung cancer patients, in which 14 patients with pathogenic mutations and 35 patients with likely-pathogenic mutations were identified. Significantly stronger family history was found with the pathogenic group than other groups. Pathogenic mutations fell most commonly in BRCA2 (6/14), followed by CHEK2 (3/14) and ATM (2/14). Likely-pathogenic mutations fell most commonly in NTRK1 mutations (4/35) and EXT2 mutations (4/35), followed by BRIP1 (3/35) and PALB2 (3/35). These genes are involved in DNA repair (BRCA1 and BRCA2, BLM, RAD50, BRIP1, MLH3), cell cycle regulation (such as CHEK2, ATM, NTRK1 and EPCAM) and tumor suppressor (such as PALB2). The overall odds ratio (OR) value of the pathogenic group was 17.93 (95% CI: 9.74 to 33.01), and was 15.86 (95% CI: 5.999 to 133.2) for the likely-pathogenic group, suggesting that the pathogenic or the likely-pathogenic germline mutations as a whole were risk factors for lung cancer. Somatic mutation analysis revealed no significant difference in TMB among the groups, although a trend of lower TMB in the pathogenic group was found. The SNV/INDEL mutation rate of TP53 in the pathogenic group was significantly lower. Pathway enrichment analysis found no significant difference in aberrant pathways among the groups. Conclusions: 4.5% of patients carrying germline variants may be linked to increased susceptibility to lung cancer. The susceptibility is mainly reflected in family history and morbidity risk without significant influence on aberrant pathways.
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