The Pedigree Analysis of EGFR p.V1010M Germline Mutation in a Family with a Family History of Non-Small-Cell Lung Cancer (NSCLC)

Abstract Background: The causes of tumor can be divided into genetic factors and environmental factors, but previous studies have shown that genetic factors contribute less to lung cancer. EGFR is the most common driver gene in non-small-cell lung cancer (NSCLC), but most variations are found as somatic variations. In this study, we reported a pedigree of EGFR p.V1010M germline mutation for the first time, and explored the correlation between V1010M and NSCLC disease occurrence. Furthermore, the effect of the V1010M on the treatment of EGFR-TKIs was investigated through the treatment of the proband with simultaneous somatic mutation of EGFR p.L858R.Methods: The families were screened by NGS and Sanger sequencing, and the pedigree was drawn to investigate the relationship between EGFR p.V1010M and the occurrence of NSCLC disease. Schrodinger software was used to predict the structural function of mutant amino acid sequence proteins.Results: A total of 10 blood samples were collected from four generations of the family members, many of whom suffered from lung cancer. And 6 carriers of EGFR p.V1010M were detected. Pedigree analysis showed that there was still no evidence of correlation between EGFR p.V1010M and disease occurrence. Meanwhile, the proband detected the somatic mutation of EGFR p.L858R, and the response after the treatment of gifitinib was SD, which turned to PD 4 months later. Schrodinger software showed that the 1010th amino acid valine was located near the C terminal, and the variation to methionine had little effect on the structure of EGFR dimer.Conclusion: This study is the first report of a pedigree with EGFR p.V1010M germline mutation, which might be a pathogenic mutation and associated with EGFR-TKIs resistance in NSCLC.