Pedigree analysis of the EGFR p.V1010M germline mutation in a family with a family history of non-small-cell lung cancer

Ann Transl Med. 2022 Feb;10(3):154. doi: 10.21037/atm-21-6925.


Background: Tumors can be caused by genetic or environmental factors, but previous studies have shown that genetic factors contribute less to lung cancer than environmental factors. The epidermal growth factor receptor (EGFR) is the most common driver gene in non-small-cell lung cancer (NSCLC), but most variations are somatic. In this study, we reported on the pedigree of the EGFR p.V1010M germline mutation for the first time, and explored the correlation between the V1010M and the occurrence of NSCLC. Further, the effect of the V1010M on the treatment of the EGFR-tyrosine kinase inhibitors (TKIs) was investigated through the treatment of the proband with the simultaneous somatic mutation of the EGFR p.L858R.

Methods: The family members were screened using next-generation sequencing (NGS) and Sanger sequencing, and the pedigree was analyzed to examine the relationship between the EGFR p.V1010M and the occurrence of NSCLC. Schrodinger software was used to predict the structural function of the mutant amino acid sequence proteins.

Results: A total of 10 blood samples were collected from 4 generations of family members, many of whom had suffered from lung cancer. Six carriers of the EGFR p.V1010M were detected. The pedigree analysis showed that there was still no evidence of a correlation between the EGFR p.V1010M and disease occurrence. Additionally, the proband had the EGFR p.L858R somatic mutation, and the response after the treatment of gifitinib was stable disease (SD), which turned to progressive disease (PD) some 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 the EGFR dimer.

Conclusions: This study is the first report on pedigree with the EGFR p.V1010M germline mutation. Further research needs to be conducted to determine whether this mutation is pathogenic, but it is likely related to EGFR-TKI resistance in NSCLC.

Keywords: Non-small-cell lung cancer (NSCLC); epidermal growth factor receptor p.V1010M (EGFR p.V1010M); germline; pedigree; resistance.