Two germline mutations can serve as genetic susceptibility screening makers for a lung adenocarcinoma family

Lung cancer is the most common form of cancer and the leading cause of cancer death. For familial lung cancer, identification of causing genetic factors is essential for prevention and control of non-lung cancer in carriers.

We studied two generations of a family with suspected inherited lung cancer susceptibility. Four individuals in this family had lung adenocarcinoma. To identify the gene(s) that cause the lung cancer in this pedigree, we extracted DNA from the peripheral blood of four cancer individuals and blood from three cancer-free family members as the control and performed whole-genome sequencing. Our filtering strategy includes, assessment of allele frequency, functional affection on amino acids, mutation accumulation, phased blocks and evolution analysis towards the alterations.

We identified two possible mutations, including PLEKHM2 (D134N) and MCC (R448Q) in all affected family members but did not found in the control group. Then, we performed a genetic susceptibility screening for 10 non-lung cancer relatives and found two individuals with PLEKHM2 (D134N) mutation, two with MCC (R448Q) mutation and one carrying both mutations. 3 carriers performed LDCT scan and 2 of them carried MCC (R448Q) also had ground-glass opacity (GGO) lesion in their lung.

Our data suggested that WGS together with our filtering strategy was successful in identifying PLEKHM2 (D134N) and MCC (R448Q) as the possible driver mutations in this family. Genetic susceptibility screening of non-lung cancer carriers will be a useful approach to prevent and control lung cancer in families with high-risk for the disease.