Germline Whole‐Exome Sequencing in Non‐Smoker Lung Cancer Patients Reveals Pathogenic Variants in Lung Cancer Driver Genes

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Abstract
Approximately 10%–15% of all lung cancers arise in non‐smokers. Although there are no established aetiological factors, non‐smokers with a family history of cancer have an increased risk of lung cancer, implying host genetic factors in lung cancer susceptibility. We sought to identify, in a cohort of 75 patients recruited before lung lobectomy, germline alterations with a strong association with lung cancer. Whole‐exome sequencing was performed on genomic DNA from peripheral blood. Six resources were used to select pathogenic germline variants with strong clinical significance. In total, 33 pathogenic or likely pathogenic variants in 31 genes were identified. Of these, 13 were located in cancer‐predisposing genes (nine were lung cancer drivers), most of which were involved in DNA repair mechanisms and diseases of metabolism. Among DNA repair‐related genes, BRCA1 and BRCA2, and ATM have also been identified in other studies on non‐smokers. Our results strongly support the hypothesis that a number of non‐smoker lung cancer patients carry germline variants in cancer‐predisposing genes, suggesting that lung cancer patients, particularly non‐smokers, should be considered for germline molecular testing.

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