Biological and therapeutic implications of the cancer-related germline mutation landscape in lung cancer

Although smoking is the primary cause of lung cancer, only about 15% of lifelong smokers develop the disease. Moreover, a substantial proportion of lung cancer cases occur in never-smokers, highlighting the potential role of inherited genetic factors in the cause of lung cancer. Lung cancer is significantly more common among those with a positive family history, especially for early-onset disease. Therefore, the presence of pathogenic germline variants might act synergistically with environmental factors. The incorporation of next-generation sequencing in routine clinical practice has led to the identification of cancer-predisposing mutations in an increasing proportion of patients with lung cancer. This Review summarises the landscape of germline susceptibility in lung cancer and highlights the importance of germline testing in patients diagnosed with the disease, which has the potential to identify individuals at risk, with implications for tailored therapeutic approaches and successful prevention through genetic counselling and screening.