Search

Pathogenic genetic variants (formerly called mutations) present in the germline of some individuals are associated with a clinically relevant increased risk of developing lung cancer. These germline pathogenic variants are hereditary and are transmitted in an autosomal dominant fashion. There are two major lung cancer susceptibility syndromes, and both seem to be specifically associated with the adenocarcinoma subtype. Li-Fraumeni syndrome is caused by variants in the TP53 tumour-suppressor gene. Carriers are mainly at risk of early-onset breast cancer, sarcoma, glioma, leukaemia, adrenal cortical carcinoma and lung cancer. EGFR variants, T790M in particular, cause the EGFR susceptibility syndrome. Risk seems limited to lung cancer. Emerging data suggest that variants in ATM, the breast and pancreatic cancer susceptibility gene, also increase lung adenocarcinoma risk. As for inherited lung disease, cancer risk is increased in SFTPA1 and SFTPA2 variant carriers independently of the underlying fibrosis. In this review, we provide criteria warranting the referral of a lung cancer patient to the cancer genetics clinic. Pathogenic variants are first identified in patients with cancer, and then in a subset of their relatives. Lung cancer screening should be offered to asymptomatic carriers, with thoracic magnetic resonance imaging at its core.