Molecular Pathogenesis of Lung Cancer: Evolving Landscapes Based on Past Experience

Lung cancers are characterized by abundant genetic diversity with relatively few recurrent mutations occurring at high frequency. However, genetic aberrations often affect oncogenic signalling pathways. There have been vast improvements in our understanding of the molecular biology that underpins lung carcinoma in recent years, and this has led to a revolution in the diagnosis and treatment of lung carcinomas based on the genotype of an individual’s tumour. New technologies are identifying key and potentially targetable genetic alterations in lung carcinoma. Lung cancer mutations have been identified in Kirsten rat sarcoma viral oncogene homolog (KRAS), epidermal growth factor receptor (EGFR), BRAF and the parallel phosphatidylinositol 3-kinase (PI3K) pathway oncogenes and more recently in MEK and HER2 while structural rearrangements in ALK, ROS1 and RET provide new therapeutic targets. Amplification is another mechanism of activation of oncogenes such as MET in adenocarcinoma and fibroblast growth factor receptor 1 (FGFR1) in squamous cell carcinoma. Intriguingly, many of these genetic alternations are associated with smoking status and particular racial and gender differences, which may provide insight into the mechanisms of carcinogenesis and the role of host factors in lung cancer development and progression. The role of the tumour-suppressor genes is increasingly recognized with aberrations reported in TP53, PTEN, RB1 and p16/CDKN2A. Identification of biologically significant genetic alterations in lung cancer that lead to the activation of oncogenes and inactivation of tumour-suppressor genes has the potential to provide further therapeutic opportunities. It is hoped that these discoveries may make a major contribution to improving outcomes for patients with this poor prognosis disease.