Molecular and Genetic Pathogenesis of Lung Cancer: Differences Between Small-Cell and Non-Small-Cell Carcinomas

Lung cancer is classified into small-cell carcinoma (SCLC) and non-small-cell carcinoma (NSCLC). The pro- file of molecular and genetic alterations considerably differs between SCLC and NSCLC, as well as among the subtypes of NSCLC. Tp53 is inactivated in nearly 50% of NSCLC, while its mutations with functional inactivation are greatly prevalent in SCLC (70-100%). Rb gene alterations and protein loss are found in virtually all SCLC, but rarely in NSCLC. Instead, the Rb function is abrogated due to dysfunction of the upstream regulators of the Rb pathway. Tp53 alterations are later events in adenocarcinoma, while they occur early in squamous cell carcinoma carcinogenesis. Recent studies demonstrated activating mutations of the epidermal growth factor receptor (EGFR) gene play a significantly important role in adenocarcinoma carcinogenesis. Activation of PIK3 catalytic alpha gene was recently found in nearly half of squamous cell carcinoma cases. Smoking is associated strongly with alterations of Tp53, K-ras, and PIK3 catalytic alpha, but weakly with EGFR gene mutations. Taken together silencing alterations of both the Rb and Tp53 genes are most likely to be important and early events in the development of SCLC, whereas alterations of the EGFR signaling pathway play significant and important roles in NSCLC carcinogenesis. The biological behavior and phenotype of the respective types of lung cancer would be attributable to these molecular and genetic alterations, but also reflect the difference in the ability of their precursor cells. Identifying the airway stem cell(s) and elucidating the molecular mechanism of its mainte- nance and activation are required.