Inherited lung cancer syndromes targeting never smokers

Lung cancer is the leading cause of cancer death worldwide. Most of lung cancers develop sporadically and thus inherited lung cancers are rare. Several reports show that germline mutations in the kinase domain of epidermal growth factor receptor (EGFR) such as R776G, R776H, T790M, V843I and P848L, predispose to develop lung cancer. Most lung cancer cases with germline EGFR T790M mutations had secondary EGFR somatic mutations. Never smokers with germline EGFR T790M mutations develop lung cancer more frequently than ever smokers. In addition, germline EGFR T790M mutations favored female gender. Therefore, germline EGFR T790M mutations result in a unique inherited lung cancer syndrome targeting never smokers. The authors previously reported a Japanese familial lung cancer pedigree with germline mutations in the transmembrane domain of human epidermal growth factor receptor 2 (HER2). The female proband and her mother in this pedigree, who were light or never smokers, developed multiple lung adenocarcinomas, and had germline HER2 G660D mutations. They had no EGFR somatic mutations or other genes known to cause lung cancers. Although we know only one pedigree with germline HER2 mutations, these mutations may also cause inherited lung cancers targeting female never smokers. Based on our in vitro analyses, we administered HER2 inhibitor afatinib to the proband and achieved partial response. These lung cancers arising from germline mutations of receptor tyrosine kinases such as EGFR and HER2 may have different features from those with sporadic mutations.