Inherited Lung Cancer Syndromes Targeting Never Smokers

Hiromasa Yamamoto; Yasushi Yatabe; Shinichi Toyooka


Transl Lung Cancer Res. 2018;7(4):498-504. 

In This Article

Abstract and Introduction


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.


Lung cancer is one of the refractory malignancies and the leading cause of cancer death worldwide.[1–3] This disease is often diagnosed at the advanced stages, in which the treatment is less effective, and thus it still has a poor outcome. To improve a worse prognosis, various researches have been conducted. One of the significant research progress is the discovery of the somatic activating mutations in the tyrosine kinase domain of epidermal growth factor receptor (EGFR).[4–6] These mutations mainly consist of exon 19 deletion and exon 21 point mutation (L858R), and frequently occur in adenocarcinoma, female, East Asian, and never smokers.[7] Lung cancers with EGFR activating mutations initially well respond to EGFR tyrosine kinase inhibitors (TKIs), such as gefitinib and erlotinib.[4–6] EGFR-TKIs showed prolonged disease-free survival in phase III clinical trials.[8–10] However, the tumors eventually acquire the resistance to TKIs, which is the issue to be overcome. One of the major mechanisms for the acquired resistance to TKIs is a secondary EGFR mutation T790M in exon 20.[11,12] T790M mutations may exist in treatment-naïve tumors, and the clones with T790M are selected in the course of the TKI treatment.[13] More recently, immune checkpoint inhibitors have brought change to the treatment of lung cancer and showed the promising therapeutic effect.[14] In this manner, the treatment of lung cancer has been drastically changed. However, to improve the outcome of lung cancer more, it is necessary to further understand molecular oncology, and one of the approaches may be the comprehension of cancer susceptibility including inherited germline alterations.

Although vast majority of malignancies from various organs develop sporadically, we sometimes encounter inherited cancer syndromes, such as hereditary non-polyposis colorectal cancer (HNPCC), familial adenomatous polyposis (FAP), hereditary breast and ovarian cancer syndrome (HBOC), Li-Fraumeni syndrome, retinoblastoma, and multiple endocrine neoplasia.[15–20] Compared to other organs, most of lung cancers develop sporadically and inherited lung cancers are rare. While inherited lung cancers are rarely observed, several reports investigated genetic susceptibility to inherited lung cancers.[21–26] Those previous reports describing inherited lung cancers did not much focus on the relationship between genetic factors and smoking status.

In this review, we introduce the reported inherited lung cancer pedigrees with germline mutations, and discuss the features of such inherited lung cancers, especially smoking status, sex, and ethnicity.