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.
Driver mutations in lung cancer
Malignant tumors develop due to the accumulation of the mutations in a portion of genes, which provide growth advantage. Systematic resequencing of cancer genomes led to the discovery of the new cancer-related genes. While many somatic mutations are observed in cancers, most of them are likely to be “passengers”, which do not contribute to carcinogenesis. On the other hand, “driver” mutations exist in a subset of somatic mutations, which are responsible to develop cancers (27). In lung cancer, several gene mutations are reported to be drivers. In addition to EGFR described above, mutations of KRAS, ALK, human epidermal growth factor receptor 2 (HER2), BRAF, PIK3CA, AKT1, MAP2K1 and MET are reported to be drivers in lung cancer (28). These alterations are potential therapeutic targets, and molecular targeting drugs such as EGFR-TKI are developed.
Previously reported inherited lung cancer pedigrees with germline EGFR mutations
As described above, inherited lung cancers are rarely observed. However, several reports investigated genetic susceptibility to inherited lung cancers, and the reports describing EGFR germline mutations in lung cancer pedigrees draw the attention of us (29-37). In addition to these reports, lung cancer cases with germline EGFR mutations are reported, although the evident familial history of lung cancers are not obtained (38-40). Reported EGFR germline mutations are R776G, R776H, T790M, V843I and P848L, which are all located in the kinase domain of EGFR (Figure 1), and notably, T790M mutations are frequently reported (29,31,32,34,35,37) (Table 1). In the pedigrees with EGFR germline mutations including T790M, many of affected family members develop secondary somatic EGFR activating mutations such as exon 19 deletion and L858R. Presumably, T790M mutation itself is a weak oncogene. However, when secondary somatic mutations occur, the oncogenic power of combined germline and somatic mutations should become enormous. Gazdar et al. studied the pedigrees with germline EGFR T790M mutations in detail. Several patients with germline T790M mutations had multiple lung tumors, and computed tomography (CT) scans of unaffected carriers revealed multiple ground glass nodules of uncertain etiology, implying that they have multiple preinvasive lesions (29). They also showed the association of sex and smoking status with developing lung cancer, indicating that germline T790M mutations targeted female never smokers, different from sporadic lung cancers, most of which target ever smokers (29). Interestingly, all the affected family members with germline T790M mutations are Caucasians or East Indians, that is, the absence of reported T790M germline mutations in East Asian ethnicity, whereas sporadic EGFR mutations mainly occur in East Asians. Reported affected members with germline EGFR V843I mutations in 2 reports are East Asians and another report shows a Caucasian (Table 1).
Germline mutation of HER2 in a Japanese pedigree of inherited lung cancer
There is a possibility for the oncogenes other than EGFR to cause inherited lung cancers. We previously reported a family of Japanese descent with inherited lung cancers, in which germline HER2 mutations were detected (41). The proband was 53-year-old female at the time of the analysis with multiple lung adenocarcinomas in the bilateral lungs. She was a light smoker with 1.2-pack-year history of smoking. In addition, normal-appearing lung parenchyma obtained from a lobectomy in the proband revealed innumerable small preinvasive lesions, implying the presence of precancerous changes throughout the lung. Her mother, who was a never smoker, also suffered from multiple lung adenocarcinomas. We performed exome sequencing using tumor and blood samples of affected and unaffected family members. Novel germline HER2 mutations G660D were detected in the transmembrane domain, although reported HER2 somatic mutations are located in the kinase domain (42,43). In contrast to the lung cancers with germline EGFR mutations, we were not able to detect secondary somatic mutations of the genes known to cause lung cancers including EGFR (Table 1). We also confirmed no copy number gain of HER2 in the examined tumors. Based on our in vitro analyses (44), we administered HER2 inhibitor afatinib to the proband and achieved partial response (45). We tested the mutational status of HER2 using the blood sample for the proband’s daughter, who received the genetic counseling before testing and after the results were obtained. She also had germline HER2 G660D mutation. Her tobacco exposure was 4.5 pack-years, indicating a light smoker. Computed tomography (CT) scan of the chest for her at the age of 30 is shown in Figure 2. Multiple ground-glass nodules in bilateral lungs were observed, similar to the carriers with germline EGFR T790M mutations. In this pedigree, among nine lung cancer patients, female patients are six, accounting for 66.7% (41). Although information of smoking status in this pedigree is limited to only the proband (with lung cancer), her mother (with lung cancer) and her daughter (carrier with multiple ground glass nodules), those three members are never or light smokers. Therefore, there is also the possibility that germline HER2 transmembrane mutations target female never smokers, same as germline EGFR T790M mutations.
Germline mutations other than EGFR/HER2 that predispose to lung cancer
There are several reports that describe germline mutations other than EGFR/HER2, which predispose to lung cancer. Germline mutation of BRCA-associated protein-1 (BAP1) has been associated with the high risk for malignant mesothelioma, lung adenocarcinoma, uveal melanoma, and cutaneous melanoma (46). Germline BRCA1 mutation was detected in a patient with non-small cell lung cancer who responded to cisplatin/gemcitabine plus HSP90 inhibitor DEBIO0931 (47). Rare variant BRCA2 K3326X was reported to be associated with squamous cell lung cancer (48). A familial CDKN2A mutation R112dup has been associated with an increased risk of lung, head and neck and gastroesophageal cancer in patients who smoke (49). LKB1 is mutated in the germ-line of patients with the Peutz-Jeghers syndrome, which have an increased incidence of several cancers including lung cancers (50). Germline SFTP2A mutation is reported to cause familial idiopathic pulmonary fibrosis and lung cancer (51).
Next generation sequencing technology makes it possible to perform comprehensive analysis of genome in high speed. Some studies successfully narrowed down the several candidate genes (22,52). While functional analysis is critical, accumulation of these knowledge will lead to identification of causative genes, which results in elucidating carcinogenesis of lung cancer as well as in developing the new therapeutic strategies of lung cancer.
Single nucleotide polymorphisms (SNPs) and susceptibility of lung cancer
Single nucleotide polymorphism (SNP) is a variation at a single position in the genome, if the frequency of the variation is more than 1% in the population. Several SNPs are reported to be associated with the susceptibility of lung cancer. Genome wide association studies (GWAS) revealed that SNPs at 15q25, which is the site of nicotinic acetylcholine receptor subunit genes CHRNA5, CHRNA3, CHRNB4, were strongly associated with lung cancer (53). Lan and colleagues revealed three susceptibility loci at 10q25.2 (rs7086803), 6q22.2 (rs9387478) and 6p21.32 (rs2395185) in Asian women who never smoked. They also observed that no evidence of association for lung cancer at 15q25 in never-smoking women in Asia (54). Wang and colleagues reported that SNPs at 5p15.33-TERT (rs2736100) and 5p15.33-CLPTM1L (rs4975616) were associated with lung cancer in never smokers (55). Another GWAS study reported that 10 SNPs including newly detected two loci, 17q24.3-BPTF (rs7216064) and 6p21.3-BTNL2 (rs3817963), were associated with lung adenocarcinoma risk in never-smoking Asian women. Of these 10 SNPs, three SNP markers TERT, TP63 and 9p21.3 were also significantly associated with lung adenocarcinoma risk in Western never-smokers. Among Western smokers, only two out of 10 SNPs (TERT and TP63) were significantly associated with lung adenocarcinoma risk (56).
Germline EGFR T790M mutations cause rare and characteristic inherited lung cancer syndromes, which target female never smokers. Although only one pedigree is so far reported regarding inherited lung cancer syndrome with germline HER2 mutations, this syndrome may also target female never smokers. Because unaffected family members in these pedigrees have an increased risk to develop lung cancer, it is necessary to follow them deeply by the CT scan of the chest. Even though inherited lung cancers are rare, these molecular characteristics may be contributory to understanding the pathogenesis of lung cancer, and thus they also may shed light on the elucidation of sporadic lung cancers.
This work was supported by a Management Expenses Grants for National University Corporations in Japan.
Conflicts of Interest: The authors have no conflicts of interest to declare.
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