TUMOURS OF THE LUNG
Lung (bronchial) cancer accounts for 14 % of all new cases of cancer in males and 11 % in females. The two most common histological types of lung cancer (small cell and squamous) are known to be strongly related to cigarette smoking. It is estimated that 90 % of lung cancer in males and 85 % in females is attributable to cigarette smoking. Adenocarcinoma (moderately associated with smoking) and alveolar cell carcinoma (not associated with smoking) account for 10 % of all lung cancer. In addition to smoking, other environmental agents such as asbestos, radiation, and air pollution have been associated with lung cancer. The most frequent somatic events in lung cancer are inactivation of TP53 and mutations in KRAS or EGFR mutations (mainly in adenocarcinoma) and alterations in the CDKN2A/ARF/RB1 pathway (Brennan et al. 2011).
Familial clustering of lung cancer occurs, but as relatives of lung cancer patients are more likely than average to be smokers or passive smokers, careful studies are required to distinguish the effects of shared environment (e.g., asbestos exposure) and lifestyle (e.g., smoking) from that of genetic predisposition. Although studies of the familial incidence of smoking-related lung cancer should be interpreted cautiously, there is evidence for an increased risk of lung cancer among relatives of affected patients. Sellers et al. (1990) performed segregation analysis which allowed for variable age at onset and smoking history in affected patients. They concluded that familial clustering of lung cancer was consistent with Mendelian codominant inheritance of a rare autosomal gene with variable age at onset. It was estimated that at age 50 years, 69 % of lung cancer resulted from genetic factors acting in combination with smoking, but that at age 70 years, 72 % of lung cancer could be attributed to environmental factors alone. In a subsequent analysis, Sellers et al. (1994) provided further evidence that Mendelian factors may influence the occurrence of smoking-related cancers in the relatives of lung cancer probands. Schwartz et al. (1996) analyzed the family histories of nonsmokers with lung cancer and found a 7.2-fold increased risk of lung cancer in the first-degree relatives of nonsmokers who developed lung cancer aged 40–59 years. Risk of lung cancer was also increased in the offspring of nonsmoking cases. These findings suggest that a subset of relatives of early-onset, nonsmoking lung cancer cases is at increased genetic risk, and genetic factors have been particularly linked to early-onset cases (Cassidy et al. 2006).
Candidate gene lung cancer susceptibility studies have generally not been replicated by genome-wide association studies, though glutathione S transferase M1 (GSTM1) genotype has been associated with lung cancer risk in a meta-analysis, and the I157T CHEK2 variant that has been reported to predispose to breast cancer has also been associated with a reduced risk of lung cancer (Brennan et al. 2011).
Genome-wide association studies have repeatedly demonstrated an association between lung cancer risk and common variants in the CHRNA5- CHRNA3-CHRNB4 nicotinic acetylcholine receptor subunit gene cluster on chromosome 15q25 (relative risk ~1.3). However, it was unclear whether the association was direct or whether the link was indirect via susceptibility to cigarette smoking though recent data suggests the latter option (Wang et al. 2011). A locus for familial lung cancer susceptibility has been mapped to 6q23-25 and RGS17 suggested as the possible candidate gene responsible (You et al. 2009). A TERT SNP histology on chromosome 5p15.33 has been associated with lung adenocarcinoma risk but not with other histologies (Landi et al. 2009). However, it has been estimated that <10 % of the familial risk of lung cancer can be explained by the susceptibility loci at 15q25, 5p14, and 6p21 (Brennan et al. 2011). The role of rare variants in lung cancer susceptibility remains to be fully investigated, but a germline EGFR variant (T790M) was detected in a family with multiple cases of non-small cell lung cancer (Bell et al. 2005). For a discussion of the genetics of the rare pediatric lung Tumours pleuropulmonary blastoma.