Lung cancer is the leading cause of cancer deaths in the U.S. and worldwide. The 2 major forms of lung cancer are nonsmall cell lung cancer and small cell lung cancer (see 182280), which account for 85% and ... Lung cancer is the leading cause of cancer deaths in the U.S. and worldwide. The 2 major forms of lung cancer are nonsmall cell lung cancer and small cell lung cancer (see 182280), which account for 85% and 15% of all lung cancers, respectively. Nonsmall cell lung cancer can be divided into 3 major histologic subtypes: squamous cell carcinoma, adenocarcinoma, and large cell lung cancer. Cigarette smoking causes all types of lung cancer, but it is most strongly linked with small cell lung cancer and squamous cell carcinoma. Adenocarcinoma is the most common type in patients who have never smoked. Nonsmall cell lung cancer is often diagnosed at an advanced stage and has a poor prognosis (Herbst et al., 2008).
Joishy et al. (1977) described identical twins who developed symptoms of alveolar cell carcinoma almost simultaneously.
Ahrendt et al. (2001) noted that incidence rates for squamous cell and small cell lung carcinoma began falling among males ... Joishy et al. (1977) described identical twins who developed symptoms of alveolar cell carcinoma almost simultaneously. Ahrendt et al. (2001) noted that incidence rates for squamous cell and small cell lung carcinoma began falling among males in the mid-1980s, but a decline in the incidence of primary adenocarcinoma of the lung among males was not observed until 5 to 10 years later. Similarly, although the incidence rates of squamous cell, large cell, and small cell lung carcinoma among women leveled off or started to decrease, the incidence of adenocarcinoma continued to increase. With these changes in the incidence among the different histologic types of lung carcinoma over the 1990s, adenocarcinoma of the lung became the most common type of lung carcinoma in the U.S. (Wingo et al., 1999).
Ding et al. (2008) sequenced 623 genes with known or potential relationship to cancer in 188 human lung adenocarcinomas. Their analysis identified 26 genes that are mutated at significantly high frequencies and are probably involved in carcinogenesis. The ... Ding et al. (2008) sequenced 623 genes with known or potential relationship to cancer in 188 human lung adenocarcinomas. Their analysis identified 26 genes that are mutated at significantly high frequencies and are probably involved in carcinogenesis. The frequently mutated genes include tyrosine kinases, among them the EGFR homolog ERBB4 (600543); multiple ephrin receptor genes, notably EPHA3 (179611); KDR (191306); and NTRK (191315). Their data provide evidence of somatic mutations in primary lung adenocarcinoma for several tumor suppressor genes involved in other cancers, including NF1 (613113), APC (611731), RB1 (614041), and ATM (607585), and for sequence changes in PTPRD (601598) as well as the frequently deleted gene LRP1B (608766). The observed mutational profiles correlate with clinical features, smoking status, and DNA repair defects. In general, Ding et al. (2008) found that genetic alterations in lung adenocarcinoma frequently occur in genes of the MAPK (see 176948), p53 (191170), WNT (see 164820), cell cycle, and mTOR (601231) signaling pathways. In affected members of 2 families with idiopathic pulmonary fibrosis (178500), some of whom also had lung cancer, Wang et al. (2009) identified 2 heterozygous missense mutations in the SFTPA2 gene (see 178642.0001 and 178642.0002, respectively). Kan et al. (2010) reported the identification of 2,576 somatic mutations across approximately 1,800 megabases of DNA representing 1,507 coding genes from 441 tumors comprising breast, lung, ovarian, and prostate cancer types and subtypes. Kan et al. (2010) found that mutation rates and the sets of mutated genes varied substantially across tumor types and subtypes. Statistical analysis identified 77 significantly mutated genes including protein kinases, G protein-coupled receptors such as GRM8 (601116), BAI3 (602684), AGTRL1 (600052), and LPHN3, and other druggable targets. Integrated analysis of somatic mutations and copy number alterations identified another 35 significantly altered genes including GNAS (see 139320), indicating an expanded role for G-alpha subunits in multiple cancer types. Experimental analyses demonstrated the functional roles of mutant GNAO1 (139311) and mutant MAP2K4 (601335) in oncogenesis. - p53 Mutations and Lung Cancer Among members of 97 families enrolled in a cohort study of families ascertained through childhood soft tissue sarcoma patients, Hwang et al. (2003) studied the role of cigarette smoking and lung cancer risk in people with a genetic susceptibility based on a p53 germline mutation. They assessed the incidence of lung and smoking-related cancers in 33 carriers of germline p53 mutations and in 1,230 noncarriers from the same families. They observed an increased risk of a variety of histologic types of lung cancer in the carriers of the p53 mutations. Mutation carriers who smoked had a 3.16-fold (95% CI = 1.48-6.78) higher risk for lung cancer than the mutation carriers who did not smoke. - EGFR Mutations and Lung Cancer In tumors from patients with NSCLC responsive to the tyrosine kinase inhibitor gefitinib, Lynch et al. (2004) and Paez et al. (2004) identified mutations in the EGFR gene (131550.0001-131550.0005). Paez et al. (2004) found somatic mutations in EGFR in 15 of 58 unselected NSCLC tumors from Japan and 1 of 61 from the United States. EGFR mutations showed a striking correlation with patient characteristics. Mutations were more frequent in adenocarcinomas than in other NSCLCs, being present in 15 (21%) of 70 and 1 (2%) of 49, respectively; more frequent in women than in men, being present in 9 (20%) of 45 and 7 (9%) of 74, respectively; and more frequent in patients from Japan than in those from the United States, being present in 15 (26%) of 58 and 14 (32%) of 41 adenocarcinomas versus 1 (2%) of 61 and 1 (3%) of 29 adenocarcinomas, respectively. The patient characteristics that correlated with the presence of EGFR mutations were those that correlated with clinical response to gefitinib treatment. The striking difference in the frequency of EGFR mutation and response to gefitinib between Japanese and U.S. patients raised general questions regarding variation in the molecular pathogenesis of cancer in different ethnic, cultural, and geographic groups and argued for the benefit of population diversity in cancer clinical trials. Pao et al. (2004) found that in-frame deletions in exon 19 of the EGFR gene and somatic point mutations in codon 858 (exon 21) were common particularly in lung cancers from 'never smokers' and were associated, as found by others, with sensitivity to the tyrosine kinase inhibitors gefitinib and erlotinib. Pao et al. (2004) found EGFR tyrosine kinase domain mutations in 7 of 10 gefitinib-sensitive tumors and 5 of 7 erlotinib-sensitive tumors. No mutations were found in 8 gefitinib-refractory tumors and 10 erlotinib-refractory tumors. Because most of the mutation-positive tumors were adenocarcinomas from 'never smokers' (defined as patients who smoked less than 100 cigarettes in a lifetime), Pao et al. (2004) screened EGFR exons 2 through 28 for mutations in 15 adenocarcinomas resected from untreated 'never smokers.' Seven tumors had tyrosine kinase domain mutations, in contrast to 4 of 81 nonsmall cell lung cancers resected from untreated former or current smokers. Collectively the data showed that adenocarcinomas from 'never smokers' comprise a distinct subset of lung cancers, frequently containing mutations within the tyrosine kinase domain of EGFR that are associated with kinase inhibitor sensitivity. Maheswaran et al. (2008) identified the EGFR T790M (131550.0006) mutation in pretreatment tumor samples from 10 (38%) of 26 patients with nonsmall cell lung cancer. Although low levels of the drug-resistant mutation did not preclude response to treatment, it was highly correlated with reduced progression-free survival. Use of a microfluidic-based isolation device and sequence amplification technology allowed for detection of EGFR mutations in circulating tumor cells from 11 (92%) of 12 patients. Serial analysis of circulating tumor cells showed that a reduction in the number of captured cells was associated with a radiographic tumor response; an increase in the number of cells was associated with tumor progression, with the emergence of additional EGFR mutations in some cases. Maheswaran et al. (2008) concluded that molecular analysis of circulating tumor cells from the blood of patients with EGFR-related nonsmall cell lung cancer could offer the possibility of monitoring changes in tumor genotype. - MET Amplification and Drug Resistance in Lung Cancer The EGFR kinase inhibitors gefitinib and erlotinib are effective treatments for lung cancers with EGFR activating mutations, but these tumors invariably develop drug resistance. Engelman et al. (2007) described a gefitinib-sensitive lung cancer cell line that developed resistance to gefitinib as a result of focal amplification of the MET (164860) protooncogene. Inhibition of MET signaling in these cells restored their sensitivity to gefitinib. MET amplification was detected in 4 (22%) of 18 lung cancer specimens that had developed resistance to gefitinib or erlotinib. Engelman et al. (2007) found that amplification of MET caused gefitinib resistance by driving ERBB3 (190151)-dependent activation of phosphoinositide 3-kinase, a pathway thought to be specific to EGFR/ERBB family receptors. Thus, Engelman et al. (2007) proposed that MET amplification may promote drug resistance in other ERBB-driven cancers as well. - KRAS Mutations and Lung Adenocarcinoma In a study of 106 prospectively enrolled patients with primary adenocarcinoma of the lung, Ahrendt et al. (2001) found that 92 (87%) were smokers. KRAS mutations were detected in 40 (38%) of 106 tumors and were significantly more common in smokers compared with nonsmokers (43% vs 0%; P = 0.001). Thirty-nine of the 40 tumors with KRAS mutations had 1 of 4 changes in codon 12, the most common being gly12 to cys (190070.0001), which was present in 25. - BRAF Mutations and Lung Adenocarcinoma Mutations of the BRAF protein serine/threonine kinase gene (164757) have been identified in a variety of human cancers, most notably melanomas. Naoki et al. (2002) analyzed the BRAF sequence in 127 primary human lung adenocarcinomas and found mutations in 2 tumor specimens, one in exon 11 (164757.0006) and another in exon 15 (164757.0007). The specimens belonged to the same adenocarcinoma subgroup as defined by clustering of gene expression data. The authors proposed that BRAF may provide a target for anticancer chemotherapy in a subset of lung adenocarcinoma patients. - ERBB2 Mutations and Lung Cancer The Cancer Genome Project and Collaborative Group (2004) sequenced the ERBB2 gene from 120 primary lung tumors and identified 4% that had mutations within the kinase domain; in the adenocarcinoma subtype of lung cancer, 10% of cases had mutations. In-frame deletions within the kinase domain of EGFR (e.g., 131550.0001) are associated with lung tumors that respond to therapy with gefitinib, an EGFR inhibitor. The Cancer Genome Project and Collaborative Group (2004) suggested that ERBB2 inhibitors, which had to that time proved to be ineffective in treating lung cancer, should be clinically reevaluated in the specific subset of patients with lung cancer whose tumors carry ERBB2 mutations. - STK11 Mutations and Lung Cancer Ji et al. (2007) used a somatically activatable mutant Kras-driven model of mouse lung cancer to compare the role of Lkb1 (STK11; 602216) to other tumor suppressors in lung cancer. Although Kras mutation cooperated with loss of p53 or Ink4a/Arf (CDKN2A; 600160), in this system, the strongest cooperation was seen with homozygous inactivation of Lkb1. Lkb1-deficient tumors demonstrated shorter latency, an expanded histologic spectrum (adeno-, squamous, and large-cell carcinoma), and more frequent metastasis compared to tumors lacking p53 or Ink4a/Arf. Pulmonary tumorigenesis was also accelerated by hemizygous inactivation of Lkb1. Consistent with these findings, inactivation of LKB1 was found in 34% and 19% of 144 analyzed human lung adenocarcinomas and squamous cell carcinomas, respectively. Expression profiling in human lung cancer cell lines and mouse lung tumors identified a variety of metastasis-promoting genes, such as NEDD9 (602265), VEGFC (601528), and CD24 (600074), as targets of LKB1 repression in lung cancer. Ji et al. (2007) concluded that their studies establish LKB1 as a critical barrier to pulmonary tumorigenesis, controlling initiation, differentiation, and metastasis. - PIK3CA Mutations and Lung Cancer Samuels et al. (2004) identified a somatic mutation in the PIK3CA gene (171834) in 1 (4%) of 24 lung cancers examined. - NKX2-1 Amplification and Lung Adenocarcinoma Weir et al. (2007) reported a large-scale project to characterize copy number alterations in primary lung adenocarcinomas. By analysis of 371 tumors using dense single-nucleotide polymorphism arrays, Weir et al. (2007) identified 57 significantly recurrent events. Weir et al. (2007) found that 26 of 39 autosomal chromosome arms showed consistent large-scale copy number gain or loss, of which only a handful had been linked to a specific gene. They also identified 31 recurrent focal events, including 24 amplifications and 7 homozygous deletions. Only 6 of these focal events were associated with mutations in lung carcinomas. The most common event, amplification of chromosome 14q13.3, was found in about 12% of samples. On the basis of genomic and functional analyses, Weir et al. (2007) identified NKX2-1 (600635), which lies in the minimal 14q13.3 amplification interval and encodes a lineage-specific transcription factor, as a novel candidate protooncogene involved in a significant fraction of lung adenocarcinomas. - HMOX1 Polymorphism and Susceptibility to Lung Adenocarcinoma Kikuchi et al. (2005) screened the heme oxygenase-1 gene (HMOX1; 141250) for (GT)n repeat length in 151 Japanese patients with lung adenocarcinoma and 153 controls. The proportion of L allele carriers was significantly higher among patients than controls (p = 0.02); the adjusted odds ratio for lung adenocarcinoma for L allele carriers was 1.8 (95% CI, 1.1-3.0) compared with non-L allele carriers. The risk of lung adenocarcinoma for L allele carriers versus non-L allele carriers was greatly increased in the group of male smokers (OR = 3.3; 95% CI, 1.5-7.4; p = 0.004); however, in female nonsmokers, the proportion of L allele carriers did not differ between patients and controls, nor did it differ between 108 patients with lung squamous cell carcinoma and 100 controls. Kikuchi et al. (2005) suggested that a large (GT)n repeat in the HMOX1 gene promoter may be associated with the development of lung adenocarcinoma in Japanese male smokers. - CDKN1A Polymorphism and Susceptibility to Lung Cancer Sjalander et al. (1996) found an increased frequency of the p21 arg31 allele (116899.0001) in lung cancer patients, especially in comparison with patients with chronic obstructive pulmonary disease (COPD); p = 0.004. Thus allelic variants of both p53 and its effector protein p21 may have an influence on lung cancer. - GSTM1 Polymorphism and Susceptibility to Lung Cancer Bennett et al. (1999) studied genes whose products activate (CYP1A1; 108330) or detoxify (GSTM1, 138350; GSTT1, 600436) chemical carcinogens found in tobacco smoke in never-smoking women who were exposed to environmental tobacco smoke (ETS) and developed lung cancer. Archival, paraffin-embedded, and DNA yielding, surgically resected lung cancer tissues were obtained from 106 white women who never smoked and developed lung cancer. When compared with 55 never smokers who developed lung cancer without ETS exposure, 51 never smokers who developed lung cancer with ETS exposure were more likely to be GSTM1-null homozygotes (OR, 2.6; 95% CI, 1.1-6.1). No evidence was found of associations between lung cancer risk due to ETS exposure and GSTT1 deficiency or the CYP1A1 valine variant. The authors concluded that white women who never smoke and are homozygous for the GSTM1 null allele, which occurs in about 50% of the white population, have a statistically significant greater risk of developing lung cancer from ETS. - FAS and FASL Polymorphisms and Susceptibility to Lung Cancer Zhang et al. (2005) genotyped 1,000 Han Chinese lung cancer patients and 1,270 controls for 2 functional polymorphisms in the promoter regions of the FAS and FASL genes, -1377G-A (TNFRSF6; 134637.0021) and -844T-C (TNFSF6; 134638.0002), respectively. Compared to noncarriers, there was a 1.6-fold increased risk of developing lung cancer for carriers of the FAS -1377AA genotype and a 1.8-fold increased risk for carriers of the FASL -844CC genotype. Carriers of both homozygous genotypes had a more than 4-fold increased risk, indicative of multiplicative gene-gene interaction; the increased risk was consistently observed in all subtypes of lung cancer. Zhang et al. (2005) stated that these results support the hypothesis that the FAS- and FASL-triggered apoptosis pathway plays an important role in human carcinogenesis. - CASP8 Polymorphism and Protection Against Lung Cancer Caspases are important in the life and death of immune cells and therefore influence immune surveillance of malignancies. Using a haplotype-tagging SNP approach, Sun et al. (2007) identified a 6-nucleotide deletion (-652 6N del) variant in the CASP8 promoter (601763.0004) associated with decreased risk of lung cancer in a population of Han Chinese subjects. The deletion destroyed a binding site for stimulatory protein-1 (SP1; 189906) and decreased transcription. Biochemical analyses showed that T lymphocytes with the deletion variant had lower caspase-8 activity and activation-induced cell death upon stimulation with cancer cell antigens. Case-control analyses of 4,995 individuals with cancer and 4,972 controls in a Chinese population showed that this genetic variant is associated with reduced susceptibility to multiple cancers, including lung, esophageal, gastric, colorectal, cervical, and breast cancers, acting in an allele dose-dependent manner. - CYP2A6 Polymorphism and Protection Against Lung Cancer Miyamoto et al. (1999) studied the relationship between genetic polymorphism of the CYP2A6 gene (122720) and lung cancer risk in a case-control study of Japanese. They found that the frequency of subjects homozygous for the CYP2A6 gene deletion (122720.0002), which causes lack of the enzyme activity, was lower in the lung cancer patients than in the healthy control subjects. These findings suggested that deficient CYP2A6 activity due to genetic polymorphism reduces lung cancer risk. Oscarson et al. (1999) found that this deletion allele was rare in Europeans but had a frequency of 15.1% among 96 Chinese subjects. - MPO Polymorphism and Protection Against Lung Cancer in Smokers Taioli et al. (2007) found that the -463G/A polymorphism in the MPO gene (606989.0008) conferred resistance to lung cancer among smokers. - SOX2 Amplification in Lung Cancer Bass et al. (2009) showed that a peak of genomic amplification on chromosome 3q26.33 found in squamous cell carcinomas of the lung and esophagus contains the transcription factor gene SOX2 (184429), which is necessary for normal esophageal squamous development (Que et al., 2007) and differentiation and proliferation of basal tracheal cells (Que et al., 2009), and cooperates in induction of pluripotent stem cells, as summarized by Bass et al. (2009). Bass et al. (2009) found that SOX2 expression is required for proliferation and anchorage-independent growth of lung and esophageal cell lines, as shown by RNA interference experiments. Furthermore, ectopic expression of SOX2 in this study cooperated with FOXE1 (602617) or FGFR2 (176943) to transform immortalized tracheobronchial epithelial cells. SOX2-driven tumors showed expression of markers of both squamous differentiation and pluripotency. Bass et al. (2009) concluded that these characteristics identified SOX2 as a lineage-survival oncogene in lung and esophageal squamous cell carcinoma. - DOK2 Deletion in Lung Cancer Berger et al. (2010) showed that, of 199 primary human lung adenocarcinoma samples, 37% showed a deletion of 1 copy of the DOK2 gene (604997) , which maps to chromosome 8p21.3, one of the regions most frequently deleted in human lung cancer. The deletion correlated with loss of DOK2 protein expression. Loss of the DOK1 gene (602919), which maps to chromosome 2p13.1, occurred in 1.5% of samples, and loss of the DOK3 gene (6111435), which maps to chromosome 5q35.3, occurred in 7.0% of samples. Further studies in mice showed that haploinsufficiency of Dok2 was sufficient for tumor formation, as the wildtype allele was retained in most tumor samples. Berger et al. (2010) suggested a tumor-suppressor role for DOK2 in human lung cancer. - C10ORF97 Polymorphism and Susceptibility to Nonsmall Cell Lung Cancer Shi et al. (2011) identified a 216C-T SNP (dbSNP rs2297882) in the promoter region of the C10ORF97 gene (611649) that affected the efficiency of translation. The T allele was associated with lower protein levels than the C allele. Genotyping of 418 Chinese patients with nonsmall cell lung cancer and 743 controls showed an association between the TT genotype and lung cancer compared to the TC or CC genotype (odds ratio of 1.73, p = 4.6 x 10(-5)). The findings suggested that C10ORF97 may act as a tumor suppressor gene, and that low levels of it may be associated with tumorigenesis.
Haiman et al. (2006) investigated differences in the risk of lung cancer associated with cigarette smoking in 183,813 African American, Japanese American, Latino, Native Hawaiian, and white men and women. Their analysis included 1,979 cases of incident lung ... Haiman et al. (2006) investigated differences in the risk of lung cancer associated with cigarette smoking in 183,813 African American, Japanese American, Latino, Native Hawaiian, and white men and women. Their analysis included 1,979 cases of incident lung cancer identified prospectively over an 8-year period. They found that among cigarette smokers, African Americans and Native Hawaiians are more susceptible to lung cancer than whites, Japanese Americans, and Latinos. Risch (2006) discussed the problems of dissecting racial and ethnic differences in relation to the frequency of disease. He stated that it is 'difficult to discuss the role of genetics in differences among groups, because of the fear that such discourse may reinforce notions of biologic determinism. Some insist that racial and ethnic categories are purely social and devoid of genetic content, or at least of minimal relevance.'