Lung Cancer

A number sign (#) is used with this entry because mutations in several genes are associated with lung cancer. Both germline and somatic mutations have been identified in the EGFR (131550) and p53 (TP53; 191170) genes, and somatic mutations have been identified in the KRAS (190070), BRAF (164757), ERBB2 (164870), MET (164860), STK11 (602216), PIK3CA (171834), and PARK2 (602544) genes. Amplification of several genes, including EGFR, ERBB2, MET, PIK3CA, and NKX2-1 (600635), is also associated with lung cancer. Deletion of several genes, including DOK2 (604977), is also associated with lung cancer. An ALK/EML4 fusion gene (see 105590) has been identified in lung cancer. Several polymorphisms are associated with lung cancer susceptibility, including a 5-prime SNP in the ERCC6 gene (609413) and SNPs in the nicotinic acetylcholine receptor gene cluster on chromosome 15q25.1 (see LNCR2; 612052). Lung cancer susceptibility loci have been mapped to chromosome 6q23-q25 (LNCR1; 608935), 5p15 (LNCR3; 612571), 6p21 (LNCR4; 612593), and 3q28 (LNCR5; 614210). Deletion alleles in the CYP2A6 (122720) and CASP8 (601763) genes are associated with a reduced risk of lung cancer in Japanese and Han Chinese individuals, respectively. A SNP in the MPO gene (606989) is associated with reduced risk of lung cancer in smokers.

Description

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 (summary by Herbst et al., 2008).

Clinical Features

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).

Inheritance

Braun et al. (1994) conducted a genetic analysis of lung cancer mortality in the National Academy of Sciences/National Research Council Twin Registry. The registry is composed of 15,924 male twin pairs who were born in the U.S. between 1917 and 1927 and who served in the armed forces during World War II. As evidence for a genetic effect on lung cancer, they required concordance for lung cancer death to be greater among monozygotic than among dizygotic twin pairs. No genetic effect on lung cancer mortality was observed. The ratio of observed to expected concordance among monozygotic twins did not exceed that among dizygotic twins, even though monozygotic twin pairs were more likely to be concordant for smoking than dizygotic twin pairs in this population. A cohort analysis (accounting for age, sex, race, and smoking intensity) of lung cancer mortality found no lung cancer deaths during the 300 person-years of follow-up among 47 monozygotic twins smokers whose smoking twin died of lung cancer, even though smoking histories were very similar within twin pairs.

In a multicenter study of lung cancer in lifetime nonsmokers in the United States, 646 female lung cancer patients and 1,252 population controls were interviewed regarding history of cancer in their first-degree relatives. Wu et al. (1996) summarized the findings. A 30% increased risk was associated with a history of respiratory tract cancer in parents or sibs after adjustment for exposure to environmental tobacco smoke in adult life. Lung cancer, which represented approximately two-thirds of the respiratory tract cancers, occurred more frequently in first-degree relatives of lung cancer patients than in comparable relatives of population controls. A significant 3-fold increased risk for lung cancer was associated with lung cancer diagnosed in mothers and sisters. Wu et al. (1996) also observed the increased risk in relation to family history of lung cancer among parents and sibs who were smokers as well as in those who were nonsmokers. The association with family history of lung cancer was strengthened when the analysis was restricted to adenocarcinoma of the lung. However, the authors pointed out that there was no association between family history of other cancers and risk of lung cancer in nonsmokers.

Population Genetics

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.'

Pathogenesis

In the DNA from 1 colon and 2 lung carcinoma cell lines, Perucho et al. (1981) demonstrated the same or closely related transforming elements. By DNA-mediated gene transfer, mouse fibroblasts could be morphologically transformed and rendered tumorigenic in nude mice.

Starting from studies of lung adenocarcinomas, Ramaswamy et al. (2003) explored the molecular differences between human primary tumors and metastases by comparing their gene expression profiles. They found a 17-gene-expression signature that distinguished primary from metastatic adenocarcinomas. Notably, they found that a subset of primary tumors resembled metastatic tumors with respect to this gene-expression signature. They confirmed their findings by applying the expression signature to data on 279 primary solid tumors of diverse types. They found that solid tumors carrying the gene-expression signature were most likely to be associated with metastasis and poor clinical outcome (P less than 0.03). These results suggested that the metastatic potential of human tumors is encoded in the bulk of a primary tumor, thus challenging the notion that metastases arise from rare cells within a primary tumor that have the ability to metastasize. The results supported the idea that some primary tumors are preconfigured to metastasize, and that this propensity is detectable at the time of initial diagnosis.

A considerable proportion of the refined gene-expression signature that Ramaswamy et al. (2003) found to be associated with metastasis seemed to be derived from nonepithelial components of the tumor. Specifically, these included genes encoding the type 1 collagens (COL1A1, 120150; COL1A2, 120160) whose expression is restricted to fibroblasts. Some of the 17 genes constituting the signature were upregulated in metastases, others were downregulated. The upregulation of collagen genes in primary tumors with metastatic potential is consistent with observations that epithelial-mesenchymal interactions are critical determinants of tumor cell behavior. High levels of type 1 collagen in metastatic lesions and in the serum of individuals with metastatic disease have been reported. In general, the findings were consistent with the existence of a molecular program of metastasis that is shared by multiple solid-tumor types, suggesting the possible existence of therapeutic targets common to different cancers.

Brock et al. (2008) analyzed methylation of 7 genes in tumor tissue and lymph nodes from 51 patients with stage I nonsmall cell lung cancer (NSCLC) who underwent curative resection but had a recurrence within 40 months and from 116 age-, sex-, NSCLC stage-, and date of surgery-matched patients who underwent curative resection and did not have a recurrence within 40 months. In a multivariate model, the authors found that promoter methylation of the CDKN2A (600160), CDH13 (601364), RASSF1A (605082), and APC (611731) genes in tumors and in histologically tumor-negative lymph nodes was associated with tumor recurrence, independently of NSCLC stage, age, sex, race, smoking history, and histologic characteristics of the tumor. Methylation of the promoter regions of CDKN2A and CDH13 in both tumor and mediastinal lymph nodes was associated with an odds ratio of recurrent cancer of 15.50 in the original cohort and an OR of 25.25 when the original cohort was combined with an independent validation cohort of 20 patients with stage I NSCLC.

Winslow et al. (2011) modeled human lung adenocarcinoma, which frequently harbors activating point mutations in KRAS (190070) and inactivation of the p53 (191170) pathway, using conditional alleles in mice. Lentiviral-mediated somatic activation of oncogenic Kras and deletion of p53 in the lung epithelial cells of Kras(LSL-G12D/+);p53(flox/flox) mice initiates lung adenocarcinoma development. Although tumors are initiated synchronously by defined genetic alterations, only a subset becomes malignant, indicating that disease progression requires additional alterations. Identification of the lentiviral integration sites allowed Winslow et al. (2011) to distinguish metastatic from nonmetastatic tumors and determine the gene expression alterations that distinguish these tumor types. Cross-species analysis identified the NK2-related homeobox transcription factor Nkx2-1 (600635) as a candidate suppressor of malignant progression. In this mouse model, Nkx2-1 negativity is pathognomonic of high-grade poorly differentiated tumors. Gain- and loss-of-function experiments in cells derived from metastatic and nonmetastatic tumors demonstrated that Nkx2-1 controls tumor differentiation and limits metastatic potential in vivo. Interrogation of Nkx2-1-regulated genes, analysis of tumors at defined developmental stages, and functional complementation experiments indicated that Nkx2-1 constrains tumors in part by repressing the embryonically restricted chromatin regulator Hmga2 (600698). Whereas focal amplification of NKX2-1 in a fraction of human lung adenocarcinomas had focused attention on its oncogenic function, Winslow et al. (2011) stated that their data specifically linked Nkx2-1 downregulation to loss of differentiation, enhanced tumor seeding ability, and increased metastatic proclivity. Winslow et al. (2011) concluded that the oncogenic and suppressive functions of Nkx2-1 in the same tumor type substantiate its role as a dual function lineage factor.

De Bruin et al. (2014) sequenced 25 spatially distinct regions from 7 operable NSCLCs and found evidence of branched evolution, with driver mutations arising before and after subclonal diversification. There was pronounced intratumor heterogeneity in copy number alterations, translocations, and mutations associated with APOBEC (see 600130) cytidine deaminase activity. Despite maintained carcinogen exposure, tumors from smokers showed a relative decrease in smoking-related mutations over time, accompanied by an increase in APOBEC-associated mutations. In tumors from former smokers, genome doubling occurred within a smoking-signature context before subclonal diversification, which suggested that a long period of tumor latency had preceded clinical detection. De Bruin et al. (2014) concluded that regionally separated driver mutations, coupled with the relentless and heterogeneous nature of the genome instability processes, are likely to confound treatment success in NSCLC.

Zhang et al. (2014) applied multiregion whole-exome sequencing to 11 localized lung adenocarcinomas. All tumors showed clear evidence of intratumor heterogeneity. On average, 76% of all mutations and 20 out of 21 known cancer gene mutations were identified in all regions of individual tumors, which suggested that single-region sequencing may be adequate to identify the majority of known cancer gene mutations in localized lung adenocarcinomas. With a median follow-up of 21 months after surgery, 3 patients had relapsed, and all 3 had significantly larger fractions of subclonal mutations in their primary tumors than patients without relapse. Zhang et al. (2014) concluded that a larger subclonal mutation fraction may be associated with increased likelihood of postsurgical relapse in patients with localized lung adenocarcinomas.

Reviews of Lung Cancer Pathogenesis

Herbst et al. (2008) reviewed lung cancer with a focus on the origins and biology of squamous cell carcinoma and adenocarcinoma, which constitute the majority of diagnosed lung cancers.

Clinical Management

In a multiinstitutional phase II trial, Fukuoka et al. (2003) found a higher rate of response to the tyrosine kinase inhibitor gefitinib (Iressa) in Japanese patients with nonsmall cell lung cancer (NSCLC) than in a predominantly European-derived population (27.5% vs 10.4%). See 'EGFR Mutations and Lung Cancer' in MOLECULAR GENETICS for information on EGFR (131550) mutations associated with gefitinib-responsive lung cancer.

In a randomized control trial of 1,217 East Asian patients with nonsmall cell lung cancer, Mok et al. (2009) found that the 12-month rate of progression-free survival was 24.9% in patients treated with gefitinib and 6.7% in those treated with carboplatin-paclitaxel. In the subgroup of 261 patients who were positive for an EGFR mutation, progression-free survival was significantly longer among those who received gefitinib than among those who received carboplatin-paclitaxel, whereas in the subgroup of 176 patients who were negative for a mutation, progression-free survival was significantly longer among those who received carboplatin-paclitaxel. The findings indicated that gefitinib is superior to carboplatin-paclitaxel as an initial treatment for pulmonary adenocarcinoma among nonsmokers or former light smokers in East Asia, and showed that the presence in the tumor of an EGFR mutation is a strong predictor of a better outcome with gefitinib.

Rosell et al. (2009) concluded that large-scale screening of patients with lung cancer for EGFR mutations is feasible and can have a role in treatment decisions. EGFR mutations were identified in tumor tissue of 350 (16.6%) of 2,105 Spanish patients with nonsmall cell lung cancer. Mutations were more frequent in women (69.7%), in patients who had never smoked (66.6%), and in those with adenocarcinomas (80.9%). The mutations were deletions in exon 19 (62.2%) and L858R (131550.0002) (37.8%). Median progression-free survival and overall survival for 217 patients who received erlotinib were 14 months and 27 months, respectively. Multivariate analysis showed an association between poor progression-free survival and male sex (hazard ratio of 2.94), and the presence of the L858R mutation (hazard ratio of 1.92) as compared with a deletion in exon 19. The most common adverse events were mild rashes and diarrhea. The results suggested that EGFR-mutant lung cancer is a distinct class of nonsmall cell lung cancer.

Bivona et al. (2011) used a pooled RNAi screen to show that knockdown of FAS (134637) and several components of the NF-kappa-B pathway (see 164011) specifically enhanced cell death induced by the EGFR (131550) tyrosine kinase inhibitor (TKI) erlotinib in EGFR-mutant lung cancer cells. Activation of NF-kappa-B through overexpression of c-FLIP (603599) or IKK (603258), or silencing of I-kappa-B (see 164008), rescued EGFR-mutant lung cancer cells from EGFR TKI treatment. Genetic or pharmacologic inhibition of NF-kappa-B enhanced erlotinib-induced apoptosis in erlotinib-sensitive and erlotinib-resistant EGFR-mutant lung cancer models. Increased expression of the NF-kappa-B inhibitor I-kappa-B predicted improved response and survival in EGFR-mutant lung cancer patients treated with EGFR TKI. Bivona et al. (2011) concluded that their data identified NF-kappa-B as a potential companion drug target, together with EGFR, in EGFR-mutant lung cancers and provided insight into the mechanisms by which tumor cells escape from oncogene dependence.

Zhang et al. (2012) reported increased activation of AXL (109135) and evidence for epithelial-to-mesenchymal transition (EMT) in multiple in vitro and in vivo EGFR-mutant lung cancer models with acquired resistance to erlotinib in the absence of the EGFR T790M alteration (131550.0006) or MET activation. Genetic or pharmacologic inhibition of AXL restored sensitivity to erlotinib in these tumor models. Increased expression of AXL and, in some cases, of its ligand GAS6 (600441) was found in EGFR-mutant lung cancers obtained from individuals with acquired resistance to tyrosine kinase inhibitors.

Mapping

In 3 varieties of nonsmall cell cancer of the lung, Weston et al. (1989) found evidence of loss of heterozygosity in chromosome 17p and chromosome 11. Only a minority had loss of heterozygosity involving a chromosomal locus on 3p previously shown to be lost consistently in small cell cancer of the lung (SCLC1; 182280).

Dai et al. (2003) used restriction landmark genomic scanning (RLGS) to identify novel amplified sequences in primary lung carcinomas and lung cancer cell lines. Enhanced RLGS fragments indicative of gene amplification were observed in tumors and cell lines of both nonsmall cell lung cancer and small cell lung cancer. The authors identified a novel amplicon on chromosome 11q22, in addition to previously reported amplicons that include oncogenes MYC (190080), MYCL1 (164850), and previously identified amplification of chromosomal regions 6q21 and 3q26-27. The amplified region of 11q22 was refined to 0.92 Mb in 1 patient sample. Immunohistochemistry and Western blot analysis identified CIAP1 (BIRC2; 601712) and CIAP2 (BIRC3; 601721) as potential oncogenes in this region, since both are overexpressed in multiple lung cancers with or without higher copy numbers.

Bailey-Wilson et al. (2004) mapped a major lung cancer susceptibility locus to chromosome 6q23-q25 (LNCR1; 608935).

Molecular Genetics

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.

The Cancer Genome Atlas Research Network (2012) profiled 178 lung squamous cell carcinomas to provide a comprehensive landscape of genomic and epigenomic alterations, and showed that the tumor type is characterized by complex genomic alterations with a mean of 360 exonic mutations, 165 genomic rearrangements, and 323 segments of copy number alteration per tumor. The Cancer Genome Atlas Research Network (2012) found statistically recurrent mutations in 11 genes, including mutations in TP53 in nearly all specimens. Previously unreported loss-of-function mutations were seen in the HLA-A class I major histocompatibility gene (142800). Significantly altered pathways included NFE2L2 (600492) and KEAP1 (606016) in 34%, squamous differentiation genes in 44%, phosphatidylinositol-3-OH kinase pathway genes in 47%, and CDKN2A (600160) and RB1 (614041) in 72% of tumors. The Cancer Genome Atlas Research Network (2012) identified a potential therapeutic target in most tumors, offering new avenues of investigation for the treatment of squamous cell lung cancers.

The Cancer Genome Atlas Research Network (2014) reported molecular profiling of 230 resected lung adenocarcinomas using mRNA, microRNA, and DNA sequencing integrated with copy number, methylation, and proteomic analyses. High rates of somatic mutation were observed (mean 8.9 mutations per megabase). Eighteen genes were statistically significantly mutated, including RIT1 (609591) with activating mutations and MGA (616061) with loss-of-function mutations that were mutually exclusive with focal MYC amplification. EGFR (131550) mutations were more frequent in female patients, whereas mutations in RBM10 (300080) were more common in males. Aberrations in NF1 (613113), MET (164860), ERBB2 (164870), and RIT1 occurred in 13% of cases and were enriched in samples otherwise lacking an activated oncogene, suggesting a driver role for these events in certain tumors. DNA and mRNA sequences from the same tumor highlighted splicing alterations driven by somatic genomic changes, including exon 14 skipping in MET mRNA in 4% of cases. MAPK (see 176948) and PI3K (see 601232) pathway activity, when measured at the protein level, was explained by known mutations in only a fraction of cases, suggesting additional, unexplained mechanisms of pathway activation.

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 (611435), 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 (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.

Cytogenetics

ALK/EML4 Fusion Gene

Soda et al. (2007) identified a fusion gene, ALK/EML4 (see 105590), that was present in 5 of 75 Japanese nonsmall cell lung cancer patients examined. None of these patients had mutations in EGFR.

Copy Number Variation at the MAPKAPK2 Locus

Liu et al. (2012) investigated the role in lung cancer of a copy number variant (CNV), g.CNV-30450, which spans the MAPKAPK2 (602006) promoter region and has 1.7-kb sequences from -1098 to approximately +664 nucleotides to the initiation transcription codon. This variant was found to have an allele frequency of 6/30 (0.20) in the Database of Genetic Variants. The authors detected 2, 3, or 4 copies of g.CNV-30450 among 4,789 Chinese individuals. Liu et al. (2012) investigated the association between cancer risk and g.CNV-30450 in 3 independent case-control studies of 2,332 individuals with lung cancer and 2,457 controls, and also studied the effects of this CNV on cancer prognosis in 1,137 individuals with lung cancer with survival data in Southern and Eastern Chinese populations. Liu et al. (2012) found that those subjects who had 4 copies of g.CNV-30450 had an increased cancer risk (OR = 1.94, 95% CI = 1.61-2.35) and, in individuals with lung cancer, a worse prognosis (with a median survival time of only 9 months) (hazard ratio = 1.47, 95% CI = 1.22-1.78) compared with those with 2 or 3 copies (with a median survival time of 14 months). Liu et al. (2012) also showed that 4 copies of g.CNV-30450 significantly increased MAPKAPK2 expression, both in vitro and in vivo, compared with 2 or 3 copies.