It is estimated that 90% of lung cancers are caused by cigarette smoking (Doll, 1994). However, a diverse range of genetic abnormalities are seen in lung cancer cells. Some may be markers of disease progression, others may have a direct role in lung cancer
aetiology in the context of gene-environment interactions.
TP53 mutations are among the most frequent abnormalities occurring in 80-100% of SCLC and 50-80% of NSCLC. Mutations of RB1 are also seen in most SCLCs (80-90%), while they are less frequent in NSCLC
(20-30%). Abnormalities of CDKN2A (P16 INK4A) are inversely correlated with RB1 mutation; these are seen in about 60% of NSLC, while less than 1 in 10 SCLC have CDKN2A abnormalities.
Another frequent mutation is in FHIT which is abnormally spliced in about 75% of both SCLC and NSCLC. It has been suggested that the gene is a target of tobacco carcinogens and asbestos. Upregulation of the RNA component of telomerase is seen in most lung cancers (98% of SCLC). This may provide a target for future therapies.
A host of other genes have been implicated in lung cancer including MYCN, KRAS, TP73, MADH2, MADH4, PPP2R1B, and
PTEN. Common chromosomal abnormalities include del(3p) and del(9p).
Common polymorphisms of certain genes may help explain why some smokers (and passive smokers) are more susceptible to lung cancer than others. In particular, the GSTM1 null allele is associated with increased risk of lung cancer,
especially in women.
Kohno T, Yokota J How many tumor suppressor genes are involved in human lung carcinogenesis ? [Review] Carcinogenesis 1999;20(8):1403-10 Related articles (PubMed)
Braithwaite KL, Rabbitts PH Multi-step evolution of lung cancer. [Review] Semin Cancer Biol 1999; 9(4):255-65 Related articles (PubMed)
Amos CI, et al. Is there a genetic basis for lung cancer susceptibility? Recent Results Cancer Res 1999; 151:3-12 Related articles (PubMed)
Bennett WP, et al. Molecular epidemiology of human cancer risk: gene-environment interactions and p53 mutation spectrum in human lung cancer. J Pathol 1999; 187(1):8-18 Related articles (PubMed)
Doll R, et al. Mortality in relation to smoking: 40 years' observations on male British doctors. BMJ 1994; 309(6959):901-11 Related articles (PubMed)
Medline Search: lung cancer AND genetics AND review[PT] (PubMed)
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 Lung Cancer Genetics
Lung Cancer : Clinical and Epidemiological Information
 del(1p36) in Lung Cancer
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Medline Search: lung cancer[TI] AND chromosome 1 AND deletion (PubMed)
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Lung Cancer Genetics
Lung Cancer : Clinical and Epidemiological Information
Chromosme 1
| del(3p) in Lung Cancer
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Hung J, et al. Allele-specific chromosome 3p deletions occur at an early stage in the pathogenesis of lung carcinoma. JAMA 1995; 273(7):558-63 Related articles (PubMed)
Hosoe S, et al. Detailed deletion mapping of the short arm of chromosome 3 in small cell and non-small cell carcinoma of the lung. Lung Cancer 1994; 10(5-6):297-305 Related articles (PubMed)
Kohno H, et al. p53 mutation and allelic loss of chromosome 3p, 9p of preneoplastic lesions in patients with nonsmall cell lung carcinoma. Cancer. 1999; 85(2):341-7 Related articles (PubMed)
Medline Search: lung cancer[TI] AND chromosome 3 AND deletion (PubMed)
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Lung Cancer Genetics
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Chromosme 3
| del(9p) in Lung Cancer
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Kishimoto Y, et al. Allele-specific loss in chromosome 9p loci in preneoplastic lesions accompanying non-small-cell lung cancers. J Natl Cancer Inst. 1995; 87(16):1224-9 Related articles (PubMed)
Kohno H, et al. p53 mutation and allelic loss of chromosome 3p, 9p of preneoplastic lesions in patients with nonsmall cell lung carcinoma. Cancer. 1999; 85(2):341-7 Related articles (PubMed)
Medline Search: lung cancer[TI] AND chromosome 9 AND deletion (PubMed)
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Lung Cancer Genetics
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Chromosme 9
| Telomerase Activity and Lung Cancer
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Telomerase is an enzyme that adds TTAGGG nucleotide repeats onto the ends of vertebrate chromosomal DNA (telomeres) to compensate for losses that occur with each round of DNA replication. Normal somatic cells do not have telomerase activity and stop
dividing when the telomeric ends of the chromosomes have been shortened to a critical length. It is thought that some cancer cells become "immortalized" because they express telomerase and can therefore continue to proliferate indefinitely.
Unlike normal lung tissues, some lung cancers express telomerase. A number of studies suggest that telomerase expression is an adverse prognostic factor for lung cancers. In a study of 91 lung tumours (Sarvesvaran, 1999) found that upregulation of the
RNA component of telomerase occured in 98% of SCLCs. They suggest that SCLC would be a prime target for therapies directed at the RNA component of human telomerase.
Xinarianos G, et al. Telomerase activity in non-small cell lung carcinomas correlates with smoking status. Int J Oncol 1999; 15(5):961-5 Related articles (PubMed)
Taga S, et al. Prognostic impact of telomerase activity in non-small cell lung cancers. Ann Surg. 1999; 230(5):715-20 Related articles (PubMed)
Marchetti A, et al. Telomerase activity as a prognostic indicator in stage I non-small cell lung cancer. Clin Cancer Res. 1999; 5(8):2077-81 Related articles (PubMed)
Sarvesvaran J, et al. Is small cell lung cancer the perfect target for anti-telomerase treatment? Carcinogenesis 1999; 20(8):1649-51 Related articles (PubMed)
Hiyama K, et al. Telomerase activity in small-cell and non-small-cell lung cancers. J Natl Cancer Inst 1995; 87(12):895-902 Related articles (PubMed)
Medline Search: telomerase[TI] AND lung cancer (PubMed)
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- Related Resources
- TERC gene (Telomerase RNA component)
| Smoking, Genes, and Susceptibility to Lung Cancer
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It is estimated that 90% of lung cancers are caused by cigarette smoking (Doll, 1994). Knowledge about complex gene-environment interactions relating to tabacco smoking and lung cancer are emerging.
Glutathione S-transferases including GSTM1, GSTM3, GSTP1 and GSTT1 play a role in
the detoxification of metabolites of carcinogens in tobacco smoke. There is some evidence to suggest that people with common polymorphisms of these genes may have an increased susceptibility to lung cancer when exposed to Tobacco. There are conflicting
results about the relationship between specific polymorphisms and lung cancer. Research is ongoing to clarify their roles in gene-environment interactions.
In a case-control study of 136 NSCLC patients (Tang, 1998) results suggested that the effect of the GSTM1 null genotype is greatest in female smokers. Other research indicates that people with the GSTM1 null allele may be more suseptible to lung cancer
on exposure to envoronmental tabacco smoke .
In a study of 71 NSCLCs (Xinarianos, 1999) a significant correlation was found between the presence of telomerase activity and smoking status at diagnosis.
Spitz MR, et al. Genetic susceptibility to tobacco carcinogenesis. [Review] Cancer Invest 1999;17(8):645-59 Related articles (PubMed)
Shields PG. Molecular epidemiology of lung cancer. [Review] Ann Oncol 1999;10 Suppl 5:S7-11 Related articles (PubMed)
Jourenkova-Mironova N, et al. Role of glutathione S-transferase GSTM1, GSTM3, GSTP1 and GSTT1 genotypes in modulating susceptibility to smoking-related lung cancer. Pharmacogenetics 1998; 8(6):495-502 Related articles (PubMed)
Tang DL, et al. Associations between both genetic and environmental biomarkers and lung cancer: evidence of a greater risk of lung cancer in women smokers. Carcinogenesis 1998; 19(11):1949-53 Related articles (PubMed)
Xinarianos G, et al. Telomerase activity in non-small cell lung carcinomas correlates with smoking status. Int J Oncol 1999; 15(5):961-5 Related articles (PubMed)
Doll R, et al. Mortality in relation to smoking: 40 years' observations on male British doctors. BMJ 1994; 309(6959):901-11 Related articles (PubMed)
Medline Search: lung cancer AND smoking AND genetics (PubMed)
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- GSTM1 gene
- Smoking and Smoking Ceasation
- Lung Cancer - Causes and Prevention
| Environmental Tabacco Smoke and lung Cancer
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There is now mounting evidence for an increased risk of lung cancer from exposure to environmental tobacco smoke (ETS). Epidemiological, biochemical, and toxicological studies indicate there is a causal association between ETS and lung cancer. In a large
meta-analysis of 4,626 cases (Hackshaw, 1997) the excess risk of lung cancer was 24% (95% confidence interval 13% to 36%) in non-smokers who lived with a smoker. About 1 in 6 nonsmokers are exposed
to tobacco smoke from smokers in their own homes (UK). Exposure to ETS has also been shown to increase risk of heart disease.
Research suggests that some people may be more suseptible to lung cancer on exposure to ETS. Bennett (1999) found that non-smokers with a common genetic polymorphism of GSTM1 have a statistically significant greater risk of lung
cancer from ETS. About half the population carry this polymorphism; the "GSTM1 null allele". Further research is needed to confirm these findings.
Hackshaw AK, et al. The accumulated evidence on lung cancer and environmental tobacco smoke. BMJ 1997; 315(7114):980-8 Related articles (PubMed)
Law MR, et al. Environmental tobacco smoke exposure and ischaemic heart disease: an evaluation of the evidence. BMJ 1997; 315(7114):973-80 Related articles (PubMed)
Bennett WP, et al. Environmental Tobacco Smoke, Genetic Susceptibility, and Risk of Lung Cancer in Never-Smoking Women J Natl Cancer Inst. 1999; 91(23): 2009-14 Related articles
Medline Search: lung cancer AND smoking AND environmental (PubMed)
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- Smoking and Smoking Ceasation
- Lung Cancer - Causes and Prevention
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