Cancer Research UK : Lung Cancer molecular biology and genetics

Lung Cancer molecular biology and genetics

No clearly inherited forms of lung cancer have been described, although the disease is occasionally seen in individuals with Li-Fraumeni syndrome, which is caused by inherited faults in the TP53 gene.1 In these cases, the disease develops at an earlier than expected age.

Carriers of germ-line mutations in the retinoblastoma gene RB1 are also at an increased risk.2

Although the greatest risk factor for developing lung cancer is smoking, a recent meta-analysis suggests that individuals with a family history of lung cancer are at an increased risk of developing the disease.3 This is particularly true for families with a number of affected individuals and where cases have been diagnosed at a young age.

By looking at the incidence data in people who had never smoked, the meta-analysis suggests that there is a genetic component to this increased risk. A susceptibility locus for familial lung cancer has been mapped to chromosome region 6q23-25,4 and recently a candidate tumour suppressor, p34, has been found in this region.5

This gene does not seem to be involved in familial lung cancer susceptibility, but may play a role in sporadic cases of the disease.5

As many smokers do not develop lung cancer it is likely that inherited factors influence the effects of tobacco. There is considerable interest in variants of genes that help detoxify the carcinogens in tobacco smoke, such as members of the cytochrome P450, GST and NAT gene families.6 The capacity to repair DNA damage is also reduced in people with lung cancer – in the laboratory, cells from lung cancer patients are less able to repair DNA damage caused by chemicals in tobacco than cells from normal individuals.7

Lung cancer progression is characterised by cumulative alterations in key molecules involved in the cell cycle, signalling and angiogenesis pathways. Most lung cancer patients demonstrate chromosomal abnormalities at the site of tumour suppressor genes or have mutations in known oncogenes. Loss of heterozygosity is common, particularly at the chromosome regions 3p (which includes the FHIT gene, a candidate tumour suppressor mutated in over 70% of lung cancers), 9p (including the p16INK4a, p19ARF genes, which are involved in the RB signalling pathway), 13q (RB) and 17p (TP53).8

Loss of 3p and 9p are thought to be early events in lung cancer development, whereas loss of 17p occurs later.8 Distinct patterns of chromosomal imbalances, including duplications and loss of heterozygosity, have been observed in adenocarcinomas from both smokers and non-smokers.9, 10

Many oncogenes have been implicated in lung carcinogenesis, including EGFR, erbB2, MYC and K-RAS.7, 11 The most commonly observed activating K-RAS mutations have been correlated with exposure to tobacco carcinogens.12

Over the past 20 years improvements in the understanding of the molecular and biological basis of lung cancer have led to the identification of a number of suitable targets for treatment or chemoprevention of lung cancer. One of the most closely investigated therapeutic targets is the epidermal growth factor receptor (EGFR). Overexpression of EGFR is common in lung cancer, and correlates with a poor prognosis.13

Lung cancers also often overexpress the EGFR ligands, EGF and TGFα, establishing autocrine loops; disturbing these loops is the main aim of EGFR-targeted therapies. Early clinical trials of two EGFR inhibitors, gefitinib (Iressa®) and erlotinib (Tarceva®) showed that certain subsets of patients did respond to these drugs. These groups harboured specific mutations in EGFR, and an individual’s response could be correlated with their mutation type.13

However, Erlotinib has also shown a survival benefit for an unselected population group,14 and is now licensed in Europe for patients with advanced NSCLC that has continued to grow after chemotherapy. Investigation of markers for response to erlotinib and gefitinib is continuing. A number of other EGFR-targeted therapies are also in development.15

The cyclo-oxygenase enzyme COX2 is activated both by oncogenes and the carcinogens in tobacco smoke, and is frequently over-expressed in NSCLC, where it is associated with a worse prognosis in early-stage disease.7 Overexpression of COX2 is linked to inhibition of apoptosis, and increased angiogenesis and metastasis.7 A clinical trial has demonstrated that the COX2 inhibitor celecoxib can enhance the response to chemotherapy in early-stage NSCLC.16

Considerable effort is being directed towards the identification of biomarkers for early detection and prognosis, which would also be useful in monitoring the success of chemoprevention therapies.17

References

Nichols, K.E., et al., Germ-line p53 mutations predispose to a wide spectrum of early-onset cancers. Cancer Epidemiol Biomarkers Prev, 2001. 10(2): p. 83-7
Wikenheiser-Brokamp, K.A., Retinoblastoma regulatory pathway in lung cancer. Curr Mol Med, 2006. 6(7): p. 783-93
Matakidou, A., T. Eisen, and R.S. Houlston, Systematic review of the relationship between family history and lung cancer risk. Br J Cancer, 2005. 93(7): p. 825-33
Bailey-Wilson, J.E., et al., A major lung cancer susceptibility locus maps to chromosome 6q23-25. Am J Hum Genet, 2004. 75(3): p. 460-74
Wang, M., et al., Identification of a novel tumor suppressor gene p34 on human chromosome 6q25.1. Cancer Res, 2007. 67(1): p. 93-9
Bouchardy, C., et al., Metabolic genetic polymorphisms and susceptibility to lung cancer. Lung Cancer, 2001. 32(2): p. 109-12
Breuer, R.H., P.E. Postmus, and E.F. Smit, Molecular pathology of non-small-cell lung cancer. Respiration, 2005. 72(3): p. 313-30
Soria, J.-C., et al., Chemoprevention of lung cancer. The Lancet Oncology, 2003. 4(11): p. 659
Wong, M.P., et al., Primary Adenocarcinomas of the Lung in Nonsmokers Show a Distinct Pattern of Allelic Imbalance. Cancer Res, 2002. 62(15): p. 4464-4468
Sy, S.M., et al., Distinct patterns of genetic alterations in adenocarcinoma and squamous cell carcinoma of the lung. Eur J Cancer, 2004. 40(7): p. 1082-94
Pisick, E., S. Jagadeesh, and R. Salgia, Small cell lung cancer: from molecular biology to novel therapeutics. J Exp Ther Oncol, 2003. 3(6): p. 305-18
Gao, H.G., et al., Distribution of p53 and K-ras mutations in human lung cancer tissues. Carcinogenesis, 1997. 18(3): p. 473-8
Sharma, S.V., et al., Epidermal growth factor receptor mutations in lung cancer. Nat Rev Cancer, 2007. 7(3): p. 169-81
Shepherd, F.A., et al., Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med, 2005. 353(2): p. 123-32
Renehan, A.G., et al., Insulin-like growth factor (IGF)-I, IGF binding protein-3, and cancer risk: systematic review and meta-regression analysis. The Lancet, 2004. 363(9418): p. 1346
Altorki, N.K., et al., Celecoxib, a selective cyclo-oxygenase-2 inhibitor, enhances the response to preoperative paclitaxel and carboplatin in early-st age non-small-cell lung cancer. J Clin Oncol, 2003. 21(14): p. 2645-50
Hirsch, F.R. and S.M. Lippman, Advances in the biology of lung cancer chemoprevention. J Clin Oncol, 2005. 23(14): p. 3186-97

Lung Cancer molecular biology and genetics

References

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