Lung cancer is the leading cause of cancer mortality in Western countries. It also provides an archetypal example of how inherited predisposing genetic variants may interact with an environmental influence (smoking) to modulate individual cancer risk.
The Molecular Genetics of Lung Cancer describes how the new techniques, methods and approaches of molecular genetics are being used to unravel the complexities of the mechanisms underlying lung tumorigenesis by analysis at the DNA, RNA and protein levels with potentially important implications for tumour classification, diagnosis, prognosis and treatment as well as providing new insights into how lung tumours arise and how they progress to malignancy.
Chapter 1 An Introduction to the Molecular Basis of Cancer
Cancer genes: Oncogenes. Tumour suppressor genes. Mutator genes and genetic instability. Cell cycle control genes. Apoptosis regulatory genes. Cancer, signaling and acquired capabilities.- Mutational mechanisms in cancer: Pathological mutations in inherited disease and cancer. Mutational spectra in cancer. Mutation in lung cancer.-
Chapter 2 Lung Cancer: Setting the Scene
Introduction.- Human lung development.- A short history of lung cancer research.- Lung cancer classification, staging, treatment and prognosis.- Familial aggregation of lung cancer.- Clues to candidate genes from cytogenetic abnormalities and loss of heterozygosity studies.-
Chapter 3 Genes Involved in Sporadic Forms of Lung Cancer
Oncogenes.- Tumour suppressor genes.- Apoptosis regulatory genes.- Cell cycle control and DNA damage checkpoint genes.- Mutator (DNA mismatch repair) genes and microsatellite instability.- DNA methylation and lung cancer.- The potential significance of tumour suppressor gene location in lung cancer.- The potential significance of oncogene location for chromosomal amplification and gene over-expression in lung cancer.- Telomere length and telomerase activity.-
Chapter 4 Somatic Mutation in Lung Cancer
Functional consequences of somatic mutation in lung cancer: Ras/MAP kinase pathway. Rb/E2F pathway. p53 pathway. APC/beta-catenin. TGF-beta signaling pathway. Protein phosphatases. Retinoic acid-mediated growth inhibition. DNA repair. Cell cycle control and DNA damage checkpoint genes. Apoptosis signaling pathways. Autocrine and paracrine growth factors. Angiogenesis. Metastasis. Evasion of host immunity. Other miscellaneous genes.- Order and timing of mutations and changes in gene expression in lung cancer,- Detection of mutations or aberrant methylation in sputum or plasma from lung cancer patients.- Early diagnosis and identification of prognostic factors.- Molecular genetics of chemotherapy and chemoresistance.-
Chapter 5 Genetic Approaches to Studying the Association Between Smoking and Lung Cancer
Genetic changes associated with smoking: Loss of heterozygosity and smoking. Aberrant DNA methylation in lung cancers of smokers. Telomerase activity and smoking. Gene expression studies of lung tumour tissue from smokers and non-smokers. Differences in mutation frequency/mutational spectra between smokers and non-smokers.- p53 mutations, benzo[alpha]pyrene and lung cancer: the controversy. The BPDE-induced mutagenesis model. Endogenous versus exogenous causes of mutation. A re-examination of the BPDE-induced mutagenesis model. Have some TP53 mutations occurred during cell culture rather than in the tumour? Other problems for the BPDE-induced mutagenesis model. The key importance of the quality of the IARC database.- Putting the p53/BPDE-induced mutagenesis controversy in its proper context.- The genetics of nicotine addiction.-
Chapter 6 Evidence for genetic susceptibility to lung cancer derived from polymorphism-disease association studies
Polymorphisms and polymorphism-disease association studies.- Polymorphism-disease association studies in lung cancer.- Interpreting the role of xenobiotic metabolizing enzyme polymorphisms in lung cancer.- Interpreting the role of DNA repair enzyme polymorphisms in lung cancer.- DNA repair activity for oxidative damage; the contribution of OGG1.- TP53 gene polymorphisms and lung cancer risk.-
Chapter 7 Gene Expression Studies in Lung Cancer
Studies of the expression of individual genes.- Studies of the expression of multiple genes by microarrays and similar techniques.- Lung tumour cell ontogeny may be determined by gene expression pathways that recapitulate lung development.-