Chapter 2 - Genetic Basis for Susceptibility to Lung Cancer: Recent Progress and Future Directions
Section snippets
Introduction: Overview of Studies on Genetic and Environmental Factors Involved in Lung Cancer Susceptibility
Lung cancer is the leading cause of cancer death worldwide (Sun et al., 2007). Therefore, identification of genetic factors as well as environmental factors is very important in developing novel methods of lung cancer prevention. Since cigarette smoking is the major environmental risk factor for the development of lung cancer, genetic factors for tobacco-induced lung cancer have been extensively investigated by candidate gene association studies for many years. Genes involved in the metabolism
Differences in the Process of Lung Cancer Development Between Smokers and Never-Smokers
Lung cancers are divided into the two major categories of small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) from clinicopathological aspects (Sun et al., 2007). NSCLCs are further divided into three major histological types, adenocarcinoma (ADC), squamous cell carcinoma (SQC), and large cell carcinoma (LCC). However, LCC is thought to be poorly or undifferentiated forms of and more heterogeneous than the other three types of lung cancer, and only limited information is
Candidate Gene Association Studies
Histological heterogeneity of lung cancer has been known for many years. However, lung cancers in never-smokers have not been classified into a different disease until recently. Therefore, in the last two decades, genetic susceptibility for tobacco-induced lung cancer has been extensively investigated by a candidate gene approach focusing on the metabolism of tobacco smoke carcinogens and the suppression of tobacco-induced genetic alterations. Lung cancer cells developed in smokers have been
Genome-Wide Association Studies
Recent GWA studies have lead to the identification of a number of candidate lung cancer susceptibility genes (Table III). Three chromosomal loci, 15q24-25.1, 5p15.33, and 6p21, have been shown to be associated with lung cancer risk in Europeans and Americans (Amos et al., 2008, Hung et al., 2008, McKay et al., 2008, Thorgeirsson et al., 2008, Wang et al., 2008). The chromosome 15q24-25.1 region contains the nicotinic acetylcholine receptor subunit genes, CHRNA3 and CHRNA5, and their products
Assessment of Lung Cancer Risk in Each Individual by Combined Genotypes (Gene–Gene Interactions)
For many years, gene–gene interaction has been investigated among candidate genes with functional polymorphisms. In particular, interactions among CYP-family genes and GST-family genes have been indicated by both molecular epidemiological studies and biological studies (Alexandrov et al., 2002, Bartsch et al., 2000, Schwartz et al., 2007). Biologically, activities of CYP1A1 and GSTM1 are a critical determinant for the dose of carcinogenic BPDE and other DNA-reactive PAH; however, there has been
Smoking-Associated Differences (Gene–Environment Interactions)
Cigarette smoking increases the risk for all three major histological types of lung cancers, although the risk is less for ADC than for SQC and SCLC (Govindan, 2010, Sobue et al., 2002, Subramanian and Govindan, 2008, Sun et al., 2007, Travis et al., 2004). The smoking habit is largely attributed to nicotine dependence, because nicotine is addictive. Therefore, although nicotine itself is not carcinogenic, it has been assumed that nicotine dependence is indirectly associated with lung cancer
Necessity of Further Association Studies
To obtain more conclusive information on the genetic basis for susceptibility to lung cancer, we will have to analyze all the polymorphic sequences in the human genome for association with susceptibility. Various SNP array platforms have been developed to date, and the numbers of SNPs analyzable in one platform have been increasing year by year. In 2010, over a million SNPs can be analyzed by a single SNP array. However, it has been assumed that there are at least 10 million SNPs with a minor
Future Directions
Recent GWA studies have identified three lung cancer susceptibility gene loci at chromosomes 15q24-25.1, 5q15.33, and 6p21. The 15q24-25.1 locus is associated not only with lung cancer but also with smoking behavior and other smoking-related diseases. Associations of the 15q24-25.1 genotypes with lung cancer risk in never-smokers and with lung ADC risk have been inconsistently observed among studies. In addition, the frequency of the risk allele is markedly different among ethnic groups.
Acknowledgments
This study was supported in part by a Grant-in-Aid from the Ministry of Health, Labor, and Welfare for the third-term Comprehensive 10-year Strategy for Cancer Control and a Grant-in-Aid for the Program for Promotion of Fundamental Studies in Health Sciences of the National Institute of Biomedical Innovation (NiBio), Japan.
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