Genetic Basis for Susceptibility to Lung Cancer: Recent Progress and Future Directions

doi:10.1016/B978-0-12-380890-5.00002-8

Advances in Cancer Research

Volume 109, 2010, Pages 51-72

https://doi.org/10.1016/B978-0-12-380890-5.00002-8 Get rights and content

Lung cancer is the leading cause of cancer death worldwide, and cigarette smoking is the major environmental factor for its development. To elucidate the genetic differences in the susceptibility to lung cancer among individuals, genetic factors involved in tobacco-induced lung cancers have been extensively investigated and a number of genetic polymorphisms have been identified to date as candidates. Most of the polymorphisms identified are of genes encoding proteins associated with the activity to metabolize tobacco smoke carcinogens and to suppress mutations induced by those carcinogens, and functional significances have been elucidated for some of these polymorphisms. However, the significance of these polymorphisms in the contribution to lung cancer development still remains unclear. Recently, several novel lung cancer susceptibility genes, including those on chromosomes 5p15.33, 6p21, and 15q24-25.1, have been identified by large-scale genome-wide association (GWA) studies. The 15q25 region contains three nicotine acetylcholine receptor subunit genes, and their polymorphisms have been also reported as being associated with nicotine dependence. The 5p15.33 region is associated with risks specifically for lung adenocarcinoma, the commonest histological type and weakly associated with smoking. This locus has been shown to be associated with risks for a wide variety of cancers, including lung adenocarcinoma. Associations of the 6q21 region have not been consistently replicated among studies. The 6q23-25 and 13q31.3 regions were also identified by recent GWA studies as being associated with risk for lung cancer, particularly in never-smokers. However, contributions of genetic differences on these five loci to the susceptibility to overall lung cancer seem to be small. There are several molecular pathways for the development of lung adenocarcinomas, and environmental factors for their development are still unclear, especially those in never-smokers. In addition, geographic differences as well as gender differences in lung cancer risk have been indicated. Furthermore, various genes identified by candidate gene association studies have not been reevaluated for their significance together with genes identified by GWA studies in the same population. Therefore, further studies will be necessary to assess the individual susceptibility to lung cancer based on the combination of polymorphisms in multiple genes, and to establish a novel way of evaluating the individual risk for lung cancer for its prevention.

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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REV3L single nucleotide variants lead to increased susceptibility towards non-small cell lung cancer in the population of Jammu and Kashmir
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Since the advent of Genome-Wide Association Studies (GWAS), rapid progress has been made in the identification of lung cancer susceptibility genes, such as those on chromosomal regions 5p15.33, 6p21, and 15q24–25.1 [29]. Besides these, individual gene mutation profiling studies and the case-control association studies have also contributed significantly in the identification of lung cancer susceptibility genes such as EGFR, TP53, and RB1 [29,30]. TLS polymerases, although play an important role in preventing more deleterious effect of stalled replication fork, their error prone nature often result in the introduction of genomic instability, a potential cause for malignancy [15].
Non-small cell lung cancer (NSCLC) is the most common lung cancer, accounting for 80–85% of all lung cancer cases. Various genetic studies have associated REV3L (Protein reversion less 3-like) gene mutations, which encodes the catalytic subunit of error prone translesion synthesis polymerase zeta with cancer, including lung cancer; however, no such data is available from any North Indian population. In this study we attempted to screen the North Indian population of Jammu and Kashmir (J&K) for the potential role of REV3L gene polymorphisms in NSCLC.
A total of four REV3L single nucleotide variants were selected for genotyping based on the available literature. The genotyping was carried out by using the TaqMan allele discrimination assay in 500 subjects (200 NSCLC patients and 300 age and sex matched healthy controls). The association of variants with NSCLC was evaluated by logistic regression.
Out of the four REV3L variants genotyped; rs1002481, rs462779, and rs465646 were found significantly associated with NSCLC risk under the recessive model, with an Odds Ratio (OR) of 3.52(2.14–5.8 at 95% CI, p-value = 0.00000062), 3.7 (1.8–7.6 at 95% CI, p-value = 0.00031), and 2.2 (1.47–3.37 at 95% CI, p-value = 0.0003), respectively.
Our data supports a strong association between variants rs1002481, rs462779, rs465646 and NSCLC, indicating a potential role of these REV3L variants in increasing the risk for the development of NSCLC in the studied population. Although a first report from any Indian population, these variants have been previously reported to be associated with lung and colorectal cancers in different world populations. Our data along with the existing data supports the notation that these variants can be used as potential genetic predisposition markers.
Data generated and analysed during study is not available publicly but can be made available from the corresponding author upon reasonable request.
Identification of nicotinic acetylcholine receptor subunits in different lung cancer cell lines and the inhibitory effect of alpha-conotoxin TxID on lung cancer cell growth
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Studies illustrated that α3, α5, α7, β4 nAChR subunits played a critical role in lung cancer development. Genome wide association studies identified lung cancer susceptibility locus on chromosome 15q24-25, containing CHRNA3, CHRNA5 and CHRNB4 genes, which could code α3, α5 and β4 nAChR subunits (Thorgeirsson et al., 2008; Yokota et al., 2010). Blocking and antagonizing α3, α5 and β4 nAChR subunits can inhibit the growth of lung cancer cells (Improgo et al., 2013).
Lung cancer is an aggressive tumor with high incidence and mortality rate. There was growing evidence supporting that nicotinic acetylcholine receptors (nAChRs) play vital role inlung cancer development. In this study, the expression of α3, α4, α5, α6, α7, α9, α10, β2, β3, β4 nAChR subunits on protein and mRNA level were studied in A549, NCI–H1299, NCI–H1688, DMS114 and normal human embryonic lung fibroblast (HEL) cell lines by real-time quantitative PCR (qPCR) and Western blot assay respectively. The results indicated that most of these nAChR subunits were expressed in these five cell lines. Compared with normal cells, the expression of α3 and β4 nAChR subunits were upregulated in A549 and NCI–H1299. Thus, we treated A549 and NCI–H1299 with an antagonist α-conotoxin TxID which potently and selectively blocks α3β4 nAChRs. TxID treatment could inhibit A549 and NCI–H1299 cell growth and enhance the inhibitory effect of adriamycin when treated simultaneously. To sum up, our study identified the expression of nAChR subunits in different lung cells and the anti-tumor effect of α-conotoxin TxID, which may provide novel strategies for lung cancer therapy.
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If eQTLs found in relevant tissues, which would be used to draw inferences about the causal effect of gene expression to complex trait variation, and would be a remarkable advance in finding gene targets for complex diseases (Visscher and Yang, 2016.). Many examples of the genetic basis of inherited predisposition to cancer have been discovered through the candidate-gene approach and genome-wide associations (Yokota et al., 2010). Approximately 3% of cancers are thought to result from an inherited susceptibility (Wei et al., 2016).
Genetic variants can predict other “linked” diseases because alterations in one or more genes in vivo may affect relevant phenotype properties. Our study systematically explored the pan-cancer common gene and cancer type-specific genes based on GWAS loci and TCGA data of multiple cancers. It was found that there were 17 SNPs were significantly associated with the expression of 18 genes. Associations between the 18 cis-regulatory genes and the pathologic stage of each cancer showed that MYL2 and PTGFR in HNSC, 4 genes (F8, SATB2, G6PD and UGT1A6) in KIRP, 3 genes (CHMP4C, MAP3K1 and MECP2) in LUAD were all strongly associated with cancer stage levels. Additionally, the survival association analysis showed that SATB2 was correlated with HNSC survival, and MPP1 was strongly associated with the survival of SARC. This study will shed light on the biological pathways involved in cancer-genetic associations, and has the potential to be applied to the predictions of the risk of cancers developing in healthy individuals.
Single nucleotide variations in the Wnt antagonist sFRP3 (rs7775 & rs288326) and sFRP4 (rs1802073 & 1802074) genes and their association with lung cancer risk in North Indians
2017, Meta Gene
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It has been established that tobacco intake is the prime initiator of lung cancer in 80% of the total cases (Wogan et al., 2004) but recently evidences from familial clustering and segregation studies have revealed that genetic susceptibility might confer an important role in occurrence of lung cancer. A distinct amalgam of polymorphic traits in each individual affects his/her susceptibility towards lung cancer (Yokota et al., 2010). Therefore, it is important to understand the role of various cancer related genes including the dominant oncogenes, recessive tumor suppressor genes and their respective polymorphic forms in the process of lung carcinogenesis, so as to find out the populations who would be at a higher risk of acquiring the disease.
To evaluate the role of genetic variants or single nucleotide polymorphic variants (rs288326, rs7775, rs1802073 and rs1802074) in Secreted frizzled related protein in modulating lung cancer susceptibility.
A total of 610 subjects were genotyped using PCR-RFLP technique for each polymorphic site including 300 cases and 310 controls. Further association analysis was carried out using logistic regression approach to obtain adjusted odds ratio and statistical significance.
The two genetic variants of sFRP3 (rs288326 and rs7775) didn't show any significant role in modulating the susceptibility towards lung cancer whereas the two sFRP4 variants (rs1802073 and rs1802074) did show a significant impact and were found to be significantly associated with risk of developing lung cancer. Individuals with the mutant genotype for sFRP4 Pro³²⁰Thr variant were found to have a three times higher risk of developing lung cancer (OR = 3.21, 95% CI: 1.88–5.4 p < 0.0001). Adenocarcinoma patients were found to be more susceptible as compared to other histological subtypes, in case of all the four genetic variants.
Hence, the four genetic variants of the Secreted frizzled related protein did confer an impact on the susceptibility of North Indians towards lung cancer.
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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

Differences in the Process of Lung Cancer Development Between Smokers and Never-Smokers

Candidate Gene Association Studies

Genome-Wide Association Studies

Assessment of Lung Cancer Risk in Each Individual by Combined Genotypes (Gene–Gene Interactions)

Smoking-Associated Differences (Gene–Environment Interactions)

Necessity of Further Association Studies

Future Directions

Acknowledgments

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Cell

Am. J. Hum. Genet.

Lancet Oncol.

Cell

Clin. Lung Cancer

Lancet Oncol.

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Genome-wide association scan of tag SNPs identifies a susceptibility locus for lung cancer at 15q25.1

Nat. Genet.

A susceptibility locus on chromosome 6q greatly increases lung cancer risk among light and never smokers

Cancer Res.

Genetic polymorphism of CYP genes, alone or in combination, as a risk modifier of tobacco-related cancers

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