[Frontiers in Bioscience S3, 1463-1477, June 1, 2011]

Genetic susceptibility to lung cancer

Haruhiko Sugimura1, Hong Tao,1 Masaya Suzuki1, Hiroki Mori1, Masaru Tsuboi1, Shun Matsuura2, Masanori Goto1, Kazuya Shinmura1, Takachika Ozawa3, Fumihiko Tanioka4, Naomi Sato5, Yoshitaka Matsushima6, Shinji Kageyama1, Kazuhito Funai7, Pei-Hsin Chou8, Tomonari Matsuda8

1Department of Pathology, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, Shizuoka, 431-3192, Japan, 2Department of Pulmonary Medicine, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku,Hamamatsu, Shizuoka, 431-3192, Japan, 3Department of Pathology, Hamamatsu Medical Center, 328 Tomizuka-cho, Naka-ku, Hamamatsu, Shizuoka, 432-8580, Japan, 4Department of Pathology and Laboratory Medicine, Iwata City Hospital, 512-3 Okubo, Iwata, Shizuoka, 438-8550, Japan, 5Department of Clinical Nursing, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku,Hamamatsu, Shizuoka, 431-3192, Japan, 6Department of Chemistry, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku,Hamamatsu, Shizuoka, 431-3192, Japan, 7Department of Thoracic Surgery, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, Shizuoka, 431-3192, Japan, 8Research Center for Environmental Quality Management, Kyoto University, 1-2 Yumihama, Otsu, Shiga, 520-0811, Japan

TABLE OF CONTENTS

1. Abstract
2. Introduction
3. Candidate genes of lung cancer susceptibility
3.1. Carcinogen-activation genes
3.2. Carcinogen-detoxification genes
3.3. Repair gene polymorphism and lung cancer susceptibility 
3.4. Oncogene and suppressor gene polymorphisms, and other genetic and epigenetic variations to modify lung Cancer susceptibility
4. The Era of genome-wide association study
5. Smoking behavior and lung cancer susceptibility
6. Exposure assessment and lung cancer susceptibility
7. Perspectives
8. Acknowledgements
9. References

1. ABSTRACT

Lung cancer is a highly environmental disease, but cancer researchers have long been interested in investigating genetic susceptibility to lung cancer. This paper is a historical review and provides updated perspectives on lung cancer susceptibility research. The recent introduction of easier genotyping methods and the availability of an almost complete human genome database facilitated the association study to thousands of cases and controls for millions of genetic markers. Discoveries in the field of behavior genetics, that is, the genetic aspects of smoking behavior and nicotine addiction, unexpectedly indicated that polymorphisms in the human central nervous system play an important role in eventually leading to lung cancer. These findings were achieved by using comprehensive approaches, such as a genome, transcriptome, or proteome approach, and the studies were often conducted without a hypothesis. Another-omics approach, the "adductome" or "exposome" approach to how life style information can be integrated into the framework of genetic association studies, has recently emerged. These new paradigms will influence the area of lung cancer risk evaluation in genome cohort studies.

2. INTRODUCTION

The genetic aspects of the etiology of lung cancer have been considered less important, because the urban vs. country, male vs. female, and smoker vs. non-smoker differences in its incidence, twin studies, and immigration studies taken together have indicated that the etiology of lung cancer is largely environmental (1). On the other hand, in animal carcinogenesis studies Kouri et al. found that the inducibility of aryl hydrocarbon hydroxylase is associated with susceptibility to induction of lung cancer by 3-methylcholanthrene (2), and in 1984, Ayesh and Idle published a study showing that debrisoquine hydroxylase activity was higher in lung cancer patients than in healthy controls. Debrisoquine was a popular anti-hypertensive drug used in Europe at the time (3). The work by Ayesh and Idle pioneered the field of pharmacogenetics, and carcinogenesis researchers started to investigate genetic susceptibility to environmental cancers to test the hypothesis that the cancer susceptibility of people exposed to certain environmental carcinogens varies with their genetic capacity to handle (activate, detoxify) xenobiotics. The discipline of molecular epidemiology of human cancer combined with dosimetry studies to assess individual exposure to particular environmental carcinogens burgeoned (4-7).

3. CANDIDATE GENES FOR INCREASED LUNG CANCER SUSCEPTIBILITY

3.1. Polymorphisms in carcinogen-activating enzymes and lung cancer susceptibility

After Ayesh's work on individual differences in metabolizing debrisoquine (debrisoquine hydroxylase), genes responsible for xenobiotic metabolism were cloned, and a nomenclature system was devised according to the new cDNA sequences that were being isolated on an almost daily basis during that period.

Individual differences in the cytochrome P450 family of genes, the most important family of genes encoding enzymes that are responsible for the metabolism or activation of various environmental chemicals in cells, were extensively investigated by using the polymorphisms of these genes, which had just started to be discovered and to accumulate. An enzyme that activates polyaromatic hydrocarbons (PAHs) to their nucleophilic forms, CYP1A1 (cytochrome P450, family 1, subfamily A, polypeptide 1), was studied most extensively in regard to lung cancer susceptibility, especially tobacco-related lung cancer susceptibility. Kawajiri first reported identification of a polymorphism near the CYP1A1 locus (actually an Msp I polymorphism in the 3' flanking region; m1, 4646903) and its relation to lung cancer susceptibility (8). Since the polymorphism first proposed was in the non-coding area of the gene, the mechanistic rationale was obscure. Subsequently, however, a more convincing polymorphism, an amino acid substitution polymorphism (m2, Ile462Val in exon 7, the substrate binding region, A2455G; rs1048943 according to current nomenclature) linked to the Msp I polymorphism (m1, rs4646903), was discovered (9). Follow-up studies of Japanese, Okinawan, and Brazilian subjects, in addition to Caucasian subjects, were conducted (10-14), and the association between the single nucleotide polymorphism known as reference SNP rs1048943 and tobacco-related cancer susceptibility was replicated in some but not all of the studies. Actually, the overall results of the follow-up studies on the association between lung cancer and rs1048943 were less convincing than reported earlier, because the associations were not always replicated. To begin with, since the prevalence of the minor, presumably high-risk allele of CYP1A1 was found to be very low in non-Asians, very large populations were required to obtain a modest increase in odds ratio in non-Asian populations, for example, in Scandinavians. Next, the correlation between the CYP1A1 polymorphism and lung cancer seemed to exist only in regard to tobacco-related lung cancer according to the hypothesis that tobacco-related carcinogens induce tobacco-related cancers via this allele that has higher carcinogen-activating capacity. Obviously, rigorous study designs that integrate the histological type of the lung cancer in the case and smoking history and other confounding factors of cases and controls require much more labor and time, especially in populations where the frequency of the high- risk allele is lower. It was only later that a pooled analysis revealed the association between the CYP1A1 polymorphism and lung cancer, both squamous cell carcinoma and adenocarcinoma, in a Caucasian population (15).

Another group of Japanese researchers investigated the relationship between CYP2E1 polymorphisms and lung cancer susceptibility in a Japanese population (16, 17), and CYP2E1 polymorphisms were subsequently investigated in various populations (18-20). Since CYP2E1 is involved in the activation and metabolism of alcohols and nitrosamines (presumed carcinogens in food in addition to tobacco smoke), the research was directed at gastrointestinal cancers. An interaction between CYP2E1 polymorphism and dietary meat and vegetable intake was reported in colorectal cancer (21). On the other hand, in the field of tobacco-related lung carcinogenesis, Kato et al. measured 7-methyl-dGMP (deoxyguanosine monophosphate), N-nitrosamines, and PAH-dGMP adducts in human autopsy lungs and correlated the amounts of various adducts derived from tobacco smoke, environmental tobacco smoke, and exposure to products of combustion of substances other than tobacco, e.g., products of combustion in occupational settings and fuel combustion products) with genotypes of CYP2E1, CYP2D6, CYP1A1, and GSTM1 (22). Their study revealed that higher 7-methyl-dGMP adduct levels were associated with the presence of CYP2E1 minor alleles.

CYP2A6 is thought to be responsible for nitrosamine and nicotine metabolism and has been another important target of research on CYP family gene polymorphisms (23). A group led by Kamataki investigated hundreds of lung cancers in Japan and discovered that a deletion- type polymorphism at the CYP2A6 locus reduces the risk of lung cancer (24, 25). CYP2A6 is located adjacent to its pseudogene, and identification of the deletion is sometimes technically demanding, but introducing this kind of genotyping by means of SmartAmpTM technology into clinical settings, such as outpatient clinics with a smoking cessation program, is now being widely considered (26, 27).

3.2. Polymorphisms of genes responsible for detoxification and conjugation of carcinogen metabolites

Glutathione-S-transferases (GSTs) are the most extensively studied class of enzymes that are characterized by individual differences in detoxifying activity. The deletion type polymorphism (null type) was well known long (28-30) before extensive copy number analysis of the entire human genome revealed the presence of tremendous insertion/deletion polymorphisms and copy number variations in the human genome (31). Combinations of polymorphisms of genes responsible for detoxification of carcinogens and for activation of procarcinogens were used to evaluate the cancer risk of individuals. Information on life-style factors that increase cancer proneness (e.g., smoking) or that some evidence indicates may be cancer-protective (e.g., consumption of green tea) was also included in multifactorial analyses of the gene-environmental interactions of the polymorphisms of the genes described above (12, 32, 33).

3.3. Repair-gene polymorphisms and lung cancer susceptibility

The canonical "carcinogen and consequent mutation theory" states that the ultimate carcinogen binds to DNA, thereby producing a DNA adduct that induces a base-pair replacement (mutation) in the next cycle of DNA replication, unless the DNA adduct is removed or the cell dies. Humans have a huge redundant system to repair such DNA damage (34, 35).

A classical example of a link between a defect in repair genes and human cancer is xeroderma pigmentosum, which comprises at least 9 different diseases, each with its own responsible gene (36-38). However, the most extensively studied gene from the standpoint of human genetic susceptibility to cancer is hOGG1, a base excision repair gene that removes 8-oxo-guanine (7,8-dihydro-8-oxoguanine) opposite cytosines. Soon after the isolation and characterization of hOGG1 by several groups (39-42), a nonsynonymous variation Ser326Cys (rs1052133) was identified (43), and the first case-control association study of human lung cancer was performed (44). It was a small study, and many studies, pooled studies, and meta-analyses of different populations followed (45-50). One report proposed a mechanistic basis for the contribution of the minor variant 326C to carcinogenesis (51). Since the original hypothesis was based on the reasoning that oxygen free radicals damage DNA, which results in mutations if DNA repair is inadequate, and the mutations in turn lead to a predisposition to cancer, especially in the organs often exposed to damage by reactive oxygen species, such as the lungs of smokers. The inference would be that tobacco-related cancer is more significantly correlated with the polymorphism than non-tobacco-related cancer. Actually, the first paper to describe an association between OGG1 and lung cancer reported finding a positive correlation between OGG1 polymorphism and squamous cell carcinoma of the lung (44). However, a meta-analysis of studies in which there were high numbers of cases of adenocarcinoma of the lung indicated a possible association between the OGG1 Ser/Cys polymorphism and adenocarcinoma, too (50).

Another issue raised by many researchers is ethnic differences, e.g., with respect to the CYP1A1 Ile426Val polymorphism (rs1048943). A meta-analysis of a total of 6375 cases and 6406 controls revealed an association between the CYP1A1 Ile426Val polymorphism (rs1048943) and lung cancer in Asians alone (45). The meta-analysis did not mention any interaction with the histological subtypes of the lung cancers, whose subtyping is sometimes very subjective and affected by severe inter-observer bias despite widespread standardization as in the WHO classification, and not all of the studies included in the meta-analysis contained complete smoking histories. The conclusion of the meta-analysis that "careful matching should be considered in future larger genetic association studies that include multiple ethnic groups" is quite obvious.

Another polymorphism in repair genes that has been studied extensively in an epidemiological framework is xeroderma pigmentosum group D (XPD) or excision repair cross-complementing rodent repair deficiency, complementation group 2 (ERCC2). XPD, i.e., ERCC2, is a well- characterized DNA helicase that is required for nucleotide excision repair of bulky DNA lesions (larger than adducts like 8-oxoguanine). A relatively rare missense variant, Lys751Gln (persons with the Lys/Lys genotype are less able to repair DNA), was discovered (52), and although no association with lung cancer was found in an earlier study (53), a significant difference between cases and controls was found in a Chinese study (54, 55). In contrast to the first report by Lunn et al., the Gln allele was found to be a high-risk allele in another Chinese lung cancer case-control set (56). However, the Asp312Asn polymorphism did not appear to affect DNA repair in the first study (52), but the results of the next study suggested a negative effect on DNA repair capacity in the homozygous Asn/Asn genotype (57). A meta-analysis of 9 papers in 2005 found no clear correlation between XPD polymorphism and lung cancer (58).

In 2008, an international lung cancer consortium analyzed the previous papers on 12 repair genes and their 18 polymorphisms and lung cancer susceptibility, and the consortium concluded that OGG1 Ser326Cys, TP53 Arg72Pro, XRCC3 Thr241Met, and XPD Lys751Gln were weakly associated with increased lung cancer susceptibility (47)(Table 1). The consortium suggested that further data pooling and a genome-wide association study approach were needed.

3.4. Oncogene and suppressor gene polymorphisms, and other genetic and epigenetic variations to modify lung cancer susceptibility

Some of the inter-individual variation of the genes tightly involved with human carcinogenesis has also been a topic enthusiastically investigated. The champion of this category would be an Arginine-Proline polymorphism in the exon 4 of TP53 (Arg72Pro, rs1042522). A comprehensive meta-analysis consisting of 302 case-control studies of cancers of all the organs suggested the contribution of this polymorphism depends on anatomic site of cancers (59). A meta-analysis consisting of 7495 lung cancer cases and 8362 controls based on 23 studies concluded that Pro allele is a low penetrant risk factor for developing lung cancer (60). Among the oncogenes, K-RAS is often mutated in lung cancer (61) and has been suggested to be responsible for genetic susceptibility to mouse pulmonary adenoma (62). In human lung cancer, the SNP around the K-RAS locus was not known to be associated to lung cancer susceptibility, so far.

Recently, frequent somatic methylatin of LKB1 in human lung cancer was found especially in Caucasian lung cancer and it is elusive this phenomenon is related to some genetic predispositions (63). Some of the germline variants in methyl-group metabolism genes are reported to be associated with somatic methylation profile of several genes including LKB1 in lung cancers (64).

Involvement of the genes which often somatically mutated or methylated in lung cancers are expected to explain some of lung cancer risk (65). However, the epigenetic change passable to the next generation (epimutation) was not found in lung cancer (66).

In addition to the SNPs in the genes mentioned above, any SNPs in the loci of the genes associated with human carcinogenesis have great potential in terms of possible contributions of efficient identification of lung cancer risk. Actually genome-wide association study disclosed an association of TP63 polymorphism and adenocarcinoma of the lung (67).

4. THE ERA OF THE GENOME-WIDE ASSOCIATION STUDY (GWAS)

The first GWAS on lung cancer susceptibility was published in 2007 (68). DNA from 100 cases and 100 matched controls was used, presumably to minimize cost. The experiments were performed on the Affymetrix (Santa Clara, CA) GeneChip platform by applying the human mapping 50K Xba240 and Hind240 arrays according to the manufacturer's protocols (68). The study identified 38 SNPs that might be associated with increased lung cancer susceptibiltiy. By current standards, the small numbers of samples used to conduct the investigation and the economical strategy of using pooled DNAs were very modest. The authors were aware that the 100K chip did not contain some of the SNPs that had already been reported to be associated with lung cancer. Several large-scale studies were published in the spring of the following year (47, 69-72), and they had investigated more than 300,000 SNPs (Illumina HumanHap300 v1.1 BeadChips) in case-control sets of more than 1000 pairs. Moreover, all of the studies included replication study sets that consisted of additional thousands of case-controls. Amazingly and interestingly, the loci indentified encoded nicotinic acetylcholine receptors (chromosome 15q25.1) that had been thought to be related to smoking behaviors. The rs10151730, rs8034191, and rs16969968 (Asp398Arg substitution polymorphism of CHRNA5) polymorphisms were significantly associated with lung cancer in people of European descent. A study of Icelanders (72) revealed the important finding that the rs1015730 locus was related to nicotine dependence, lung cancer, and peripheral arterial diseases. Late the same year, another locus was identified, based on an additional 3000 or so cases-controls (73). This study corroborated the previous studies that showed an association with chromosome 15q25 loci, especially with the rs1015730 locus, identified as rs402710 and rs2736100, which the investigators claimed, were independent, and the nearby genes were TERT and CLPTM1L, respectively. Another study, published at almost at the same time, identified two loci at 6p21 and an additional polymorphism in the CLPTM1L gene locus (intron 13, rs401681) (74).

The presumed risk-alleles above were tested in lung cancer cases in which there was a family history of lung cancer (75). At the same time, the group that reported finding an association between CHRNA5-A3 (rs1051730 and rs803419) and lung cancer (69) discovered that these genotypes were also associated with both nicotine dependence and lung cancer causation (76).

Many replication studies on the relationship between CHRNA5-A3 loci, nicotine dependence, and lung cancer were published in the next several years. Amos et al. reported associations between multiple loci (including rs169698) and increased risk of lung cancer in African Americans, instead of smoking (behavioral) phenotype (77). Wu et al. identified three novel SNPs (rs2036534C>T, rs667282C>T, rs12910984G>A, and rs6495309T>C) that are common in Asians and are related to smoking behavior and increased lung cancer risk in a Chinese population (78). Shiraishi et al. even demonstrated a possible contribution of three SNPs around the CHRNA5 locus to lung cancer risk in Japanese, whose prevalence of minor alleles at the three loci (rs8034190, rs16969968 and rs1051730) is very low (79).

The above genome-wide studies and a later one recruited thousands of case-controls in several populations, but the overall contributions of the genotypes accounted for only 1% of the excess familial risk of lung cancer (80). The authors of the later study claimed that a larger sample of DNAs from a series of lung cancer cases and controls with records of smoking behavior would be necessary in addition to the currently or previously collected DNAs in order to identify genes associated with increased risk of lung cancer (71)!

GWASs conducted in the last several years have demonstrated that new technology enables hundreds of SNPs to be processed in thousands of cases without a set of working hypotheses (81). The susceptibility alleles that have been discovered with the new technology by GWASs are common (present in 10% or more of Caucasians). Each allele makes a small contribution, and the odds ratios calculated for the high-risk genotypes are usually less than 1.3. The pursuit of lung cancer susceptibility genes by GWASs has been same as the pursuit of susceptibility genes for other diseases by GWASs.

However, probably because lung cancer is a very environmental disease, as previously mentioned, based on current theoretical inferences, only three genes are suspected of being lung cancer susceptibility genes, far fewer than in more genetic cancers (prostate cancer, for example, in which the number is estimated to be 30). In view of the largely environmental nature of lung cancer and the fact that there are expected to be fewer genetic components than in other cancers, an extra twist in the strategy will be necessary to zero in on lung cancer susceptibility genes. For example, the next association study must include stratification of lung cancers according to smoking history in addition to ethnicity and histological type (82, 83). On the other hand, smoking itself is now considered a highly genetically controlled behavior. The genetic aspect of smoking behavior is addressed in the next section.

5. SMOKING BEHAVIOR AND LUNG CANCER SUSCEPTIBILITY

Smoking by male members of the same family is common in many cultures, especially in many traditionally male chauvinistic cultures. Actually, two papers, one published in1963 and the other in 2003, stated that familial clustering of lung cancer can be explained by familial clustering of smokers (84, 85). However, the results of a recent simulation study did not support clustering of smokers in families as a cause of familial cases of lung cancer (86).

On the other hand, the heritability of substance dependence, including dependence on tobacco (nicotine), has been investigated in many populations (87). Nicotine dependence is now recognized as a disease according to the International Statistical Classification of Disease and Related Health Problems (ICD) 10 and is treated in smoking-cessation clinics, and various genes have been assessed as candidates for genes responsible for nicotine dependence (88). Candidate genes related to) dopaminergic pathways have attracted the attention of many investigators (89), but a genome-wide approach was proposed (90) and several ambitious trials have been conducted (91). Saccone et al. have found a few chromosomal regions by performing a genome-wide linkage analysis and Bierut identified several other regions by using high-density SNP arrays (92, 93). The results of those studies yielded a very long list of candidates for addiction genes (94). Hundreds of genes responsible for addiction may play a role in tobacco-related carcinogenesis, including in lung cancer. Smoking behavior has traditionally been assessed by means of several different types of questionnaire, and the most-widely used questionnaire is the Fagerström Test for Nicotine Dependence (FTND) (95). Another test, the Tobacco Dependence Screener (TDS), was recently developed. The questions in the TDS regarding each symptom or trait correspond to the criteria in the ICD -10 and Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) (96). Many other questionnaires have been devised besides these two, but only a few studies have used more than two of the questionnaires to compare their ability to detect dependence and detect associations with genotypes, and each questionnaire may actually detect different genetic traits related to smoking (92, 97, 98). The Tobacco and Genetics Consortium, which consists of 116 researchers, recently showed that multiple loci are associated with smoking behavior (99), and Liu et al. confirmed that a locus on chromosome 15, the promoter region of CHRNA5, is a locus responsible for smoking behavior (nicotine addiction) in one of the same cohorts, the Oxford-GlaxoSmithKlein cohort (100). Interestingly, the Consortium identified BDNF, which is related to various neurological functions in humans, as an initiation gene, and DBH, an important gene related to the dopaminergic pathway, as a continuation (failure to stop smoking) gene. These findings prompted the Consortium to devise a flowchart showing the pathways from the start of smoking to the development of lung cancer (101). (Figure 1) This concept that a genetically determined smoking behavior pattern is the origin of human lung cancer as depicted in Figure 1 is obviously an oversimplification, but it warrants verification in various populations and in various SNPs of the candidate genes.

6.EXPOSURE ASSESSMENT AND LUNG CANCER SUSCEPTIBILITY

The susceptibility of an individual to lung cancer depends more on the extent to which the individual has been exposed to carcinogens than on the pattern of gene expression in each of the individual's organs (lung, brain, etc.). Estimating how many possible carcinogens are in the body is a challenge, because the tissue samples are usually inadequate, and we do not know exactly what kind of chemicals might be present. The history of painstaking isolation and synthesis of chemicals that cause cancer in animals since Yamagiwa succeeded in inducing skin cancer by painting tar on a rabbit's ear (102) revealed that numerous chemicals that were products of combustion, endogenous oxidation, and generated in vivo as byproducts of inflammation can cause cancer. Furthermore, how these carcinogens act on DNA, form covalent bonds with DNA, cause mutations, and induce neoplastic transformation in cells became clear, especially in in vitro systems and in experimental animals (103, 104). Moreover, recent studies have shown that a typical mutagenic carcinogen is involved in carcinogenesis via its actions on physiologically important cell machinery that are not necessarily accompanied by mutation induction (105, 106). Thus, the remaining questions are how to validate the formation of these adducts that "carcinogenesis" studies have indicated occurs in the human body and how to evaluate their effects. Several methodologies have been invented to answer these questions, and some have succeeded in detecting causes of human carcinogenesis, i.e., a particular adduct in a particular cancer in a particular setting (4, 107, 108), but since these methods are capable of detecting only a limited numbers of adducts and human body may contain a wide variety of adducts it was hoped that a more efficient method that would detect multiple species of adducts in many samples would be found. The recent progress in the field of bio-measurement has facilitated the simultaneous detection of multiple adducts in the same human tissues (109, 110). DNA adducts have been found to vary with the organ analyzed in the same individual (Figure 2), showing that each organ has a different profile of adducts, probably as a result of exposure to different sets of carcinogens, e.g., the lung to air-bone carcinogens, the colon to food-borne carcinogens, the skin to environmental carcinogens, etc., and organ-specific metabolism. In the adductome map in Figure 2 liquid chromatography retention time is shown on the horizontal axis, and mass spectrometry molecular weight per charge on the vertical axis. Only some of the spots have been annotated (109). Complete annotation would reveal the overall exposure status of human organs and promote further quantitative characterization of the modified DNAs, including the mutagenicity of the modified DNAs. Even in this pilot study, differences in numbers and sizes reflecting the approximate amount of the individual adducts can be seen between smokers' lungs and never-smokers' lungs (100). Chou et al. applied the adductome approach to larger numbers of cases and succeeded in discovering considerable amounts of lipid peroxidation-induced DNA adducts (110). Lipid peroxidation-induced DNA adducts are derived from omega 3 and omega 6 polyunsaturated fatty acids, which are endogenous in all body tissues. These adducts can be used as a surrogate markers to estimate how much an individual has been exposed and will provide a clue as to how environmental or endogenous mutagens trigger neoplastic transformation in cells. A specific analysis of how the cellular machinery responds to these adducts in the human body andpresumed individual differences in their repair capacity is needed.

6. PERSPECTIVES

As Gazdar provocatively mentioned, lung cancer is mainly associated with smoking behavior and with environmental exposure to tobacco smoke in other words, it is a highly environmental disease. Lung cancers in never-smokers account for 25% of all lung cancers, and the histological type found in never- smokers is very different from the histological types found in smokers) (111). The results of some SNP analyses of lung cancers were not replicated in a subsequent meta-analysis that included never-smokers' lung cancers (112), probably because the study was "underpowered" (only thousands of cases!). Copy number variants have never been fully estimated in lung cancer susceptibility studies. Genomic analyses will soon become more economical, and the era of personal genome analysis is at hand. Obviously, careful and comprehensive studies on genotype-phenotype associations (113) need to be performed in humans. When we review the previous progress in methodologies for analyzing both the nature and nurture aspects of cancer susceptibility (Figure 3-5), we cannot avoid expecting a future in which "personal genome x personal adductome" information will provide a definitive assessment of each individual's risk of lung cancer.

8. ACKNOWLEDGEMENTS

This work was supported by Grants-in-Aid for Scientific Research (C) (22590356) and for priority areas (20014007 and 221S0001) from the Japanese Ministry of Education, Culture, Sports, Science and Technology, Grants-in-Aid for the 3rd Term Comprehensive 10-Year-Strategy for Cancer Control, for Cancer Research (21-1), and for Research on international cooperation in medical science from the Japanese Ministry of Health, Labour, and Welfare, and from the Smoking Research Foundation.

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20. L. L. Marchand, G. R. Wilkinson and L. R. Wilkens: Genetic and dietary predictors of CYP2E1 activity: a phenotyping study in Hawaii Japanese using chlorzoxazone. Cancer Epidemiol Biomarkers Prev, 8(6), 495-500 (1999)
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21. C. M. Gao, T. Takezaki, J. Z. Wu, M. B. Chen, Y. T. Liu, J. H. Ding, H. Sugimura, J. Cao, N. Hamajima and K. Tajima: CYP2E1 Rsa I polymorphism impacts on risk of colorectal cancer association with smoking and alcohol drinking. World J Gastroenterol, 13(43), 5725-30 (2007)
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24. M. Miyamoto, Y. Umetsu, H. Dosaka-Akita, Y. Sawamura, J. Yokota, H. Kunitoh, N. Nemoto, K. Sato, N. Ariyoshi and T. Kamataki: CYP2A6 gene deletion reduces susceptibility to lung cancer. Biochem Biophys Res Commun, 261(3), 658-60 (1999)
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25. M. Fujieda, H. Yamazaki, T. Saito, K. Kiyotani, M. A. Gyamfi, M. Sakurai, H. Dosaka-Akita, Y. Sawamura, J. Yokota, H. Kunitoh and T. Kamataki: Evaluation of CYP2A6 genetic polymorphisms as determinants of smoking behavior and tobacco-related lung cancer risk in male Japanese smokers. Carcinogenesis, 25(12), 2451-8 (2004)
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26. Y. Mitani, A. Lezhava, A. Sakurai, A. Horikawa, M. Nagakura, Y. Hayashizaki and T. Ishikawa: Rapid and cost-effective SNP detection method: application of SmartAmp2 to pharmacogenomics research. Pharmacogenomics, 10(7), 1187-97 (2009)
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27. Y. Mitani, A. Lezhava, Y. Kawai, T. Kikuchi, A. Oguchi-Katayama, Y. Kogo, M. Itoh, T. Miyagi, H. Takakura, K. Hoshi, C. Kato, T. Arakawa, K. Shibata, K. Fukui, R. Masui, S. Kuramitsu, K. Kiyotani, A. Chalk, K. Tsunekawa, M. Murakami, T. Kamataki, T. Oka, H. Shimada, P. E. Cizdziel and Y. Hayashizaki: Rapid SNP diagnostics using asymmetric isothermal amplification and a new mismatch-suppression technology. Nat Methods, 4(3), 257-62 (2007) 10.1038/nmeth1007
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28. S. Zhong, A. F. Howie, B. Ketterer, J. Taylor, J. D. Hayes, G. J. Beckett, C. G. Wathen, C. R. Wolf and N. K. Spurr: Glutathione S-transferase mu locus: use of genotyping and phenotyping assays to assess association with lung cancer susceptibility. Carcinogenesis, 12(9), 1533-7 (1991)
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PMid:8319207

33. A. K. Alexandrie, F. Nyberg, M. Warholm and A. Rannug: Influence of CYP1A1, GSTM1, GSTT1, and NQO1 genotypes and cumulative smoking dose on lung cancer risk in a Swedish population. Cancer Epidemiol Biomarkers Prev, 13(6), 908-14 (2004)
PMid:15184245

34. T. Lindahl and R. D. Wood: Quality control by DNA repair. Science, 286(5446), 1897-905 (1999) doi:8045 (pii)

35. R. D. Wood, M. Mitchell, J. Sgouros and T. Lindahl: Human DNA repair genes. Science, 291(5507), 1284-9 (2001)
doi:10.1126/science.1056154
PMid:11181991

36. O. D. Scharer: Hot topics in DNA repair: the molecular basis for different disease states caused by mutations in TFIIH and XPG. DNA Repair (Amst), 7(2), 339-44 (2008)
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PMid:18077223    PMCid:2246058

37. K. Sugasawa: Regulation of damage recognition in mammalian global genomic nucleotide excision repair. Mutat Res, 685(1-2), 29-37 (2010)
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    Key Words: Review, Lung cancer susceptibility, Genome-wide association study (GWAS), Single nucleotide polymorphism (SNP), Adductome, DNA adducts, DNA repair, CYP, Smoking behavior, Review

    Send correspondence to: Haruhiko Sugimura, 1-20-1 Handayama, Higashi-ku, Hamamatsu, Shizuoka, Japan 431-3192, Tel: 81-53-435-2220, Fax: 81-53-435-2225, E-mail:hsugimur@hama-med.ac.jp