Most lung cancers are attributable to tobacco smoking, which exposes airways and lung parenchyma to numerous carcinogens and procarcinogens including free radical species, aromatic amines, polycyclic aromatic hydrocarbons, and nitrosamines. Compared to cigarette smoking, other exposures implicated in lung cancer impact lung cancer risk much less [1, 2]. Approximately 15% of lung cancers in men, and 50% of lung cancers in women, are not related to tobacco smoking [3, 4]. Overall, approximately 25% of lung cancer patients are never smokers [3, 4]. Although passive inhalation of tobacco smoke, also termed environmental tobacco smoke, is believed to play a role in some percentage of cases of lung cancer in never smokers [3], these tumors are usually designated idiopathic; and their histologic types differ from the types found in cigarette smokers [5]. Many of these never smokers who develop lung cancer are young women who develop adenocarcinoma and who show an overall better prognosis than patients with smoking-related lung cancers [6, 7]. Nonsmoking-related lung cancers are being increasingly recognized; and the disease likely represents a disease process unrelated to smoking-related lung cancer. People are thought to have variable susceptibilities to cancer risk factors, including lung cancer risk factors [8–38]. A genetic basis for differing cancer risk factor susceptibilities has been proposed based on the observation that different susceptibilities appear to be inherited based on aggregation of cancers within families [39–66]. Inherited susceptibilities would help explain why some people develop lung cancer, such as individuals with minimal or no tobacco smoke exposure [30, 36, 67–75], frequently in association with family histories positive for cancer [31, 75–79], or those who develop lung cancer from exposure at a significantly earlier-than-average age [80–87].

Complex gene-environment interactions occur, and genetic differences in susceptibility to tobacco smoke carcinogens exist; and lung cancers in both smokers and never smokers may have mutually common and distinct risk factors and gene-environment interactions [5]. Host susceptibility to lung cancer, individually or in synergy with smoking, is uncertain [88]; however, gene-environment interactions and genetic differences likely have a significant role in the development of lung cancer in never smokers [3, 86]. They also likely help explain why some heavy smokers do not develop lung cancer [3, 86, 89–92] and why some lung cancer patients have strong family histories of cancer [5, 93–96]. The human genome database and improving genotyping technology have substantially aided researchers in their search for and understanding of the genetic role of lung cancer development [3, 34, 86, 87, 91, 92, 97, 98].

Epidemiological studies suggest familial clustering of lung cancer occurs [3, 86, 87, 92]; the literature is in fact robust [60, 99–101]. Studies for which smoking exposure and occupational exposure were controlled have shown an increased risk of lung cancer in relatives of lung cancer patients [45, 49, 54, 59, 64]. Inherited polymorphisms in DNA repair genes and xenobiotic-metabolizing enzyme genes might account for the elevated risk, as might the genetic influence of substance dependence, including nicotine dependence [87, 102–107]. Multiple genetic loci may relate to nicotine dependence, including the promoter region of CHRNA5, a locus on chromosome 15 [108–110]. Studies of lung cancer patients’ families who were nonsmokers or significantly younger than average have shown an increased familial risk of lung cancer, supporting the premise that genetic susceptibility is a factor in lung cancer development [33, 34, 38, 47, 49, 59, 67–71, 76, 77, 80–82, 84, 87, 92, 101, 111].

A 2012 study identified a 1.25-fold risk increase for family history of lung cancer in nonsmokers who developed lung cancer [3, 112]. It is important to understand, however, that familial aggregation of lung cancer alone does not in and of itself prove inheritance of genetic risk variants [3]. Clustering of close relatives with similar exposures to environmental risk factors may exhibit itself as a familial aggregation. However, there is evidence that some situations exhibiting familial aggregation are the result of genetic variants [3].

Gender affects lung cancer incidence [85]. Female lung cancer patients who are never smokers are influenced by familial history than by radon gas or environmental tobacco smoke exposure [85]. Research is conflicting as to whether women smokers have an increased risk of developing cancer relative to men; however, some studies suggest women have an increased risk [113]. Some studies suggest that women smokers have an increased risk of developing lung cancer relative to men with the same smoking histories; however, other studies show women’s risk to be equivalent to men’s. Environmental factors, hormonal influences, and gender differences in xenobiotic-metabolizing enzymes are proposed reasons for reported differences in gender-associated lung cancer susceptibility.

Epidermal growth factor receptor (EGFR) , echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) , proto-oncogene B-Raf (BRAF) , Kirsten rat sarcoma viral oncogene (KRAS) , and phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) are driver genes that may be mutated in pulmonary adenocarcinomas [114]. Gefitinib and erlotinib are EGFR tyrosine kinase inhibitors (EGFR-TKIs) used for molecular therapy of pulmonary adenocarcinomas [115]. EGFR-TKI-responsive EFGR mutations are identified more frequently in pulmonary adenocarcinomas of nonsmoking Asian women than in other groups of patients and are thought to arise early [116]. For example, one study of lung cancer patients showed EGFR mutations in 44% of pulmonary adenocarcinomas, with 47.5% occurring in women and 15% occurring in men and 42% occurring in nonsmokers and 14% occurring in smokers [117]. Nonsmoking Asian women whose pulmonary adenocarcinoma contains the EFFR mutation have been shown to have improved survival, particularly when the tumor demonstrates a significant lepidic pattern, compared to men with lung cancers who have a smoking history and whose pulmonary adenocarcinomas do not contain a significant lepidic pattern [2, 87, 118]. Pulmonary adenocarcinoma is identified relatively more frequently in nonsmoking women, and a relationship between EGFR mutation and membranous ERα expression has been identified as an independent prognostic factor in patients with pulmonary adenocarcinoma [116, 119]. HER2, a proto-oncogene of the receptor tyrosine kinase superfamily, binds other members of the EGFR family in the activation of EGFR signaling; and HER2 gene polymorphisms have been shown to increase susceptibility to pulmonary adenocarcinoma in nonsmoking Korean women [120].

Genome-wide association studies (GWASs ) are population-level studies to identify genetic alleles associated with disease status or clinical phenotypes within the genome rather than in relation to a specific gene [85]. Lung cancer GWASs have shown several factors that correlate with lung cancer occurrence and progression [3, 85]. Several single-nucleotide polymorphisms (SNPs) in various genetic loci related to lung cancer susceptibility have been found; however, the three major susceptible loci associated with lung cancer risk are loci 15q24–25, 5p15, and 6p21 [121–124]. Locus 15p24–25 has been associated with lung cancer risk in Caucasian populations only, while loci 5p15 and 6p21 have been associated not only with lung cancer in Caucasian populations but also with lung cancer in East Asian (Korean, Japanese, Chinese) populations [123]. Other less well-established loci, including 3q28–29, 13q12.12, 22q12.2, and 18p11.22, have been identified as being associated with lung cancer in Asian populations [125].

Polymorphisms of xenobiotic-metabolizing genes and DNA repair genes have found potential allelic variants associated with lung cancer risk [126, 127]. The concept of polymorphisms of xenobiotic-metabolizing enzymes and DNA repair enzymes is appealing; however, studies correlating single-locus alleles with lung cancer risk have generally produced conflicting results, probably due to a number of factors. In some studies, the number of cases might be too few to reliably gauge the effects on lung cancer risk. Also, the polymorphisms studied might vary. Further, different ethnic groups exhibit widely differing frequencies of some polymorphisms, effecting results according to the ethnic group studied. Finally, as the metabolism, detoxification, and repair processes involved with DNA adducts are complex, one single polymorphism most likely does not account for differences in DNA adduct levels. Studies examining several or many polymorphisms simultaneously in a single population are more likely to yield more comprehensive and consistent results; and newer technologies, permitting the study of SNPs and haplotypes, increase statistical sensitivity [85].

DNA adducts from metabolically activated intermediates of compounds found in tobacco smoke are mutagenic and carcinogenic [206]. Bulky DNA adducts can be identified with 32P-postlabeling of tumor tissues, peripheral blood lymphocytes and other tissues, immunoassays and immunohistochemistry, mass spectrometry, fluorescence, HPLC electrochemical detection, and phosphorescence spectroscopy [207]. PAH-DNA adducts can be identified by BPDE-DNA immunoassays such as the BPDE-DNA chemiluminescence immunoassay (BPDE-DNA CIA); and elevated DNA adduct levels have been found in smokers’ lung and other tissues. More DNA adducts are found in patients with smoking-related cancers than in patients without cancer [208]. A meta-analysis showed that smokers with smoking-related cancers had a statistically significant (83% higher) level of DNA adducts than controls [209]. Increased levels of DNA adducts have been in smokers’ lungs relative to non- and never smokers’ lungs [210]. Along with studies demonstrating the carcinogenicity of DNA adducts from tobacco smoke, these studies support a link between DNA adduct number and lung cancer development. However, it must be remembered that in retrospective case-control studies, the possibility that the levels of DNA adducts are the result of, rather than the cause of, the disease cannot be completely excluded. Nonetheless, that DNA adducts are causative is strongly supported by prospective studies where DNA adducts were measured in blood samples collected years before cancer onset. One study showed that disease-free current smokers with elevated levels of DNA adducts in blood leukocytes were three times more likely to be diagnosed with lung cancer 1–13 years later than current smokers with lower DNA adduct levels [211]. Peluso et al. noted that the levels of leukocyte DNA adducts in blood samples collected several years before the onset of cancer were associated with the subsequent risk of lung cancer [212]. The association with lung cancer was stronger in never smokers—whose sources would be environmental, such as secondhand tobacco smoke and air pollution—and in younger patients. These prospective studies strongly support a relationship between DNA adduct levels and lung cancer risk. The studies also suggest that individual patients have differing susceptibilities to carcinogen exposures, highlighted by the risks observed in those with fewer years of exposure, younger patients, and those with lesser levels of exposure, never smokers.

Because tobacco smoke contains carcinogenic chemicals which damage DNA, lung cancer has been shown to involve DNA damage repair genes, including O6-alkylguanine DNA alkyltransferase (AGT ) , X-ray repair cross-complementing group 1 (XRCC1 ) , NAD(P)H: quinoneoxidoreductase (NQO1 ) , human 8-oxoguanine DNA glycosylase (hOGG1 ) , cytosine DNA-methyltransferase-3B (DNMT3B ) , O6-methylguanine-DNA methyltransferase (MGMT ) , and several nucleotide excision repair (NER ) genes [195]. These gene polymorphisms inhibit the repair of damaged DNA, increasing the risk of carcinogenesis caused by tobacco [195]. In cultured lymphocytes, DNA repair capacity (DRC ) can be measured using the host-cell reactivation assay and a reporter gene damaged by the activated tobacco carcinogen BPDE. A fivefold variation in DRC has been found in the general population. Also, decreased DRC has been associated with increased lung cancer risk [213–216]. Polymorphisms in DNA repair genes may be related to differences in efficiency of DNA repair; and decreased or increased ability to repair DNA damage is thought to impact the accumulation of significant genetic abnormalities required for cancer development.

Prevalence of XPD alleles and genotypes varies greatly by ethnicity. Polymorphisms in codons 156, 312, 711, and 751 of the XPD gene are noted commonly, with an allele frequency greater than 20%. Polymorphisms of codon G23592A (Asp312Asn) of exon 10 and codon A35931C (Lys751Gln) of exon 23 cause amino acid changes in the XPD protein and have been studied with respect to lung cancer susceptibility [217–223]. Studies have examined the levels of DNA adducts associated with these polymorphisms as an indication of the efficiency of the different alleles at DNA repair. Most likely a higher level of adducts suggests that the allele has less efficiency at excising DNA adducts. With respect to codon 312 polymorphisms, most studies have found a higher level of DNA adducts in association with the Asn allele than with the Asp allele. The majority of studies have identified a higher level of DNA adducts in association with the Gln allele. As such, most studies indicate a difference in DNA repair efficiency between these specific XPD alleles [217, 221, 223, 224]. Hu et al., in a meta-analysis of data from nine case-control studies including 3725 lung cancer cases and 4152, found that patients with the XPD 751CC genotype have a 21% higher risk of lung cancer compared to patients with the XPD 751AA genotype and that patients with the XPD 312AA genotype have a 27% higher risk of lung cancer compared to the ones with the XPD 312GG genotype [224]. Performing a meta-analysis derived from the same studies as Hu et al., including 2886 lung cancer cases and 3085 controls for the XPD-312 polymorphism from 6 studies, and 3374 lung cancer cases and 3880 controls for the XPD-751 polymorphism from 7 studies, Benhamou and Sarasin were unable to conclude that one or the other of these polymorphisms was associated with an increased risk of lung cancer [224, 225]. After the conflicting meta-analyses, Hu et al. performed a case-control study that included 1010 lung cancer cases and 1011 age- and sex-matched cancer-free controls in a Chinese population [223]. Hu et al., studying eight SNPs/DIPs (deletion/insertion polymorphisms) of XPD/ERCC2 and XPB/ERCC3, found that none of the eight polymorphisms was individually associated with lung cancer risk; however, the combination of genetic variants in ERCC2 and ERCC3 contributed to the risk of lung cancer in a dose-response manner.

In other studies, an increased lung cancer risk with combinations of XPD polymorphisms and polymorphisms of other DNA repair genes has been identified [226]. Zhou et al. identified a significantly increased lung cancer risk in patients with five or six variant alleles of XPD Asp312Asn, XPD Lys751Gln, and XRCC1 Arg399Gln polymorphisms versus patients with no variant alleles [227]. Chen et al. found that patients with variant alleles for both XPD Lys751Gln and XRCC1 Arg194Trp polymorphisms have a higher lung cancer risk than patients with only one variant allele in a Chinese population [228].

Telomerase reverse transcriptase (TERT ) and cleft lip and palate transmembrane 1-like protein (CLPTM1L) , both on chromosome 5p15.33, have been reproducibly associated with lung cancer risk [121]. TERT encodes a telomerase subunit involved in maintenance of telomere ends. GWASs have identified chromosome 5p15.33 as a region related to risk of pulmonary adenocarcinoma [121]. Lung cancer risk has also been associated with SNPs in the 5p15.33 region [242]. TERT and CLPTM1L are two candidate susceptibility genes found on chromosome 5p15.33. Because TERT encodes a telomerase subunit important in the maintenance of telomere ends, its overexpression causes cellular life span prolongation. CLPTM1L, also termed cisplatin resistance-related protein 9, provides apoptosis resistance [243]. The rs2361000 SNP in the TERT gene has shown a strong association with lung cancer risk in never smokers; and an increased frequency of rs2736100 (TERT) as the risky allele has been seen in pulmonary adenocarcinoma, with the most significant association of rs2736100 at 5p15.33 in pulmonary adenocarcinoma in nonsmokers [242, 244, 245]. Besides 5q15.33, studies have shown no association at three additional susceptible loci at 10q25.2, 6q22.2, and 6q21.32 [245–247].

Genetic factors have clearly been shown to be related to susceptibility to lung cancer, particularly pulmonary adenocarcinoma. Genetic polymorphisms have been identified that have the potential to increase lung cancer risk. These genetic polymorphisms involve genes that are associated primarily with the metabolism of tobacco smoke carcinogens and the suppression of mutations induced by those carcinogens. Tobacco-associated versus nontobacco-associated lung cancers, gender differences, and geographic differences continue to be confounding factors in the evaluation of the genetic factors involved in lung cancer risk. Future studies likely will focus increasingly on the genetic factors related to smoking behavior and the psychological processes involved, even as studies continue to address biological predisposition for the development and progression of lung cancer [248].