Risk of smoking for squamous and small cell carcinomas of the lung modulated by combinations of CYP1A1 and GSTM1 gene polymorphisms in a Japanese population

Abstract

Genes for cytochrome P4501A1 (CYP1A1) and glutathione S-transferase class mu (GSTM1) have been shown to be polymorphic, and have been implicated in tobacco-related carcinogenesis. In the present study, the role of the combined genotypes CYP1A1 and GSTM1 as a possible modulator of smoking related lung cancers was studied in relation to the tobacco smoke exposure level in 118 Japanese patients aged < 70 with squamous or small cell carcinomas of the lung. Among male smoking patients, the overall proportion of the GSTM1 null genotype (GSTM1[-]) was slightly higher than among healthy male smoker controls (56.7% versus 48.1%, P = 0.17). Little difference was observed between smoker patients and corresponding controls in overall frequencies of m2 mutant allele homozygotes (CYP1A1[m2/m2]) (16-18%) and Val encoding allele homozygotes (5-6%). However, when subjects were categorized by both CYP1A1 genotype (MspI polymorphism) and GSTM1 genotype, GSTM1(-) became markedly more expressed in patients with CYP1A1(m2/m2) when compared to the corresponding smoker controls (81.3% versus 39.4%, P < 0.01). When odds ratios were estimated using nonsmoking patients and healthy controls as a reference, the relative risk for developing lung cancer was found to increase in a cigarette dose-dependent manner across all combinations of genotypes. Furthermore, a 7- to 8-fold variation in risk was found among the various combinations; 3.2 in individuals with combined GSTM1(+) and CYP1A1(m2/m2) and 21.9 in those with combined GSTM1(-) and CYP1A1(m2/m2) genotype when the smoking index (sigma cigarettes smoked per day x years of smoking) was set at > or = 800. The results suggest that individuals having CYP1A1(m2/m2) are relatively resistant to tobacco-related lung cancers when combined with GSTM1(+), but are highly susceptible when combined with GSTM1(-). Combined CYP1A1 and GSTM1 genotype is thus a potential predictor of genetic susceptibility to smoking-related lung cancers in populations where CYP1A1 m2 or Val alleles are common.

Cytochrome P4501A1 polymorphism as a susceptibility factor for breast cancer in postmenopausal Chinese women in Taiwan

“…Since CYP1A1 is involved in the activation of procarcinogens, it is reasonable to observe an association between CYP1A1 polymorphism and cancer risk, especially in cancers caused by chemical carcinogens. For example, it has frequently been reported that an increased risk of lung cancer is related to variant CYP1A1 Msp1 genotypes (Kawajiri et al, 1993;Kihara and Noda, 1995;Xu et al, 1996); however, the results vary among ethnic groups (Drakoulis et al, 1994;Hirvonen et al, 1992;Alexandrie et al, 1994). In breast cancer, a significant association related to Msp1 polymorphism was found in African-American patients (Taioli et al, 1995); however, this was not apparent in Caucasians (Bailey et al, 1998;Ishibe et al, 1998).…”

Relationship between genetic polymorphisms of metabolizing enzymes CYP2E1, GSTM1 and Kazakh’s esophageal squamous cell cancer in Xinjiang, China

“…Phase II enzymes can detoxify and process the activated metabolites for final breakdown or excretion. Therefore, the genotypes with high phase I enzyme activity and low phase II enzyme level are considered to pose a high risk of cancer development [2] . Cytochrome P450 (CYP) isoenzymes are one major kind of phase I enzymes and play an important role in the oxidation of chemical compounds, such as polycyclic aromatic hydrocarbons (PAH), often resulting in the formation of highly reactive compounds that are the ultimate carcinogens [3] .…”

Study on Polymorphism and Activities of GSTM1 and CYP1A1 Genes in Connection with Various Cancer Types in Turkey Population

“…Several studies have investigated the association between CYP1A1 polymorphisms and breast cancer risk. For the CYP1A1 polymorphism the reports are also inconclusive; one study reports a decrease in breast cancer risk in Japanese women associated with the CYP1A1 (11). Seven studies examined, individually, the frequencies of both GSTM1 and GSTT1 null genotypes in cases and controls.…”

“…All patients and controls were of turkish population. Genotyping assays CYP1A1 genetic polymorphisms were determined as previously described (8,9,11,14). Primer pair sets were used to detect the polymorphism within exon 7 of the CYP1A1 gene by PCR where the praimer set consisted of sense primer 1A1A: 5'-GAAGTGTATCGGTGAGACCA-3' and antisense primer c53: 5'-GTAGACAGAGTCTAGGCCTCA-3', located about 190 bp downstream of the polymorphism site (Fig.…”