GSTM1 and NAT2 polymorphisms in operable and non-operable lung cancer patients

Abstract

We have genotyped 657 Norwegian men, including 282 lung cancer patients (147 non-operable and 135 operable) and 375 healthy referents (210 smokers and 165 non-smokers), to study the possibility that glutathione S-transferase M1 (GSTM1)-null and/or N-acetyl transferase 2 (NAT2)-slow genotypes confer susceptibility towards lung cancer in smokers. Compared with smoking referents, there was a significant over-representation of the GSTM1-null genotype among patients with squamous cell carcinoma (SQ) [odds ratio (OR) = 1.7, 95% confidence interval (95%CI) = 1.1-2.7], and the NAT2-slow genotype among patients with large cell carcinoma or mixed histological diagnosis (LM) (OR = 2.5, 95%CI = 1.0-6.1). In contrast to operable patients, non-operable patients showed a clear over-representation of slow genotypes if they were younger (</= 63 years; versus older: OR = 3.9, 95%CI = 1.7-8.8) or younger light smokers [</= 30 pack-years (PY); versus heavy smokers: OR = 5.7, 95%CI = 1.4-23.3]. Among younger light smokers, the slow genotype appeared to be associated with an increased risk of developing non-operable tumours only (OR = 6.3, 95%CI = 1.9-20.4), especially other types of tumours than SQ (OR = 10.8, 95%CI = 1.4-83.9). The null genotype (OR = 3.9, 95%CI = 1.1-13.5) and the null/slow combination (OR = 4.5, 95%CI = 1.5-13.8) seemed to increase the risk for non-operable SQ only. These results are supported by logistic regressions of patients allowing interactions between tumour type (or treatment) and PY (or age), and indicate that the GSTM1-null genotype could be an important susceptibility factor for SQ while the NAT2-slow genotype may have an impact on other types of lung cancer. Individuals with the GSTM1-null and/or NAT2-slow genotypes may constitute susceptible groups with increased risk to contract non-operable lung cancer at younger age and lower smoking dose.

CYP1A1 and CYP1B1 genetic polymorphisms, smoking and breast cancer risk in a Finnish Caucasian population

“…Our finding agrees with the suggestions that the importance of genetic susceptibility might be more significant at lower levels of exposure to carcinogens [71]; the xenobiotic metabolizing enzymes may saturate at higher concentrations of the substrates. Accordingly, NAT2, which is known to be involved in the metabolism of tobacco carcinogens, has been suggested to be associated with increased risk of cancer especially at low doses of tobacco carcinogens in studies by us [62,72] and others [73,74].…”

Platinum/paclitaxel-based chemotherapy in advanced ovarian carcinoma: glutathione S -transferase genetic polymorphisms as predictive biomarkers of disease outcome

“…Our results are consistent with the frequencies observed in the literature of GSTM1-null and GSTT1-null genotypes. 10,19,21 No useful biological marker for resistance or sensitivity to chemotherapy is known for ovarian cancer. The treatment of ovarian cancer is evolving rapidly.…”

Polymorphism of selected enzymes involved in detoxification and biotransformation in relation to lung cancer

“…The unfavourable combination of NAT2 slow acetylator genotype with the lack of glutathione-S-transferase M1 (i.e. null genotype) presents an almost 5 and 7 -fold increase in the risk of SqCC and mesothelioma of lung, respectively [136,137]. Despite these results being promising in suggesting a role of NAT2 polymorphism in lung cancer development, some inconsistency still exist.…”