CYP2E1 Polymorphism, Cigarette Smoking, p53 Expression, and Survival in Non-small Cell Lung Cancer

Abstract

The expression of selected gene products involved in cell differentiation and cell growth and genetic polymorphism of detoxifying genes was examined in 105 surgically resected nonsmall cell lung cancer (NSCLC) patients, and the relationship of these factors was correlated with cigarette smoking and patient survival. Genotyping of peripheral blood lymphocytes from 87 patients was performed for CYP2E1, GSTM1, GSTT1, mEH, and MPO detoxifying genes using polymerase chain reaction. Formalin-fixed, paraffin-embedded tissue was immunostained with antibodies to p53, p27, phospho-AKT, and bcl-2 using the avidin-biotin-peroxidase method and tissue microarray technique. Tumors were assigned a positive or negative score based on more than 10% of tumor cells staining positive with the antibody. The subtypes of NSCLC included 48 adenocarcinomas, 47 squamous cell carcinomas, and 10 large cell undifferentiated carcinomas. A total of 54 tumors were pathologic stage I, 23 were stage II, and 26 were stage III. All subjects smoked (range, 10-175 pack-years; mean, 60 pack-years). The mean overall survival was 112 weeks (median, 129 weeks). Patients with p53-positive tumors had significantly fewer pack-years of smoking (52 pack-years vs 72 pack-years; P = 0.021), smoked fewer years (34 years vs 40 years; P = 0.018), and had significantly better survival compared with those with p53-negative tumors (P = 0.045). When smoking history was further analyzed, the authors found that p53 expression was associated with the number of years smoked and not the number of packs smoked per day. Patients with squamous cell carcinoma had smoked longer compared with those with adenocarcinoma (P = 0.011). Significant association was seen between the CYP2E1 wild-type allele and better survival (P = 0.016). Patients with stage I tumors had better survival compared with stages II and III (P = 0.032). No association was found between survival and tumor type; tumor differentiation; expression of phospho-AKT, p27, and bcl-2; and polymorphic metabolizing genes other than CYP2E1. The significant association of long duration of smoking (>40 years) with loss of p53 expression and poor survival suggests inactivation of the protective p53 pathway in those who had a history of more than 40 years of smoking.

Cytochrome P-450 Polymorphisms and Clinical Outcome in Patients with Non-Small Cell Lung Cancer

“…Likewise, the recent results of Karacaoğlan et al 9 on the CYP2E1*5B polymorphism are also in line with the findings of Li et al 18 , both in regard to response to chemotherapy and survival. However, their findings are in contrast to those of Oyama et al 24 and Haque et al 25 in respect to survival. The findings of Karacaoğlan et al 9 in regard to the effect of CYP2E1*6 polymorphism on survival also coincided with the results of Przygodzki et al 23 The only study for the CYP2E1*7B polymorphism on this issue was reported by Karacaoğlan et al 9 who observed no association between the CYP2E1*7B polymorphism and response to chemotherapy and survival in patients with NSCLC.…”

“…For example, studies on the CYP2E1*5B polymorphism are rather conflicting. Oyama et al 24 found an increase in survival in mutant allele carriers, whereas Haque et al 25 observed shorter survival in mutant carriers, and Li et al 18 found no association between this CYP gene polymorphism and survival in patients with NSCLC. Przygodzki et al 23 reported no significant association between the CYP2E1*6 polymorphism and survival in patients with NSCLC.…”

Xenobiotic/drug metabolizing enzyme and TP53 polymorphisms and clinical outcome in advanced nonsmall cell lung cancer patients

“…Emerging evidence, although inconclusive, has shown that TP53 (Arg72Pro) polymorphism is not only associated with lung cancer risk but also influences patient response to platinum-based chemotherapy and survival (28)(29)(30)(31)(32)(33). Furthermore, associations have also been shown between polymorphisms of some CYP genes such as the CYP2E1 or CYP1A1 and TP53 gene in NSCLC (5,6,9,34,35).…”

Metabolism and Toxicity of Styrene in Microsomal Epoxide Hydrolase-Deficient Mice

“…In a review of the literature, Lee et al (2002) did not find a consistent change in the carcinogenic effect of smoking according to mEH polymorphisms. However, Cajas-Salazar et al (2003) found that smokers carrying the high-activity form of mEH had a higher risk of lung cancer, and Haque et al (2004) found no effect of mEH polymorphisms on survival in smokers. As would be expected from the mouse studies with benzene, Garte et al (2008) discovered that subjects with the genotype for fast catalytic conversion of benzene, a bioactivation process, had an increased genetic susceptibility as determined by measurement of single-strand breaks in DNA.…”