Effect of a genetic polymorphism in CYP1B1 on lung cancer risk and survival

B87 Cytochrome P450 1B1 (CYP1B1) is a Phase I detoxification enzyme involved in the metabolism of both tobacco smoke and estrogen. CYP1B1 gene expression is induced by cigarette smoke exposure and is elevated in many tumors, including lung. Polymorphisms in metabolism genes have also been associated with an increased risk for the development and progression of tumors. Four Single Nucleotide Polymorphisms (SNPs) have been identified within the coding region of CYP1B1. The polymorphism at codon 48 of the CYP1B1 gene is of interest, since it confers an increased level of basal CYP1B1 gene expression. However, the impact of this polymorphism on the development of lung cancer remains under investigated. The present study was conducted to examine the effect of a polymorphism at codon 48 of the CYP1B1 gene (nucleotide transition C to G) on lung cancer risk and survival. DNA was extracted from peripheral mononuclear cells or mouthwash samples from 107 lung cancer patients and 113 healthy control individuals and genotyped using a TaqMan SNP assay (Applied Biosystems). Chi-square and logistic regression analyses were used to examine the ability of the CYP1B1 polymorphism and demographic factors, as well as their interaction, to predict lung cancer risk. Survival data were collected from the medical records of 107 patients as the time (in months) from initial surgery until the most recent follow-up appointment or death. Univariate analysis (Kaplan Meier estimation method) and the multiple Cox proportional hazard models (using all data and stratifying by gender) were used to identify predictors of survival. After controlling for covariates (gender, age and smoking status), logistic regression analyses indicate that a polymorphism at codon 48 of the CYP1B1 gene is not associated with an increased risk of developing lung cancer (P>0.5). However, this polymorphism is significantly associated with the survival of only female lung cancer patients. After controlling for covariates (age, tumor histology, clinical stage, adjuvant treatment, and smoking status) the median length of survival of females with the homozygous variant genotype (GG) was significantly less (22 months) than that of females carrying either the GC or CC (wild-type) genotypes (75 or 89 months, respectively). Survival was reduced significantly in females carrying the GG (variant genotype) instead of CC or GC genotype (HR=17.2, P=0.003 or HR=66.7, P=0.001, respectively). A larger sample size is required to confirm these associations due to the low frequency of the variant genotype. In conclusion, a polymorphism at codon 48 of the CYP1B1 gene is associated with the poor survival of women (not men) with lung cancer. Identification of this subset of female lung cancer patients will provide an opportunity for implementing alternative or more aggressive strategies for therapeutic intervention. (Supported by The Jerome M. Spencer and Arnold Zaslow Family Foundation and by fellowships from the AACR-Pennsylvania Department of Health and the American Society of Preventive Oncology/Cancer Research and Prevention Foundation).