Abstract 1602: Time-to-recurrence is decreased in head and neck cancer patients with a common cytochrome P450 1B1 variant (N453S); epidemiological and in vitro findings

Abstract

Abstract Squamous cell carcinoma of the head and neck (HNSCC) is the sixth most common type of cancer. Major risk factors for HNSCC in Western countries include tobacco and alcohol use. Carcinogenic components of tobacco smoke and ethanol can be metabolized by cytochrome P450 1B1 (CYP1B1) into mutagenic intermediates. Several common single nucleotide polymorphisms (SNPs) that introduce an amino acid change have been identified in the coding region of CYP1B1. Two of these SNPs (R48G and A119S) are linked and their function is unclear. The L432V variant has been associated with increased CYP1B1 activity while the N453S variant has been shown to accelerate the degradation of CYP1B1. The goal of this study was to evaluate the contribution of common SNPs in CYP1B1 to both the recurrence of HNSCC and overall survival of patients with HNSCC. Patients (N=155) with HNSCC, excluding oropharynx and nasopharynx, were diagnosed at FCCC between 2001-2008 (median time of follow-up - 3.3 years). DNA samples were genotyped for CYP1B1 SNPs using standard TaqMan assays. The impact of polymorphic genotypes on overall survival and recurrence was assessed using the Kaplan-Meier estimation method and the Cox proportional hazards model. Time-to-recurrence for N453S carriers was significantly greater than that of those carrying the wild-type genotype (p = 0.03). Furthermore, among patients with wild-type CYP1B1, women had a shorter time-to-recurrence than men (p = 0.02). The latter result was consistent with the known ability of CYP1B1 to metabolize estrogens to potentially carcinogenic intermediates. No difference in either survival or recurrence was observed among carriers of either R48G or L432V, as compared to wild-type carriers. In order to begin to understand the mechanism by which the N453S polymorphism may confer a shorter time-to-recurrence, cultured HNSCC cells (SCC15 and UPCI:SCC56) were transfected with plasmids encoding either wild-type CYP1B1 or variant CYP1B1 (N453S) as well as cytochrome P450 oxidoreductase (required for electron transfer) and green fluorescent protein (to measure transfection efficiency). The impact of the variant (N453S) and wild-type CYP1B1 proteins on cell proliferation and apoptosis was compared using the Fluorescent DNA Quantitation kit and the Nexin reagent, respectively. Cells with abundant levels of the N453S variant exhibited a rate of proliferation that was 5 to 8-fold lower than that of cells that overexpressed wild-type CYP1B1. In contrast, the rate of apoptosis among cells overexpressing either wild-type or variant CYP1B1 was comparable. These data provide novel insight into the mechanisms underlying carcinogenesis of the head and neck. More accurate identification of HNSCC patients with a poor prognosis could lead to new opportunities for tailored intervention with more aggressive therapeutic and surveillance strategies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1602. doi:1538-7445.AM2012-1602