Abstract A111: Genetic variations in five estrogen metabolizing genes and endometrial cancer risk

A111 BACKGROUND Estrogen plays a major role in endometrial carcinogenesis and the balance of estrogen metabolites has been hypothesized to be a determinant of risk. Cytochrome p450 (CYP) enzymes, CYP1A1, CYP1A2, and CYP3A4 catalyze the 2-OHE1 pathway, whereas the CYP1B1 catalyzes the 4-OHE1 pathway. The activity of these enzymes determines the proportion of metabolites and a higher proportion of the 4-OHE1 metabolites is thought to have a higher carcinogenic potential. Although several studies have examined the association between single nucleotide polymorphisms (SNPs) of these estrogen metabolizing genes and endometrial cancer risk, results have been inconsistent and limited to putatively functional variants. METHODS We comprehensively assessed known common genetic variation in these estrogen metabolizing genes by genotyping candidate and tagging SNPs (tagSNPs) in a population-based case-control study of 417 endometrial cancer cases and 407 controls (most of whom were postmenopausal) conducted in Poland (Warsaw and Lodz) between 2001-2003. The following criteria were used to identify tagSNPs: (1) located in the respective gene or within the 5kb flanking regions, (2) with a minor allele frequency greater than or equal to 0.01 in Caucasian populations, and (3) with pairwise r 2 =0.90 between tagSNPs and undetermined SNPs. A total of 5 SNPs for CYP1A1 , 7 for CYP1A2 , 9 for CYP1A1/A2 , 34 for CYP1B1 , 6 for CYP3A4 , and 12 for COMT were examined. Genotyping was performed using an Illumina Custom Infinium iSelect assay that included nearly 27,000 SNPs with coverage of over 1,300 candidate genes. RESULTS We did not observe significant associations for candidate variants of CYP1A1 (rs1048943 (I462V) per C allele: OR (95% CI)=0.98 (0.56-1.72); rs1799814 (T461N) per T allele: 1.75 (0.94-3.24)); CYP1A2 (rs762551 (IVS1-154C>A) per C allele:0.91(0.74-1.12)); CYP1B1 (rs1056827 (A119S) per A allele: 0.98 (0.80-1.20); rs1056836 (V432L) per C allele: 0.96 (0.79-1.18); rs1800440 (N453S) per C allele: 1.15 (0.88-1.51)); and CYP3A4 (rs2740574 (-391A>G) per C allele: 1.46 (0.84-2.54)). In addition, we did not observe any significant association with endometrial cancer risk in haplotype analyses (global p-value>0.3) or the individual tagSNPs analyses (p-trend>0.09). Meta-analysis including our study and previous reports for these SNPs did not show significant overall associations; however, there is substantial heterogeneity across studies. DISCUSSION Our findings do not provide evidence for a substantial association between common genetic variation of estrogen metabolizing genes with endometrial cancer risk. However weak associations with these genes or association with other genes in the estrogen metabolizing pathway may exist. Citation Information: Cancer Prev Res 2008;1(7 Suppl):A111.