Abstract 2850: Endometrial cancer and genetic variation in PTEN, PIK3CA, AKT1, MLH1, and MSH2: results and replication in two case-control studies

Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC PTEN, PI3KCA, AKT, MLH1, and MSH2 likely influence endometrial carcinogenesis. PTEN regulates the crucial PI3K signaling pathway, which influences AKT, a serine-threonine kinase that affects apoptosis and cell proliferation; inadequate progesterone-stimulated apoptosis plus excess estrogen-driven proliferation are crucial for endometrial carcinoma. MLH1 and MSH2 influence DNA mismatch repair and microsatellite instability, which are often defective in endometrial cancers. We investigated common genetic variation in these genes among 417 cases and 407 matched controls from the population-based Poland Endometrial Case-control Study (PECS). We genotyped 76 tagging single nucleotide polymorphisms (tagSNPs) that were located in or within 10kb upstream or 5kb downstream of these genes, had a MAF>=5% in various ethnic groups, and were not already represented by another tagSNP at a linkage disequilibrium of r2>=0.80. Genotyping was performed on an Illumina Custom Infinium iSelect assay that includes 29,289 SNPs in 1316 genes. For individual SNPs, we used unconditional logistic regression, adjusted for age and site, to generate odds ratios (ORs) and 95% confidence intervals (CIs) for heterozygous genotypes, minor homozygous genotypes, and trends for number of minor alleles under log-additive inheritance. Only 1 tagSNP, rs2677764 in PIK3CA, was statistically significantly associated with endometrial cancer. Compared with a referent group of CC, the ORs (95% CIs) were 1.47 (1.03-2.10) for CT and 1.56 (0.43-5.60) for TT. The OR for the trend was 1.42 (95% CI, 1.03-1.95; P=0.03). We chose extended blocks as the main haplotype analysis, used an E-M algorithm to simultaneously reconstruct haplotypes and estimate ORs, and used a sequential-scan method to identify statistically significant haplotypes. All global p-values for the 25 haplotypes observed in at least 5% of cases and controls were null. One haplotype in PIK3CA was significantly associated with endometrial cancer (OR=1.39. 95% CI, 1.00-1.93). We also used adaptive rank truncated product (ARTP) methods to detect gene associations, but none were statistically significant. To further assess the validity of the association with rs2677764, we genotyped that SNP in a 2nd study, the SEARCH study in the UK, with 1141 endometrial cancer cases and 2275 controls. For rs2677764, the ORs (95% CIs) were 0.93 (0.77-1.13) for CT, 1.27 (0.68-2.39) for TT, and 0.98 (0.82-1.17) for the trend test. In a fixed-effect meta-analysis combining PECS and SEARCH, rs2677764 was not associated with endometrial cancer: OR=1.15 (95% CI, 0.80-1.66; P=0.45 for trend test). The absence of replication in SEARCH of an association with rs2677764 in PIK3CA in PECS and the null results from haplotype and ARTP analyses indicate that these common genetic variations in PTEN, PI3KCA, AKT, MLH1, and MSH2 do not substantially affect endometrial cancer risk. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2850.