Endometrial cancer and genetic variation in PTEN, PIK3CA, AKT1, MLH1, and MSH2 within a population-based case-control study

ObjectiveWe assessed whether common genetic variation in PTEN, PIK3CA, AKT1, MLH1, and MSH2-genes that reportedly are frequently altered in endometrial cancer-was associated with risk of endometrial cancer.MethodsUsing data from a population-based case-control study in Poland (PECS) of 417 cases and 407 matched controls, we genotyped 76 tagging single nucleotide polymorphisms (tagSNPs; located in or within 10 kb upstream or 5 kb downstream of the gene of interest, minor allele frequency >=5% among various ethnic groups, and not already represented by another tagSNP at a LD of r2 >=0.80) on an Illumina Custom Infinium iSelect assay that included over 29,000 SNPs in 1316 genes. For individual SNPs, we used unconditional logistic regression models, adjusted for age and site, to generate odds ratios (ORs) and 95% confidence intervals (CIs). To replicate the one statistically significant association in PECS, we independently genotyped that tagSNP among 1141 endometrial cancer cases and 2275 controls from the SEARCH study in the UK. We assessed haplotypes via extended haplotype blocks and the sequential haplotype scan method.ResultsThe rs2677764 tagSNP in PIK3CA was statistically significantly associated with endometrial cancer in PECS (OR = 1.42, 95% CI, 1.03-1.95; P = 0.03) but not SEARCH (OR = 0.98, 95% CI = 0.82-1.17). Of the 25 haplotypes observed in at least 5% of cases and controls in PECS, only 1, in PIK3CA, was statistically significantly associated with endometrial cancer (OR = 1.39, 95% CI, 1.00-1.93). All haplotype global p-values were null.ConclusionCommon genetic variation in PTEN, PIK3CA, AKT1, MLH1, or MSH2 was not statistically significantly associated with endometrial cancer.

Research Highlights► tagSNP rs2677764 in PIK3CA was initially associated with endometrial cancer. ► Replication in an independent study dataset did not confirm the initial association. ► tagSNPs in PTEN, AKT1, MLH1, and MSH2 were not associated with endometrial cancer.