Abstract 3217: Influence of PIK3CA mutation and methylation of BNIP3, p16 and Dkk1 on outcome in colorectal cancer

Abstract

Abstract Many studies have exhibited that EGFR pathway triggers a complex program of intracellular signals ant is activated in various human cancers. Among the oncogenic abnormalities that affect this pathway, mutation of PIK3CA and K-Ras mutation are reported to appear most frequently in colorectal cancer (CRC). Epigenetic alteration such as promoter hypermethylation of gene, as well as genetic abnormality such as gene mutation, occurs frequently during the pathogenesis of human cancers. Recent studies exhibit the increasing observations that both epigenetic and genetic changes combine to determine the phenotype of cancer. However, the relationship between PIK3CA and KRAS mutations and methylation status remains uncertain in CRC. Therefore, we examined the mutation of PIK3CA and KRAS and the methylation status of BNIP3, p16 and hMLH1 in CRC and analyzed the influence of the combination of mutation and methylation on prognosis in CRC patients. Tissue samples from 166 CRC patients who underwent surgical resection were examined. The sequences of exons 9 and 20 of PIK3CA and exon 1 of K-Ras were determined by direct sequencing, and the methylation status by MethyLight, using genomic DNA extracted from paraffin-embedded blocks. Correlation between these factors and clinicopathological findings/patients survival were examined. As a result, mutations of PIK3CA and KRAS were found in 12% and 31% of the specimens respectively, and methylations of BNIP3, p16 and hMLH1 in 58%, 33% and 21% respectively. Mutation and methylation of each gene had no correlation with any clinicopathological factor. Patients with PIK3CA mutation and/or two or three methylations had significantly shorter disease-specific survival than those without both mutation and methylation (p=0.0082, Log-rank test). Classifying CRC based on PIK3CA mutation and BNIP3, p16 and hMLH1 methylation status may be a clinically powerful predictor of patient outcome. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3217. doi:10.1158/1538-7445.AM2011-3217