[758] Clinicopathologic and Molecular Characterization of PIK3CA Mutations in Colorectal Neoplasms

Efsevia Vakiani, Manick Janakiraman, Ronglai Shen, Zhaoshi Zeng, Jinru Shia, David S Klimstra, Philip Paty, Leonard Saltz, Martin Weiser, David B Solit. Memorial Sloan-Kettering Cancer Center, New York, NY

Background: PIK3CA mutations have been described in 10-20% of colorectal carcinomas. Only a small number of studies have examined their significance, often with conflicting results.
Design: We analyzed frozen tissue from 613 colorectal neoplasms including 34 adenomas for hotspots mutations in PIK3CA (exons 4, 7, 9 and 20), KRAS, and BRAF using a MALDI-TOF mass-spectrometry based genotyping assay. TP53 mutations were also detected using Sanger sequencing. Microsatellite instability testing was performed in 352 cases and clinicopathologic data was collected in all cases. Mutant allele frequency (MAF) was determined in 2 cases using deep sequencing.
Results: PIK3CA mutations were detected in 69 (11.3%) cases including 5 (14.7%) adenomas and the majority of mutations were in exon 9 (n=44, 63.8%). Right-sided tumors were more frequently mutated compared to left-sided and rectal tumors (16.7% vs 9.6% and 9.7%, p=0.03), but there was no association between PIK3CA mutations and sex, age or stage at presentation. PIK3CA mutations were more common in microsatellite unstable (MSI-H) tumors (29% vs. 9.7%, p<0.001), and were observed both in sporadic and hereditary non-polyposis colorectal cancer-associated cases. Compared to PIK3CA wild-type tumors, PIK3CA-mutated tumors were more likely to harbor KRAS mutations (16.1% vs. 7.7%, p=0.002). There was no significant association between PIK3CA and TP53 or BRAF mutations, although none of the tumors with PIK3CA exon 20 mutations harbored a BRAF mutation. In 2 KRAS/PIK3CA mutant cases tested the PIK3CA MAF was lower compared to the KRAS MAF, suggesting the PIK3CA mutation occurred later than the KRAS mutation. There was no significant difference in disease specific survival between PIK3CA mutant and wild type tumors even after MSI-H tumors were excluded from analysis.
Conclusions: PIK3CA mutations are present in adenomas, suggesting that they occur relatively early in colorectal carcinogenesis. They show a strong association with KRAS mutations and are more frequent in right-sided and MSI-H tumors. Contrary to a prior study, we did not observe an association with adverse prognosis.
Category: Gastrointestinal

Monday, March 19, 2012 1:00 PM

Poster Session II # 109, Monday Afternoon

 

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