Day FL, Jorissen RN, Lipton L, Mouradov D, Sakthianandeswaren A, Christie M, Li S, Tsui C, Tie J, Desai J, Xu ZZ, Molloy PL, Whitehall VL, Leggett BA, Jones IT, McLaughlin S, Ward RL, Hawkins NJ, Ruszkiewicz AR, Moore J, Busam D, Zhao Q, Strausberg RL, Gibbs P, Sieber OM
PIK3CA and PTEN Gene and Exon Mutation-specific Clinicopathological and Molecular Associations In Colorectal Cancer.
Clinical Cancer Research : an Official Journal of the American Association for Cancer Research. 2013 Apr 30;
PURPOSE: PIK3CA and PTEN mutations are prevalent in colorectal cancer (CRC), and potential markers of response to MEK inhibitors and anti-EGFR antibody therapy. Relationships between PI3K pathway mutation, clinicopathological characteristics, molecular features and prognosis remain controversial. EXPERIMENTAL DESIGN: 1,093 stage I-IV CRCs were screened for PIK3CA (exons 9, 20), KRAS (codons 12-13), BRAF (codon 600) mutations and microsatellite instability (MSI). PTEN (exons 3-8) and CpG island methylator phenotype (CIMP) status were determined in 744 and 489 cases. PIK3CA data was integrated with 17 previous reports (n=5,590). RESULTS: PIK3CA and PTEN mutations were identified in 11.9% and 5.8% of CRCs. PTEN mutation was associated with proximal tumors, mucinous histology, MSI-high, CIMP-high and BRAF mutation (P<0.02). PIK3CA mutation was related to older age, proximal tumors, mucinous histology and KRAS mutation (P<0.04). In integrated cohort analysis, PIK3CA exon 9 and 20 mutations were overrepresented in proximal, CIMP-low and KRAS mutated cancers (P=0.011). Comparing PIK3CA exonic mutants, exon 20 mutation was associated with MSI-high, CIMP-high and BRAF mutation, and exon 9 mutation was associated with KRAS mutation (P=0.027). Disease-free survival for stage II/III CRCs did not differ by PI3K pathway status. CONCLUSIONS: PI3K pathway mutation is prominent in proximal colon cancers, with PIK3CA exon 20 and PTEN mutations associated with features of the sessile serrated pathway (MSI-high/CIMP-high/BRAF(mut)), and PIK3CA exon 9 (and to a lesser extent exon 20) mutation associated with features of the traditional serrated pathway (CIMP-low/KRAS(mut)) of tumorigenesis. Our data highlight the PI3K pathway as a therapeutic target in distinct CRC subtypes.