PIK3CA and PTEN Gene and Exon Mutation-Specific Clinicopathologic and Molecular Associations in Colorectal Cancer

Day, FL; Jorissen, RN; Lipton, L; Mouradov, D; Sakthianandeswaren, A; Christie, M; Li, S; Tsui, C; Tie, J; Desai, J; Xu, ZZ; Molloy, P; Whitehall, V; Leggett, BA; Jones, IT; McLaughlin, S; Ward, RL; Hawkins, NJ; Ruszkiewicz, AR; Moore, J; Busam, D; Zhao, Q; Strausberg, RL; Gibbs, P; Sieber, OM

Author(s): Day, FL; Jorissen, RN; Lipton, L; Mouradov, D; Sakthianandeswaren, A; Christie, M; Li, S; Tsui, C; Tie, J; Desai, J; Xu, ZZ; Molloy, P; Whitehall, V; Leggett, BA; Jones, IT; McLaughlin, S; Ward, RL; Hawkins, NJ; Ruszkiewicz, AR; Moore, J; Busam, D; Zhao, Q; Strausberg, RL; Gibbs, P; Sieber, OM;
Details: Publication Year 2013-06-15,Volume 19,Issue #12,Page 3285-3296
Journal Title: CLINICAL CANCER RESEARCH
Publication Type: Journal Article
Abstract: Purpose: PIK3CA and PTEN mutations are prevalent in colorectal cancer and potential markers of response to mitogen-activated protein/extracellular signal-regulated kinase inhibitors and anti-EGF receptor antibody therapy. Relationships between phosphoinositide 3-kinase (PI3K) pathway mutation, clinicopathologic characteristics, molecular features, and prognosis remain controversial. Experimental Design: A total of 1,093 stage I-IV colorectal cancers were screened for PIK3CA (exons 9 and 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 were integrated with 17 previous reports (n = 5,594). Results: PIK3CA and PTEN mutations were identified in 11.9% and 5.8% of colorectal cancers. PTEN mutation was associated with proximal tumors, mucinous histology, MSI-high (MSI-H), CIMP-high (CIMP-H), 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 (CIMP-L), and KRAS-mutated cancers (P <= 0.011). Comparing PIK3CA exonic mutants, exon 20 mutation was associated with MSI-H, CIMP-H, and BRAF mutation, and exon 9 mutation was associated with KRAS mutation (P <= 0.027). Disease-free survival for stage II/III colorectal cancers did not differ by PI3K pathway status. Conclusion: 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-H/CIMP-H/BRAF(mut)), and PIK3CA exon 9 (and to a lesser extent exon 20) mutation associated with features of the traditional serrated pathway (CIMP-L/KRAS(mut)) of tumorigenesis. Our data highlight the PI3K pathway as a therapeutic target in distinct colorectal cancer subtypes. (C)2013 AACR.
Publisher: AMER ASSOC CANCER RESEARCH
Keywords: ISLAND METHYLATOR PHENOTYPE; MICROSATELLITE INSTABILITY; COLON-CANCER; POOR-PROGNOSIS; RECTAL-CANCER; EXPRESSION; PATHWAY; KRAS; POPULATION; RESISTANCE
Research Division(s): Systems Biology And Personalised Medicine
Publisher's Version: https://doi.org/10.1158/1078-0432.CCR-12-3614

Creation Date: 2013-06-15 12:00:00