PIK3CA and PTEN gene and exon mutation-specific clinicopathologic and molecular associations in colorectal cancer.

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.

• Authors: Fiona L Day, Robert N Jorissen, Lara Lipton, Dmitri Mouradov, Anuratha Sakthianandeswaren, Michael Christie, Shan Li, Cary Tsui, Jeannie Tie, Jayesh Desai, Zheng-Zhou Xu, Peter Molloy, Vicki Whitehall, Barbara A Leggett, Ian T Jones, Stephen McLaughlin, Robyn L Ward, Nicholas J Hawkins, Andrew R Ruszkiewicz, James Moore, Dana Busam, Qi Zhao, Robert L Strausberg, Peter Gibbs, Oliver M Sieber
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 19 Issue 12 Pg. 3285-96 (Jun 15 2013) ISSN: 1557-3265 [Electronic] United States
• PMID: 23633456 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Membrane Proteins
• Phosphatidylinositol 3-Kinases
• Class I Phosphatidylinositol 3-Kinases
• PIK3CA protein, human
• TPTE protein, human
• PTEN Phosphohydrolase

Topics

• Adult
• Aged
• Aged, 80 and over
• Class I Phosphatidylinositol 3-Kinases
• Colorectal Neoplasms (genetics, pathology)
• Exons
• Female
• Gene Expression Regulation, Neoplastic
• Humans
• Loss of Heterozygosity (genetics)
• Male
• Membrane Proteins (genetics)
• Microsatellite Instability
• Middle Aged
• Mutation (genetics)
• Neoplasm Staging
• PTEN Phosphohydrolase (genetics)
• Phosphatidylinositol 3-Kinases (genetics)
• Signal Transduction (genetics)