title: PIK3CA and PTEN gene and exon mutation-specific clinicopathologic and molecular associations in colorectal cancer.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  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-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: Ludwig Colon Cancer Initiative Laboratory, Ludwig Institute for Cancer Research, University of Melbourne, Australia.
authors: Fiona L
authors: FL
authors: Day
authors: Robert N
authors: RN
authors: Jorissen
authors: Lara
authors: L
authors: Lipton
authors: Dmitri
authors: D
authors: Mouradov
authors: Anuratha
authors: A
authors: Sakthianandeswaren
authors: Michael
authors: M
authors: Christie
authors: Shan
authors: S
authors: Li
authors: Cary
authors: C
authors: Tsui
authors: Jeannie
authors: J
authors: Tie
authors: Jayesh
authors: J
authors: Desai
authors: Zheng-Zhou
authors: ZZ
authors: Xu
authors: Peter
authors: P
authors: Molloy
authors: Vicki
authors: V
authors: Whitehall
authors: Barbara A
authors: BA
authors: Leggett
authors: Ian T
authors: IT
authors: Jones
authors: Stephen
authors: S
authors: McLaughlin
authors: Robyn L
authors: RL
authors: Ward
authors: Nicholas J
authors: NJ
authors: Hawkins
authors: Andrew R
authors: AR
authors: Ruszkiewicz
authors: James
authors: J
authors: Moore
authors: Dana
authors: D
authors: Busam
authors: Qi
authors: Q
authors: Zhao
authors: Robert L
authors: RL
authors: Strausberg
authors: Peter
authors: P
authors: Gibbs
authors: Oliver M
authors: OM
authors: Sieber
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D058534:Class I Phosphatidylinositol 3-Kinases; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology; D005091:Exons; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D019656:Loss of Heterozygosity / Q000235:genetics; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D053842:Microsatellite Instability; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009367:Neoplasm Staging; D051059:PTEN Phosphohydrolase / Q000235:genetics*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics
chemical_list: D008565:Membrane Proteins; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; C446603:TPTE protein, human; D051059:PTEN Phosphohydrolase