title: Oncogenic PIK3CA mutations in colorectal cancers and polyps.
abstract: Oncogenic PIK3CA mutations contribute to colorectal tumorigenesis by activating AKT signaling to decrease apoptosis and increase tumor invasion. A synergistic association of PIK3CA mutation with KRAS mutation has been suggested to increase AKT signaling and resistance to antiepidermal growth factor receptor inhibitor therapy for advanced colorectal cancer, although studies have been conflicting. We sought to clarify this by examining PIK3CA mutation frequency in relation to other key molecular features of defined pathways of tumorigenesis. PIK3CA mutation was assessed by high resolution melt analysis in 829 colorectal cancer samples and 426 colorectal polyps. Mutations were independently correlated with clinicopathological features including patient age, sex and tumor location as well as molecular features including microsatellite instability, KRAS and BRAF mutation, MGMT methylation and the CpG Island Methylator Phenotype (CIMP). Mutation of the helical (Exon 9) and catalytic (Exon 20) domain mutation hotspots were also examined independently. Overall, PIK3CA mutation was positively correlated with KRAS mutation (p < 0.001), MGMT methylation (p = 0.007) and CIMP (p < 0.001). Novel, exon-specific associations linked Exon 9 mutations to a subgroup of cancers characterized by KRAS mutation, MGMT methylation and CIMP-Low, whilst Exon 20 mutations were more closely linked to features of serrated pathway tumors including BRAF mutation, microsatellite instability and CIMP-High or Low. PIK3CA mutations were uncommonly, but exclusively, seen in tubulovillous adenomas (4/124, 3.2%) and 1/4 (25.0%) tubulovillous adenomas with a focus of cancer. These data provide insight into the molecular events driving traditional versus serrated pathway tumorigenesis.
authors.affiliation: Queensland Institute of Medical Research, Brisbane, Australia. Whitehall@qimr.edu.au
authors.forename: Vicki L J
authors.initials: VL
authors.lastname: Whitehall
authors.forename: Celestine
authors.initials: C
authors.lastname: Rickman
authors.forename: Catherine E
authors.initials: CE
authors.lastname: Bond
authors.forename: Ingunn
authors.initials: I
authors.lastname: Ramsnes
authors.forename: Sonia A
authors.initials: SA
authors.lastname: Greco
authors.forename: Aarti
authors.initials: A
authors.lastname: Umapathy
authors.forename: Diane
authors.initials: D
authors.lastname: McKeone
authors.forename: Rebecca J
authors.initials: RJ
authors.lastname: Faleiro
authors.forename: Ron L
authors.initials: RL
authors.lastname: Buttenshaw
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Worthley
authors.forename: Sam
authors.initials: S
authors.lastname: Nayler
authors.forename: Zhen Zhen
authors.initials: ZZ
authors.lastname: Zhao
authors.forename: Grant W
authors.initials: GW
authors.lastname: Montgomery
authors.forename: Kylie-Ann
authors.initials: KA
authors.lastname: Mallitt
authors.forename: Jeremy R
authors.initials: JR
authors.lastname: Jass
authors.forename: Nagahide
authors.initials: N
authors.lastname: Matsubara
authors.forename: Kenji
authors.initials: K
authors.lastname: Notohara
authors.forename: Tatsuhiro
authors.initials: T
authors.lastname: Ishii
authors.forename: Barbara A
authors.initials: BA
authors.lastname: Leggett
mesh_terms: D000368:Aged; D001483:Base Sequence; D058534:Class I Phosphatidylinositol 3-Kinases; D015331:Cohort Studies; D003111:Colonic Polyps / Q000235:genetics*; D015179:Colorectal Neoplasms / Q000235:genetics*; D017931:DNA Primers; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009857:Oncogenes; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics*
chemical_list: D017931:DNA Primers; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human