title: PIK3CA activating mutation in colorectal carcinoma: associations with molecular features and survival.
abstract: Mutations in PIK3CA are present in 10 to 15% of colorectal carcinomas. We aimed to examine how PIK3CA mutations relate to other molecular alterations in colorectal carcinoma, to pathologic phenotype and survival. PIK3CA mutation testing was carried out using direct sequencing on 757 incident tumors from the Melbourne Collaborative Cohort Study. The status of O-6-methylguanine-DNA methyltransferase (MGMT) was assessed using both immunohistochemistry and methyLight techniques. Microsatellite instability, CpG island phenotype (CIMP), KRAS and BRAF V600E mutation status, and pathology review features were derived from previous reports. PIK3CA mutation was observed in 105 of 757 (14%) of carcinomas, characterized by location in the proximal colon (54% vs. 34%; P<0.001) and an increased frequency of KRAS mutation (48% vs. 25%; P<0.001). High-levels of CIMP were more frequently found in PIK3CA-mutated tumors compared with PIK3CA wild-type tumors (22% vs. 11%; P = 0.004). There was no difference in the prevalence of BRAF V600E mutation between these two tumor groups. PIK3CA-mutated tumors were associated with loss of MGMT expression (35% vs. 20%; P = 0.001) and the presence of tumor mucinous differentiation (54% vs. 32%; P<0.001). In patients with wild-type BRAF tumors, PIK3CA mutation was associated with poor survival (HR 1.51 95% CI 1.04-2.19, P = 0.03). In summary, PIK3CA-mutated colorectal carcinomas are more likely to develop in the proximal colon, to demonstrate high levels of CIMP, KRAS mutation and loss of MGMT expression. PIK3CA mutation also contributes to significantly decreased survival for patients with wild-type BRAF tumors.
authors.affiliation: Cancer and Population Studies Group, Queensland Institute of Medical Research, Herston, Australia. c.rosty@uq.edu.au
authors.forename: Christophe
authors.initials: C
authors.lastname: Rosty
authors.forename: Joanne P
authors.initials: JP
authors.lastname: Young
authors.forename: Michael D
authors.initials: MD
authors.lastname: Walsh
authors.forename: Mark
authors.initials: M
authors.lastname: Clendenning
authors.forename: Kristy
authors.initials: K
authors.lastname: Sanderson
authors.forename: Rhiannon J
authors.initials: RJ
authors.lastname: Walters
authors.forename: Susan
authors.initials: S
authors.lastname: Parry
authors.forename: Mark A
authors.initials: MA
authors.lastname: Jenkins
authors.forename: Aung Ko
authors.initials: AK
authors.lastname: Win
authors.forename: Melissa C
authors.initials: MC
authors.lastname: Southey
authors.forename: John L
authors.initials: JL
authors.lastname: Hopper
authors.forename: Graham G
authors.initials: GG
authors.lastname: Giles
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Williamson
authors.forename: Dallas R
authors.initials: DR
authors.lastname: English
authors.forename: Daniel D
authors.initials: DD
authors.lastname: Buchanan
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D058534:Class I Phosphatidylinositol 3-Kinases; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000401:mortality* / Q000473:pathology; D018899:CpG Islands; D019175:DNA Methylation; D015254:DNA Modification Methylases / Q000235:genetics; D045643:DNA Repair Enzymes / Q000235:genetics; D005091:Exons; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics*; D011446:Prospective Studies; D011518:Proto-Oncogene Proteins / Q000235:genetics; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D015533:Transcriptional Activation; D025521:Tumor Suppressor Proteins / Q000235:genetics; D018631:ras Proteins / Q000235:genetics
chemical_list: C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D025521:Tumor Suppressor Proteins; D015254:DNA Modification Methylases; C515491:MGMT protein, human; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; D048493:Proto-Oncogene Proteins B-raf; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins; D045643:DNA Repair Enzymes