title: Mutations in the RAS-MAPK, PI(3)K (phosphatidylinositol-3-OH kinase) signaling network correlate with poor survival in a population-based series of colon cancers.
abstract: The RAS-MAPK, PI (3)K signaling pathways form a network that play a central role in tumorigenesis. The BRAF, KRAS and PI3KCA genes code 3 partners of this network and have been found to be activated by mutation in colorectal cancer; these mutations lead to unrestricted cell growth. We evaluated the clinicopathological features and the prognosis of patients with activated-network colon cancers in a population-based study. A total of 586 colon adenocarcinomas were evaluated using sequencing for mutations of KRAS and PI3KCA, and allelic discrimination for mutation of BRAF. Clinicopathological characteristics were correlated to the risk of bearing a mutation of the network using logistic regression. Three-year survival rates were compared with the Log rank test. A multivariate survival analysis using the Cox model was performed. After adjustment for age and microsatellite instability, activation of the network by mutation of at least 1 of the 3 genes was significantly associated with female sex (p = 0.02) and proximal location (p < 0.001). Lower levels of 3-year survival were associated with activation of the network by mutation of at least 1 of the 3 genes (59.4 and 69.4%, respectively; p = 0.009). These results remained significant in a multivariate analysis adjusted for sex, age, location, stage and microsatellite instability (HR = 1.48; CI CI(95%) = [1.07-2.04]). Our study is the first report to underline the potential role of RAS-MAPK, PI (3)K network mutations on survival in colon cancers. Because of the role of this signaling network on anticancer agents, the evaluation of its mutations could have clinical implications.
authors.affiliation: INSERM, U866, Dijon, F-21079, France.
authors.forename: Ludovic
authors.initials: L
authors.lastname: Barault
authors.forename: Nicolas
authors.initials: N
authors.lastname: Veyrie
authors.forename: Valerie
authors.initials: V
authors.lastname: Jooste
authors.forename: Delphine
authors.initials: D
authors.lastname: Lecorre
authors.forename: Caroline
authors.initials: C
authors.lastname: Chapusot
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Ferraz
authors.forename: Astrid
authors.initials: A
authors.lastname: Lièvre
authors.forename: Marion
authors.initials: M
authors.lastname: Cortet
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Bouvier
authors.forename: Patrick
authors.initials: P
authors.lastname: Rat
authors.forename: Patrick
authors.initials: P
authors.lastname: Roignot
authors.forename: Jean
authors.initials: J
authors.lastname: Faivre
authors.forename: Pierre
authors.initials: P
authors.lastname: Laurent-Puig
authors.forename: Francoise
authors.initials: F
authors.lastname: Piard
mesh_terms: D000230:Adenocarcinoma / Q000453:epidemiology / Q000235:genetics* / Q000401:mortality; D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics; D058534:Class I Phosphatidylinositol 3-Kinases; D003110:Colonic Neoplasms / Q000453:epidemiology / Q000235:genetics* / Q000401:mortality; D005260:Female; D005602:France / Q000453:epidemiology; D006801:Humans; D008297:Male; D053842:Microsatellite Instability; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D015398:Signal Transduction; D015996:Survival Rate; D018631:ras Proteins / Q000235:genetics*
chemical_list: D014408:Biomarkers, Tumor; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D020928:Mitogen-Activated Protein Kinases; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins