title: Prognostic impact of KRAS, NRAS, BRAF, and PIK3CA mutations in primary colorectal carcinomas: a population-based study.
abstract: Activation of oncogenes downstream the EGFR gene contributes to colorectal tumorigenesis and determines the sensitivity to anti-EGFR treatments. The aim of this study was to evaluate the prognostic value of KRAS, BRAF, NRAS and PIK3CA mutations in a large collection of CRC patients from genetically-homogeneous Sardinian population.
  
  
  
  A total of 1284 Sardinian patients with histologically-proven diagnosis of colorectal carcinoma (CRC) and presenting with metastatic disease were included into the study. Genomic DNA was isolated from formalin-fixed, paraffin-embedded primary tumour tissue samples of CRC patients and screened for mutations in RAS and BRAF genes, using pyrosequencing assays, and in PIK3CA gene, using automated DNA sequencing assays.
  
  
  
  Overall, mutation rates were 35.6 % for KRAS, 4.1 % for NRAS, and 2.1 % for BRAF. Among available DNA samples, 114/796 (14.3 %) primary CRCs were found to carry a mutation in the PIK3CA gene. In this subset of patients analysed in all four genes, a pathogenetic mutation of at least one gene was discovered in about half (378/796; 47.5 %) of CRC cases. A mutated BRAF gene was found to steadily act as a negative prognostic factor for either time to progression as metastatic disease (from detection of primary CRC to diagnosis of first distant metastasis; p = 0.009) or partial survival (from diagnosis of advanced disease to the time of death or last control; p = 0.006) or overall survival (p < 0.001). No significant impact on prognosis was observed for mutated KRAS, NRAS, and PIK3CA genes or combined RAS mutations (all RAS).
  
  
  
  Our study defines both prevalence and prognostic role of main activated oncogenes in a population-based large collection of CRC patients.
authors.affiliation: Institute of Biomolecular Chemistry, CNR, Sassari, Italy.
authors.forename: Grazia
authors.initials: G
authors.lastname: Palomba
authors.affiliation: Department of Surgical, Microsurgical and Medical Sciences, University of Sassari, Viale San Pietro 43, 07100, Sassari, PC, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Doneddu
authors.affiliation: Department of Surgical, Microsurgical and Medical Sciences, University of Sassari, Viale San Pietro 43, 07100, Sassari, PC, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Cossu
authors.affiliation: Department of Surgical, Microsurgical and Medical Sciences, University of Sassari, Viale San Pietro 43, 07100, Sassari, PC, Italy. panospaliogiannis@gmail.com.
authors.forename: Panagiotis
authors.identifier: 0000-0001-5485-6056
authors.initials: P
authors.lastname: Paliogiannis
authors.affiliation: Institute of Biomolecular Chemistry, CNR, Sassari, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Manca
authors.affiliation: Institute of Biomolecular Chemistry, CNR, Sassari, Italy.
authors.forename: Milena
authors.initials: M
authors.lastname: Casula
authors.affiliation: Institute of Biomolecular Chemistry, CNR, Sassari, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Colombino
authors.affiliation: Oncology Unit, Businco Hospital, Cagliari, Italy.
authors.forename: Annamaria
authors.initials: A
authors.lastname: Lanzillo
authors.affiliation: Oncology Unit, Businco Hospital, Cagliari, Italy.
authors.forename: Efisio
authors.initials: E
authors.lastname: Defraia
authors.affiliation: Medical Oncology Unit, University-Hospital of Sassari (AOU), Sassari, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Pazzola
authors.affiliation: Medical Oncology Unit, University-Hospital of Sassari (AOU), Sassari, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Sanna
authors.affiliation: Medical Oncology Unit, University-Hospital of Sassari (AOU), Sassari, Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: Putzu
authors.affiliation: Oncology Unit, Local Health Agency, Olbia, Italy.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Ortu
authors.affiliation: Department of Medical Oncology, University of Cagliari, Cagliari, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Scartozzi
authors.affiliation: Department of Medical Oncology, University of Cagliari, Cagliari, Italy.
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Ionta
authors.affiliation: Oncology Unit, Civil Hospital, Alghero, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Baldino
authors.affiliation: Oncology Unit, Zonchello Hospital, Nuoro, Italy.
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Sarobba
authors.affiliation: Oncology Unit, Zonchello Hospital, Nuoro, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Capelli
authors.affiliation: Oncology Unit, Local Health Agency, Oristano, Italy.
authors.forename: Tito
authors.initials: T
authors.lastname: Sedda
authors.affiliation: Oncology Unit, Local Health Agency, Carbonia-Iglesias, Italy.
authors.forename: Luciano
authors.initials: L
authors.lastname: Virdis
authors.affiliation: Oncology Unit, Local Health Agency, Lanusei, Italy.
authors.forename: Michela
authors.initials: M
authors.lastname: Barca
authors.affiliation: Oncology Unit, Local Health Agency, Lanusei, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Gramignano
authors.affiliation: Department of Surgical, Microsurgical and Medical Sciences, University of Sassari, Viale San Pietro 43, 07100, Sassari, PC, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Budroni
authors.affiliation: Department of Surgical, Microsurgical and Medical Sciences, University of Sassari, Viale San Pietro 43, 07100, Sassari, PC, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Tanda
authors.affiliation: Institute of Biomolecular Chemistry, CNR, Sassari, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Palmieri
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D058534:Class I Phosphatidylinositol 3-Kinases / Q000235:genetics*; D015179:Colorectal Neoplasms / Q000235:genetics*; D005260:Female; D020558:GTP Phosphohydrolases / Q000235:genetics*; D056726:Genetic Association Studies; D005820:Genetic Testing; D005843:Geography; D006801:Humans; D007558:Italy; D053208:Kaplan-Meier Estimate; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D059645:Mutation Rate; D011379:Prognosis; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*
chemical_list: C117307:KRAS protein, human; D008565:Membrane Proteins; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; D048493:Proto-Oncogene Proteins B-raf; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras)
keywords: BRAF; Colorectal cancer; KRAS; NRAS; PIC3CA