title: BRAF codons 594 and 596 mutations identify a new molecular subtype of metastatic colorectal cancer at favorable prognosis.
abstract: BACKGROUND
  While the negative prognostic role of BRAF V600E mutation in metastatic colorectal cancer (mCRC) is well established, the impact of BRAF codons 594 and 596 mutations, occurring in <1% of CRCs, is completely unknown. The present work aims to describe clinical, pathological and molecular features and prognosis of BRAF codons 594 and 596 mutant mCRCs, compared with BRAF V600E mutant and wild-type ones.
  
  
  METHODS
  Patients treated for mCRC at three Italian Institutions between October 2006 and October 2014, with available KRAS and NRAS codon 12, 13, 59, 61, 117 and 146 and BRAF codon 594, 596 and 600 mutational status, as detected by means of direct sequencing or matrix assisted laser desorption ionization time-of-flight MassArray, were included.
  
  
  RESULTS
  Ten patients bearing BRAF codons 594 or 596 mutated tumors were identified and compared with 77 and 542 patients bearing BRAF V600E mutated and BRAF wild-type tumors, respectively. While BRAF V600E mutated tumors were more frequently right-sided, mucinous and with peritoneal spread, BRAF 594 or 596 mutated were more frequently rectal, nonmucinous and with no peritoneal spread. All BRAF 594 or 596 mutated tumors were microsatellite stable. Patients with BRAF codons 594 or 596 mutated tumors had markedly longer overall survival (OS) when compared with BRAF V600E mutated [median OS: 62.0 versus 12.6 months; hazard ratio: 0.36 (95% confidence interval 0.20-0.64), P = 0.002], both at univariate and multivariate analyses.
  
  
  CONCLUSIONS
  BRAF codon 594 or 596 mutated mCRCs are different from BRAF V600E ones in terms of molecular features, pathological characteristics and clinical outcome. This is consistent with preclinical evidences of a kinase inactivating effect of these mutations. The role of CRAF in transducing the intracellular signal downstream BRAF 594 or 596 mutated proteins opens the way to further preclinical investigation.
authors.affiliation: Unit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, Pisa.
authors.forename: C
authors.initials: C
authors.lastname: Cremolini
authors.affiliation: Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan.
authors.forename: M
authors.initials: M
authors.lastname: Di Bartolomeo
authors.affiliation: S. C. Oncologia Falck, Niguarda Cancer Center, Ospedale Niguarda Ca' Granda, Milano.
authors.forename: A
authors.initials: A
authors.lastname: Amatu
authors.affiliation: Unit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, Pisa.
authors.forename: C
authors.initials: C
authors.lastname: Antoniotti
authors.affiliation: Unit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, Pisa.
authors.forename: R
authors.initials: R
authors.lastname: Moretto
authors.affiliation: Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan.
authors.forename: R
authors.initials: R
authors.lastname: Berenato
authors.affiliation: Department of Pathology and Molecular Biology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan.
authors.forename: F
authors.initials: F
authors.lastname: Perrone
authors.affiliation: Department of Pathology and Molecular Biology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan.
authors.forename: E
authors.initials: E
authors.lastname: Tamborini
authors.affiliation: Department of Medical Oncology, Azienda Ospedaliero-Universitaria, Udine.
authors.forename: G
authors.initials: G
authors.lastname: Aprile
authors.affiliation: UOC Oncologia Medica 1, Istituto Oncologico Veneto-IRCCS, Padova.
authors.forename: S
authors.initials: S
authors.lastname: Lonardi
authors.affiliation: S. C. Oncologia Falck, Niguarda Cancer Center, Ospedale Niguarda Ca' Granda, Milano.
authors.forename: A
authors.initials: A
authors.lastname: Sartore-Bianchi
authors.affiliation: Department of Surgery, Division of Pathology, University of Pisa, Pisa.
authors.forename: G
authors.initials: G
authors.lastname: Fontanini
authors.affiliation: Department of Pathology and Molecular Biology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan.
authors.forename: M
authors.initials: M
authors.lastname: Milione
authors.affiliation: University of Milan, Milan, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Lauricella
authors.affiliation: S. C. Oncologia Falck, Niguarda Cancer Center, Ospedale Niguarda Ca' Granda, Milano University of Milan, Milan, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Siena
authors.affiliation: Unit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, Pisa.
authors.forename: A
authors.initials: A
authors.lastname: Falcone
authors.affiliation: Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan.
authors.forename: F
authors.initials: F
authors.lastname: de Braud
authors.affiliation: Unit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, Pisa.
authors.forename: F
authors.initials: F
authors.lastname: Loupakis
authors.affiliation: Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan filippo.pietrantonio@istitutotumori.mi.it.
authors.forename: F
authors.initials: F
authors.lastname: Pietrantonio
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics*; D003062:Codon / Q000235:genetics*; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000401:mortality / Q000556:secondary; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D010534:Peritoneal Neoplasms / Q000235:genetics* / Q000401:mortality / Q000556:secondary; D011379:Prognosis; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D012189:Retrospective Studies; D015996:Survival Rate
chemical_list: D014408:Biomarkers, Tumor; D003062:Codon; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf
keywords: BRAF; codons 594 and 596; colorectal cancer; prognosis