title: Poor prognosis of KRAS or BRAF mutant colorectal liver metastasis without microsatellite instability.
abstract: BACKGROUND
  The discovery of practical biomarkers is important to realize personalized medicine for patients with malignant neoplasias, including colorectal cancer (CRC).
  
  
  OBJECTIVE
  The aim of this study was to determine reliable prognostic biomarkers by the analysis of patients with resectable colorectal liver metastases (CRLM).
  
  
  METHODS
  Genomic DNA was obtained from the CRLM tissues of a cohort of 126 patients with CRLM with curative hepatic resection. The KRAS/BRAF mutation spectrum and microsatellite instability (MSI) status were successfully analyzed in 100 of the 126 CRLM tissues and these findings were examined in relation to the patients' clinical outcomes.
  
  
  RESULTS
  The cohort of 100 CRLM patients consisted of 46 with synchronous and 54 with metachronous liver metastasis. Overall survival and disease-free survival at 5 years were 57.4 and 24.9 %, respectively. MSI analysis revealed that none of the 100 CRLM specimens showed any evidence of MSI. By KRAS/BRAF mutation analysis, the analyzed CRLM patients were divided into 3 groups; KRAS-mutant (KRAS-Mt; n = 27), BRAF-mutant (BRAF-Mt; n = 3), and wild-types of both genes (Wild-type; n = 70). In the survival analysis, both KRAS-Mt and BRAF-Mt patients showed significantly poorer prognoses compared with Wild-type patients. Furthermore, although the population with the BRAF mutation was small, this mutation had a significant negative impact on disease-free survival.
  
  
  CONCLUSIONS
  In this study, all tumors in the cohort of CRLM patients were non-MSI tumors, suggesting MSI cancer in primary CRC would rarely reveal metastatic potential. KRAS and BRAF mutations are suggested to be poor prognostic factors in CRLM. Genetic information has an essential role as a prognostic marker and could contribute to the decisions on treatment strategy for CRLM.
authors.affiliation: Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Okayama, Okayama 700-8558, Japan. y.umeda@d9.dion.ne.jp
authors.forename: Yuzo
authors.initials: Y
authors.lastname: Umeda
authors.forename: Takeshi
authors.initials: T
authors.lastname: Nagasaka
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Mori
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Sadamori
authors.forename: Dong-Sheng
authors.initials: DS
authors.lastname: Sun
authors.forename: Susumu
authors.initials: S
authors.lastname: Shinoura
authors.forename: Ryuich
authors.initials: R
authors.lastname: Yoshida
authors.forename: Daisuke
authors.initials: D
authors.lastname: Satoh
authors.forename: Daisuke
authors.initials: D
authors.lastname: Nobuoka
authors.forename: Masashi
authors.initials: M
authors.lastname: Utsumi
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Yoshida
authors.forename: Takahito
authors.initials: T
authors.lastname: Yagi
authors.forename: Toshiyoshi
authors.initials: T
authors.lastname: Fujiwara
mesh_terms: D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000235:genetics*; D018450:Disease Progression; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007564:Japan / Q000453:epidemiology; D008113:Liver Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000556:secondary; D008297:Male; D053842:Microsatellite Instability; D009154:Mutation; D016133:Polymerase Chain Reaction; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras); D012189:Retrospective Studies; D015996:Survival Rate / Q000639:trends; D018631:ras Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; D004273:DNA, Neoplasm; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins