title: KRAS mutation and microsatellite instability: two genetic markers of early tumor development that influence the prognosis of colorectal cancer.
abstract: BACKGROUND
  We examined two genetic markers established early in colorectal tumor development, microsatellite instability (MSI) and mutation of the KRAS proto-oncogene, to see if these genetic changes influence metastatic disease progression and survival.
  
  
  METHODS
  MSI and KRAS mutation status were assessed in 532 primary adenocarcinomas (stage I-IV) from patients treated by colon resection. Median follow-up was 4.1 years (range 0-13.3 years) overall, 5.4 years for survivors.
  
  
  RESULTS
  MSI and KRAS mutation were detected in 12 and 36% of cases, respectively. MSI was more common in early-stage disease (I, 15%; II, 21%; III, 10%; IV, 2%; P = 0.0001). Prevalence of KRAS mutation did not vary with stage (I, 36%; II, 34%; III, 35%; IV, 40%; P = ns). Disease-specific survival was far superior for MSI tumors than for microsatellite stability (MSS) tumors (5-year survival 92 vs. 59%, P < 0.0001). KRAS mutation was a marker of poor survival (5-year survival 55 vs. 68%, P = 0.0002). Using Cox regression analysis MSI, KRAS mutation, and stage were strong independent predictors of survival in the entire patient population. A high-mortality group with MSS/KRAS-mutant tumors was identified within the stage I and II cohort.
  
  
  CONCLUSIONS
  MSI and KRAS mutation provide fundamental genetic signatures influencing tumor behavior across patient subsets and stages of tumor development.
authors.affiliation: Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, USA.
authors.forename: Garrett M
authors.initials: GM
authors.lastname: Nash
authors.forename: Mark
authors.initials: M
authors.lastname: Gimbel
authors.forename: Alfred M
authors.initials: AM
authors.lastname: Cohen
authors.forename: Zhao-Shi
authors.initials: ZS
authors.lastname: Zeng
authors.forename: Mackevin I
authors.initials: MI
authors.lastname: Ndubuisi
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Nathanson
authors.forename: Jurg
authors.initials: J
authors.lastname: Ott
authors.forename: Francis
authors.initials: F
authors.lastname: Barany
authors.forename: Philip B
authors.initials: PB
authors.lastname: Paty
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D003106:Colon / Q000378:metabolism / Q000473:pathology; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D018450:Disease Progression; D005260:Female; D005500:Follow-Up Studies; D005819:Genetic Markers; D006801:Humans; D008297:Male; D053842:Microsatellite Instability; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras); D012007:Rectum / Q000378:metabolism / Q000473:pathology; D015996:Survival Rate; D016896:Treatment Outcome; D055815:Young Adult; D018631:ras Proteins / Q000235:genetics*
chemical_list: D005819:Genetic Markers; C117307:KRAS protein, human; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins