title: A let-7 microRNA SNP in the KRAS 3'UTR is prognostic in early-stage colorectal cancer.
abstract: OBJECTIVE
  Colorectal cancer (CRC) is a common cause of death worldwide. Tumor-node-metastasis-system stage is currently used to guide therapy decisions but lacks precision. Prognostic biomarkers are needed to refine stratification of patients for chemotherapy but validated biomarkers are not yet available. Recently, a SNP in a lethal-7 (let-7) miRNA complementary site (LCS6) in the KRAS 3'untranslated region was suggested to affect survival in metastatic CRC. Effects in early-stage CRC are however unknown. We studied KRAS-LCS6 genotype, hypothesizing that it might identify early-stage cases with a poor prognosis, and could potentially be used in therapy decision-making.
  
  
  METHODS
  We studied 409 early stage, 182 stage III, and 69 stage IV cases, and 1,886 subcohort members from the Netherlands Cohort Study. KRAS-LCS6 genotype was assessed with TaqMan PCR. Kaplan-Meier analyses or Cox regression were used to assess associations between genotype and CRC risk or cause-specific survival.
  
  
  RESULTS
  Early-stage cases with the KRAS-LCS6 variant had a lower CRC risk (incidence-rate ratio 0.68; 95% CI: 0.49-0.94) and a better survival (log-rank P = 0.038; HR 0.46; 95% CI: 0.18-1.14). In patients with KRAS-mutated CRC carrying the KRAS-LCS6 variant, the better outcome was enhanced as no patients died of CRC (log-rank P = 0.017). In advanced patients, no clear association between genotype and CRC risk or survival was observed.
  
  
  CONCLUSIONS
  Our results indicate that early-stage CRC cases with the KRAS-LCS6 variant have a better outcome. In advanced disease, the better outcome no longer exists. For early-stage patients, KRAS-LCS6 genotype combined with KRAS mutations merits validation as a prognostic biomarker and consideration in therapy decision-making.
authors: Departments of Pathology and Epidemiology, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, the Netherlands.
authors: Kim M
authors: KM
authors: Smits
authors: Trupti
authors: T
authors: Paranjape
authors: Sunitha
authors: S
authors: Nallur
authors: Kim A D
authors: KA
authors: Wouters
authors: Matty P
authors: MP
authors: Weijenberg
authors: Leo J
authors: LJ
authors: Schouten
authors: Piet A
authors: PA
authors: van den Brandt
authors: Fred T
authors: FT
authors: Bosman
authors: Joanne B
authors: JB
authors: Weidhaas
authors: Manon
authors: M
authors: van Engeland
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics*; D000368:Aged; D015331:Cohort Studies; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation; D009367:Neoplasm Staging; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D016016:Proportional Hazards Models; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D018570:Risk Assessment / Q000706:statistics & numerical data; D018631:ras Proteins / Q000235:genetics*
chemical_list: D020413:3' Untranslated Regions; C117307:KRAS protein, human; D035683:MicroRNAs; D011518:Proto-Oncogene Proteins; C487931:mirnlet7 microRNA, human; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins