title: Let-7 miRNA-binding site polymorphism in the KRAS 3'UTR; colorectal cancer screening population prevalence and influence on clinical outcome in patients with metastatic colorectal cancer treated with 5-fluorouracil and oxaliplatin +/- cetuximab.
abstract: BACKGROUND
  Recent studies have reported associations between a variant allele in a let-7 microRNA complementary site (LCS6) within the 3'untranslated region (3'UTR) of KRAS (rs61764370) and clinical outcome in metastatic colorectal cancer (mCRC) patients receiving cetuximab. The variant allele has also been associated with increased cancer risk. We aimed to reveal the incidence of the variant allele in a colorectal cancer screening population and to investigate the clinical relevance of the variant allele in mCRC patients treated with 1st line Nordic FLOX (bolus 5-fluorouracil/folinic acid and oxaliplatin) +/- cetuximab.
  
  
  METHODS
  The feasibility of the variant allele as a risk factor for CRC was investigated by comparing the LCS6 gene frequencies in 197 CRC patients, 1060 individuals with colorectal polyps, and 358 healthy controls. The relationship between clinical outcome and LCS6 genotype was analyzed in 180 mCRC patients receiving Nordic FLOX and 355 patients receiving Nordic FLOX + cetuximab in the NORDIC-VII trial (NCT00145314).
  
  
  RESULTS
  LCS6 frequencies did not vary between CRC patients (23%), individuals with polyps (20%), and healthy controls (20%) (P = 0.50). No statistically significant differences were demonstrated in the NORDIC-VII cohort even if numerically increased progression-free survival (PFS) and overall survival (OS) were found in patients with the LCS6 variant allele (8.5 (95% CI: 7.3-9.7 months) versus 7.8 months (95% CI: 7.4-8.3 months), P = 0.16 and 23.5 (95% CI: 21.6-25.4 months) versus 19.5 months (95% CI: 17.8-21.2 months), P = 0.31, respectively). Addition of cetuximab seemed to improve response rate more in variant carriers than in wild-type carriers (from 35% to 57% versus 44% to 47%), however the difference was not statistically significant (interaction P = 0.16).
  
  
  CONCLUSIONS
  The LCS6 variant allele does not seem to be a risk factor for development of colorectal polyps or CRC. No statistically significant effect of the LCS6 variant allele on response rate, PFS or OS was found in mCRC patients treated with 1st line Nordic FLOX +/- cetuximab.
authors.affiliation: Department of Genetics, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.
authors.forename: Janne B
authors.initials: JB
authors.lastname: Kjersem
authors.forename: Tone
authors.initials: T
authors.lastname: Ikdahl
authors.forename: Tormod
authors.initials: T
authors.lastname: Guren
authors.forename: Eva
authors.initials: E
authors.lastname: Skovlund
authors.forename: Halfdan
authors.initials: H
authors.lastname: Sorbye
authors.forename: Julian
authors.initials: J
authors.lastname: Hamfjord
authors.forename: Per
authors.initials: P
authors.lastname: Pfeiffer
authors.forename: Bengt
authors.initials: B
authors.lastname: Glimelius
authors.forename: Christian
authors.initials: C
authors.lastname: Kersten
authors.forename: Hiroko
authors.initials: H
authors.lastname: Solvang
authors.forename: Kjell M
authors.initials: KM
authors.lastname: Tveit
authors.forename: Elin H
authors.initials: EH
authors.lastname: Kure
mesh_terms: D020413:3' Untranslated Regions; D000328:Adult; D000368:Aged; D000483:Alleles; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001665:Binding Sites; D000068818:Cetuximab; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D018572:Disease-Free Survival; D055088:Early Detection of Cancer / Q000379:methods; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D005838:Genotype; D006801:Humans; D002955:Leucovorin / Q000008:administration & dosage; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D009944:Organoplatinum Compounds / Q000008:administration & dosage; D000077150:Oxaliplatin; D011110:Polymorphism, Genetic; D015995:Prevalence; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras); D055815:Young Adult; D018631:ras Proteins / Q000235:genetics*
chemical_list: D020413:3' Untranslated Regions; D061067:Antibodies, Monoclonal, Humanized; C117307:KRAS protein, human; D035683:MicroRNAs; D009944:Organoplatinum Compounds; D011518:Proto-Oncogene Proteins; C487931:mirnlet7 microRNA, human; D000077150:Oxaliplatin; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins; D000068818:Cetuximab; D002955:Leucovorin; D005472:Fluorouracil