title: A let-7 microRNA polymorphism in the KRAS 3'-UTR is prognostic in oropharyngeal cancer.
abstract: BACKGROUND
  This study aimed to investigate the effect of genetic polymorphisms in miRNA sequences, miRNA target genes and miRNA processing genes as additional biomarkers to HPV for prognosis in oropharyngeal squamous cell carcinoma (OPSCC) patients. Secondarily, the prevalence of HPV-associated OPSCC in a European cohort was mapped.
  
  
  METHODS
  OPSCC patients (n=122) were genotyped for ten genetic polymorphisms in pre-miRNAs (pre-mir-146a, pre-mir-196a2), in miRNA biosynthesis genes (Drosha, XPO5) and in miRNA target genes (KRAS, SMC1B). HPV status was assessed by p16 immunohistochemistry (IHC) and high-risk HPV in situ hybridization (ISH) or by p16 IHC and PCR followed by enzyme-immunoassay (EIA). Overall and disease specific survival were analysed using Kaplan-Meier plots (log-rank test). Cox proportional hazard model was used to calculate hazard ratios (HR).
  
  
  RESULTS
  The overall HPV prevalence rate in our Belgian/Dutch cohort was 27.9%. Patients with HPV(+) tumours had a better 5-years overall survival (78% vs. 46%, p=0.001) and a better 5-years disease specific survival (90% vs. 70%, p=0.016) compared to patients with HPV(-) tumours. In multivariate Cox analysis including clinical, treatment and genetic parameters, HPV negativity (HR=3.89, p=0.005), advanced T-stage (HR=1.81, p=0.050), advanced N-stage (HR=5.86, p=0.001) and >10 pack-years of smoking (HR=3.45, p=0.012) were significantly associated with reduced overall survival. The variant G-allele of the KRAS-LCS6 polymorphism was significantly associated with a better overall survival (HR=0.40, p=0.031).
  
  
  CONCLUSIONS
  Our results demonstrate that OPSCC patients with the KRAS-LCS6 variant have a better outcome and suggest that this variant may be used as a prognostic biomarker for OPSCC.
authors.affiliation: Department of Basic Medical Sciences, Ghent University, Proeftuinstraat 86, B-9000 Gent, Belgium. Electronic address: kim.deruyck@UGent.be.
authors.forename: Kim
authors.initials: K
authors.lastname: De Ruyck
authors.affiliation: Department of Radiotherapy, Ghent University Hospital, De Pintelaan 185, B-9000 Gent, Belgium.
authors.forename: Fréderic
authors.initials: F
authors.lastname: Duprez
authors.affiliation: Department of Pathology, Ghent University Hospital, De Pintelaan 185, B-9000 Gent, Belgium.
authors.forename: Liesbeth
authors.initials: L
authors.lastname: Ferdinande
authors.affiliation: Department of Basic Medical Sciences, Ghent University, Proeftuinstraat 86, B-9000 Gent, Belgium.
authors.forename: Chamberlain
authors.initials: C
authors.lastname: Mbah
authors.affiliation: Department of Radiation Oncology (MAASTRO Clinic), GROW School for Oncology and Developmental Biology, Maastricht University Medical Center, Doctor Tanslaan 12, 6229 ET Maastricht, The Netherlands.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Rios-Velazquez
authors.affiliation: Department of Radiation Oncology (MAASTRO Clinic), GROW School for Oncology and Developmental Biology, Maastricht University Medical Center, Doctor Tanslaan 12, 6229 ET Maastricht, The Netherlands.
authors.forename: Frank
authors.initials: F
authors.lastname: Hoebers
authors.affiliation: Department of Pathology, Ghent University Hospital, De Pintelaan 185, B-9000 Gent, Belgium.
authors.forename: Marleen
authors.initials: M
authors.lastname: Praet
authors.affiliation: Department of Head and Neck Surgery, Ghent University Hospital, De Pintelaan 185, B-9000 Gent, Belgium.
authors.forename: Philippe
authors.initials: P
authors.lastname: Deron
authors.affiliation: Department of Head and Neck Surgery, Ghent University Hospital, De Pintelaan 185, B-9000 Gent, Belgium.
authors.forename: Katrien
authors.initials: K
authors.lastname: Bonte
authors.affiliation: Department of Pathology, GROW School for Oncology and Developmental Biology, Maastricht University Medical Center, Doctor Tanslaan 12, 6229 ET Maastricht, The Netherlands.
authors.forename: Ernst-Jan
authors.initials: EJ
authors.lastname: Speel
authors.affiliation: Department of Pathology, Ghent University Hospital, De Pintelaan 185, B-9000 Gent, Belgium.
authors.forename: Louis
authors.initials: L
authors.lastname: Libbrecht
authors.affiliation: Department of Radiotherapy, Ghent University Hospital, De Pintelaan 185, B-9000 Gent, Belgium.
authors.forename: Wilfried
authors.initials: W
authors.lastname: De Neve
authors.affiliation: Department of Radiation Oncology (MAASTRO Clinic), GROW School for Oncology and Developmental Biology, Maastricht University Medical Center, Doctor Tanslaan 12, 6229 ET Maastricht, The Netherlands.
authors.forename: Philippe
authors.initials: P
authors.lastname: Lambin
authors.affiliation: Department of Basic Medical Sciences, Ghent University, Proeftuinstraat 86, B-9000 Gent, Belgium.
authors.forename: Hubert
authors.initials: H
authors.lastname: Thierens
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D000328:Adult; D000368:Aged; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000473:pathology / Q000821:virology; D005260:Female; D005500:Follow-Up Studies; D005838:Genotype; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D009959:Oropharyngeal Neoplasms / Q000235:genetics / Q000473:pathology* / Q000821:virology; D030361:Papillomavirus Infections / Q000150:complications / Q000453:epidemiology; D011110:Polymorphism, Genetic; D015995:Prevalence; D011379:Prognosis; D016016:Proportional Hazards Models; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras); D015996:Survival Rate; 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; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins
keywords: Genetic polymorphisms; HPV; KRAS; Oropharyngeal cancer; Prevalence; Prognostic biomarker; miRNA