title: Single nucleotide polymorphisms and risk of recurrence of renal-cell carcinoma: a cohort study.
abstract: BACKGROUND
  Germline genetic polymorphisms might affect the risk of recurrence in patients with localised renal-cell carcinoma. We investigated the association between genetic polymorphisms and recurrence of renal-cell carcinoma.
  
  
  METHODS
  We analysed germline DNA samples extracted from patients with localised renal-cell carcinoma treated at the Dana-Farber/Harvard Cancer Center (Boston, MA, USA). We selected a discovery cohort from a prospective database at the Dana-Farber/Harvard Cancer Center and selected a validation cohort from department records at the Brigham and Women's Hospital (Boston, MA, USA). We validated the findings from the discovery cohort in the validation cohort. We genotyped 70 genes involved in the pathogenesis of renal-cell carcinoma (including the VHL/HIF/VEGF and PI3K/AKT/mTOR pathways, and genes involved in immune regulation and metabolism) for single nucleotide polymorphisms. We assessed the association between genotype and recurrence-free survival, adjusted for baseline characteristics, with the Cox proportional hazards model, the Kaplan-Meier method, and the log-rank test. We used a false discovery rate q value to adjust for multiple comparisons.
  
  
  RESULTS
  We included 554 patients (403 in the discovery cohort and 151 in the validation cohort). We successfully genotyped 290 single nucleotide polymorphisms in the discovery cohort, but excluded five because they did not have a variant group for comparison. The polymorphism rs11762213, which causes a synonymous aminoacid change in MET (144G→A, located in exon 2), was associated with recurrence-free survival. Patients with one or two copies of the minor (risk) allele had an increased risk of recurrence or death (hazard ratio [HR] 1·86, 95% CI 1·17-2·95; p=0·0084) in multivariate analysis. Median recurrence-free survival for carriers of the risk allele was 19 months (95% CI 9-not reached) versus 50 months (95% CI 37-75) for patients without the risk allele. In the validation cohort the HR was 2·45 (95% CI 1·01-5·95; p=0·048).
  
  
  CONCLUSIONS
  Patients with localised renal-cell carcinoma and the MET polymorphism rs11762213 might have an increased risk of recurrence after nephrectomy. If these results are further validated in a similar population, they could be incorporated into future prognostic instruments, potentially aiding the design of adjuvant clinical trials of MET inhibitors and management of renal-cell carcinoma.
  
  
  BACKGROUND
  Conquer Cancer Foundation and American Society of Clinical Oncology (Career Development Award); The Trust Family Research Fund for Kidney Cancer; US National Institutes of Health, National Cancer Institute Kidney Cancer Specialized Program of Research Excellence.
authors.affiliation: Dana-Farber Cancer Institute, Boston, MA 02115, USA.
authors.forename: Fabio A B
authors.initials: FA
authors.lastname: Schutz
authors.forename: Mark M
authors.initials: MM
authors.lastname: Pomerantz
authors.forename: Kathryn P
authors.initials: KP
authors.lastname: Gray
authors.forename: Michael B
authors.initials: MB
authors.lastname: Atkins
authors.forename: Jonathan E
authors.initials: JE
authors.lastname: Rosenberg
authors.forename: Michelle S
authors.initials: MS
authors.lastname: Hirsch
authors.forename: David F
authors.initials: DF
authors.lastname: McDermott
authors.forename: Megan E
authors.initials: ME
authors.lastname: Lampron
authors.forename: Gwo-Shu Mary
authors.initials: GS
authors.lastname: Lee
authors.forename: Sabina
authors.initials: S
authors.lastname: Signoretti
authors.forename: Philip W
authors.initials: PW
authors.lastname: Kantoff
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Freedman
authors.forename: Toni K
authors.initials: TK
authors.lastname: Choueiri
mesh_terms: D000368:Aged; D000483:Alleles; D002292:Carcinoma, Renal Cell / Q000235:genetics* / Q000473:pathology; D015331:Cohort Studies; D005260:Female; D056726:Genetic Association Studies; D005838:Genotype; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000235:genetics* / Q000473:pathology; D009392:Nephrectomy; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D016016:Proportional Hazards Models; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics*; D012307:Risk Factors
chemical_list: C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met