Document Detail

Single nucleotide polymorphisms and risk of recurrence of renal-cell carcinoma: a cohort study.
MedLine Citation:
PMID:  23219378     Owner:  NLM     Status:  MEDLINE    
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.
FINDINGS: 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).
INTERPRETATION: 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.
FUNDING: 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.
Fabio A B Schutz; Mark M Pomerantz; Kathryn P Gray; Michael B Atkins; Jonathan E Rosenberg; Michelle S Hirsch; David F McDermott; Megan E Lampron; Gwo-Shu Mary Lee; Sabina Signoretti; Philip W Kantoff; Matthew L Freedman; Toni K Choueiri
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-12-07
Journal Detail:
Title:  The Lancet. Oncology     Volume:  14     ISSN:  1474-5488     ISO Abbreviation:  Lancet Oncol.     Publication Date:  2013 Jan 
Date Detail:
Created Date:  2013-01-01     Completed Date:  2013-04-03     Revised Date:  2014-08-18    
Medline Journal Info:
Nlm Unique ID:  100957246     Medline TA:  Lancet Oncol     Country:  England    
Other Details:
Languages:  eng     Pagination:  81-7     Citation Subset:  IM    
Copyright Information:
Copyright © 2013 Elsevier Ltd. All rights reserved.
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MeSH Terms
Carcinoma, Renal Cell / genetics*,  pathology
Cohort Studies
Genetic Association Studies*
Kaplan-Meier Estimate
Middle Aged
Neoplasm Recurrence, Local / genetics*,  pathology
Polymorphism, Single Nucleotide / genetics*
Proportional Hazards Models
Proto-Oncogene Proteins c-met / genetics*
Risk Factors
Grant Support
Reg. No./Substance:
EC protein, human; EC Proteins c-met
Comment In:
Urol Oncol. 2014 May;32(4):512-3   [PMID:  24767687 ]
Lancet Oncol. 2013 Jan;14(1):9-10   [PMID:  23219377 ]
Erratum In:
Lancet Oncol. 2013 Mar;14(3):e89

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