Validation and genomic interrogation of the MET variant rs11762213 as a predictor of adverse outcomes in clear cell renal cell carcinoma

A. Ari Hakimi, Irina Ostrovnaya, Anders Jacobsen, Katalin Susztak, Jonathan A. Coleman, Paul Russo, Andrew G. Winer, Roy Mano, Alexander I. Sankin, Robert J. Motzer, Martin H. Voss, Kenneth Offit, Mark Purdue, Mark Pomerantz, Matthew Freedman, Toni K. Choueiri, James J. Hsieh, Robert J. Klein

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

Abstract

BACKGROUND The exonic single-nucleotide variant rs11762213 located in the MET oncogene has recently been identified as a prognostic marker in clear cell renal cell carcinoma (ccRCC). This finding was validated with The Cancer Genome Atlas (TCGA) cohort, and the biologic implications were explored. METHODS The genotype status for rs11762213 was available for 272 patients. Paired tumor-normal data, genomic data, and clinical information were acquired from ccRCC TCGA data sets. Cancer-specific survival (CSS) was analyzed with the competing risk method, and Cox proportional hazards regression was used for the analysis of the time to recurrence (TTR). Multivariate competing risk models were fitted to adjust for the validated Mayo Clinic Stage, Size, Grade, and Necrosis (SSIGN) score. RESULTS The variant allele of rs11762213 was detected in 10.3% of the cohort. After adjustments for the SSIGN score, the risk allele remained a significant predictor for adverse CSS (hazard ratio [HR], 3.88; 95% confidence interval [CI], 1.99-7.56; P ;< ;.0001) and for TTR (OR, 2.97; 95% CI, 1.43-6.2; P ;= ;.003). The mapping of rs11762213 to regulatory regions within the genome suggested that it might affect a DNA enhancer region. RNA and protein sequencing data for MET did not reveal differences in steady-state expression with stratification by risk allele. CONCLUSIONS The exonic MET variant rs11762213 is an independent predictor of adverse CSS and TTR in ccRCC and should be integrated into clinical practice for prognostic stratification. Genomic analysis suggests that the single-nucleotide polymorphism may affect an enhancer region located in the coding region of MET. Further biological mechanistic interrogation is currently underway. Cancer 2016;122:402-410.

Original languageEnglish (US)
Pages (from-to)402-410
Number of pages9
JournalCancer
Volume122
Issue number3
DOIs
StatePublished - Feb 1 2016

Keywords

  • MET oncogene
  • The Cancer Genome Atlas (TCGA)
  • biomarker
  • renal cell carcinoma
  • variant

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Fingerprint Dive into the research topics of 'Validation and genomic interrogation of the MET variant rs11762213 as a predictor of adverse outcomes in clear cell renal cell carcinoma'. Together they form a unique fingerprint.

Cite this