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


Authors: Hakimi, A. A.; Ostrovnaya, I.; Jacobsen, A.; Susztak, K.; Coleman, J. A.; Russo, P.; Winer, A. G.; Mano, R.; Sankin, A. I.; Motzer, R. J.; Voss, M. H.; Offit, K.; Purdue, M.; Pomerantz, M.; Freedman, M.; Choueiri, T. K.; Hsieh, J. J.; Klein, R. J.
Article Title: Validation and genomic interrogation of the MET variant rs11762213 as a predictor of adverse outcomes in clear cell renal cell carcinoma
Abstract: BACKGROUNDThe 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. METHODSThe 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. RESULTSThe 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. CONCLUSIONSThe 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. (c) 2015 American Cancer Society.
Keywords: survival; methylation; accuracy; genes; recurrence; renal cell carcinoma; biomarker; association; growth; pathway; variant; single-nucleotide polymorphisms; the cancer genome atlas; cancer-risk; met oncogene; (tcga)
Journal Title: Cancer
Volume: 122
Issue: 3
ISSN: 0008-543X
Publisher: Wiley Blackwell  
Date Published: 2016-02-01
Start Page: 402
End Page: 410
Language: English
ACCESSION: WOS:000369532100013
DOI: 10.1002/cncr.29765
PROVIDER: wos
PMCID: PMC4803437
PUBMED: 26505625
Notes: Article -- Source: Wos
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MSK Authors
  1. Jonathan Coleman
    224 Coleman
  2. Paul Russo
    498 Russo
  3. Kenneth Offit
    611 Offit
  4. Robert Motzer
    923 Motzer
  5. Martin Henner Voss
    169 Voss
  6. James J Hsieh
    121 Hsieh
  7. Andrew Gordon Winer
    18 Winer
  8. Abraham Ari Hakimi
    185 Hakimi
  9. Alexander Sankin
    12 Sankin
  10. Roy Mano
    34 Mano