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 journalArticle

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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
Externally publishedYes

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Renal Cell Carcinoma
Neoplasms
Atlases
Alleles
Genome
Recurrence
Survival
Necrosis
Confidence Intervals
RNA Sequence Analysis
Nucleic Acid Regulatory Sequences
Protein Sequence Analysis
Oncogenes
Single Nucleotide Polymorphism
Nucleotides
Genotype
DNA

Keywords

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

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Hakimi, A. A., Ostrovnaya, I., Jacobsen, A., Susztak, K., Coleman, J. A., Russo, P., ... Klein, R. J. (2016). Validation and genomic interrogation of the MET variant rs11762213 as a predictor of adverse outcomes in clear cell renal cell carcinoma. Cancer, 122(3), 402-410. https://doi.org/10.1002/cncr.29765

Validation and genomic interrogation of the MET variant rs11762213 as a predictor of adverse outcomes in clear cell renal cell carcinoma. / Hakimi, A. Ari; Ostrovnaya, Irina; Jacobsen, Anders; Susztak, Katalin; Coleman, Jonathan A.; Russo, Paul; Winer, Andrew G.; Mano, Roy; Sankin, Alexander I.; Motzer, Robert J.; Voss, Martin H.; Offit, Kenneth; Purdue, Mark; Pomerantz, Mark; Freedman, Matthew; Choueiri, Toni K.; Hsieh, James J.; Klein, Robert J.

In: Cancer, Vol. 122, No. 3, 01.02.2016, p. 402-410.

Research output: Contribution to journalArticle

Hakimi, AA, Ostrovnaya, I, Jacobsen, A, Susztak, K, Coleman, JA, Russo, P, Winer, AG, Mano, R, Sankin, AI, Motzer, RJ, Voss, MH, Offit, K, Purdue, M, Pomerantz, M, Freedman, M, Choueiri, TK, Hsieh, JJ & Klein, RJ 2016, 'Validation and genomic interrogation of the MET variant rs11762213 as a predictor of adverse outcomes in clear cell renal cell carcinoma', Cancer, vol. 122, no. 3, pp. 402-410. https://doi.org/10.1002/cncr.29765
Hakimi, A. Ari ; Ostrovnaya, Irina ; Jacobsen, Anders ; Susztak, Katalin ; Coleman, Jonathan A. ; Russo, Paul ; Winer, Andrew G. ; Mano, Roy ; Sankin, Alexander I. ; Motzer, Robert J. ; Voss, Martin H. ; Offit, Kenneth ; Purdue, Mark ; Pomerantz, Mark ; Freedman, Matthew ; Choueiri, Toni K. ; Hsieh, James J. ; Klein, Robert J. / Validation and genomic interrogation of the MET variant rs11762213 as a predictor of adverse outcomes in clear cell renal cell carcinoma. In: Cancer. 2016 ; Vol. 122, No. 3. pp. 402-410.
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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.",
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T1 - Validation and genomic interrogation of the MET variant rs11762213 as a predictor of adverse outcomes in clear cell renal cell carcinoma

AU - Hakimi, A. Ari

AU - Ostrovnaya, Irina

AU - Jacobsen, Anders

AU - Susztak, Katalin

AU - Coleman, Jonathan A.

AU - Russo, Paul

AU - Winer, Andrew G.

AU - Mano, Roy

AU - Sankin, Alexander I.

AU - Motzer, Robert J.

AU - Voss, Martin H.

AU - Offit, Kenneth

AU - Purdue, Mark

AU - Pomerantz, Mark

AU - Freedman, Matthew

AU - Choueiri, Toni K.

AU - Hsieh, James J.

AU - Klein, Robert J.

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N2 - 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.

AB - 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.

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