Validation and genomic interrogation of the MET variant rs11762213 as a predictor of adverse outcomes in clear cell renal cell carcinoma.
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.
Memorial Sloan Kettering Cancer Center, New York, New York.
A Ari
AA
Hakimi
Memorial Sloan Kettering Cancer Center, New York, New York.
Irina
I
Ostrovnaya
Memorial Sloan Kettering Cancer Center, New York, New York.
Anders
A
Jacobsen
University of Pennsylvania, Philadelphia, Pennsylvania.
Katalin
K
Susztak
Memorial Sloan Kettering Cancer Center, New York, New York.
Jonathan A
JA
Coleman
Memorial Sloan Kettering Cancer Center, New York, New York.
Paul
P
Russo
Memorial Sloan Kettering Cancer Center, New York, New York.
Andrew G
AG
Winer
Memorial Sloan Kettering Cancer Center, New York, New York.
Roy
R
Mano
Memorial Sloan Kettering Cancer Center, New York, New York.
Alexander I
AI
Sankin
Memorial Sloan Kettering Cancer Center, New York, New York.
Robert J
RJ
Motzer
Memorial Sloan Kettering Cancer Center, New York, New York.
Martin H
MH
Voss
Memorial Sloan Kettering Cancer Center, New York, New York.
Kenneth
K
Offit
National Cancer Institute, Bethesda, Maryland.
Mark
M
Purdue
Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
Mark
M
Pomerantz
Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
Matthew
M
Freedman
Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
Toni K
TK
Choueiri
Memorial Sloan Kettering Cancer Center, New York, New York.
James J
JJ
Hsieh
Mount Sinai School of Medicine, New York, New York.
Robert J
RJ
Klein
D000368:Aged; D002292:Carcinoma, Renal Cell / Q000235:genetics* / Q000401:mortality* / Q000473:pathology; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D007680:Kidney Neoplasms / Q000235:genetics* / Q000401:mortality* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D009364:Neoplasm Recurrence, Local / Q000235:genetics / Q000401:mortality; D009367:Neoplasm Staging; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D011237:Predictive Value of Tests; D011379:Prognosis; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics*; D015203:Reproducibility of Results
C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met
MET oncogene; The Cancer Genome Atlas (TCGA); biomarker; renal cell carcinoma; variant