Loss of histone H3 lysine 36 trimethylation is associated with an increased risk of renal cell carcinoma-specific death

Sequencing of clear cell renal cell carcinomas identified loss-of-function mutations of SETD2 , a gene that encodes a nonredundant methytransferase responsible for histone H3 lysine 36 trimethylation (H3K36me3), and H3K36me3 is progressively deregulated in metastases. However, few data exist regardi...

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Published in:Modern pathology 2016-01, Vol.29 (1), p.34-42
Main Authors: Ho, Thai H, Kapur, Payal, Joseph, Richard W, Serie, Daniel J, Eckel-Passow, Jeanette E, Tong, Pan, Wang, Jing, Castle, Erik P, Stanton, Melissa L, Cheville, John C, Jonasch, Eric, Brugarolas, James, Parker, Alexander S
Format: Article
Language:English
Subjects:
13/51
38/1
631/67/589/1588/1351
692/53/2422
Carcinoma, Renal Cell - metabolism
Carcinoma, Renal Cell - mortality
Carcinoma, Renal Cell - pathology
Disease-Free Survival
DNA Methylation
Histones - metabolism
Humans
Kidney Neoplasms - metabolism
Kidney Neoplasms - mortality
Kidney Neoplasms - pathology
Laboratory Medicine
Medicine
Medicine & Public Health
Mutation
original-article
Pathology
Risk Factors
Survival Rate
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Summary:Sequencing of clear cell renal cell carcinomas identified loss-of-function mutations of SETD2 , a gene that encodes a nonredundant methytransferase responsible for histone H3 lysine 36 trimethylation (H3K36me3), and H3K36me3 is progressively deregulated in metastases. However, few data exist regarding the impact of loss of H3K36me3 on outcomes. We assessed the association of SETD2 DNA alterations and mRNA expression with overall survival using The Cancer Genome Atlas clear cell renal carcinoma data ( N =411). Additionally, we assessed the association of H3K36 loss of methylation with renal cell carcinoma-specific survival and progression-free survival using an independent cohort at Mayo Clinic ( N =1454). Overall survival, renal cell carcinoma-specific survival and progression-free survival were estimated using Kaplan–Meier method, and differences in survival across groups was compared using Cox regression models, adjusted for age and the Mayo SSIGN (stage, size, grade, and necrosis) score. In The Cancer Genome Atlas cohort, SETD2 DNA alterations or mRNA expression was not associated with overall survival ( P >0.05). In the Mayo cohort, patients with H3K36me3-negative tumors were two times more likely to experience renal cell carcinoma-specific death than patients with H3K36me3-positive tumors (hazard ratio, 2.23; 95% confidence interval, 1.77–2.81); P
ISSN:0893-3952
1530-0285
DOI:10.1038/modpathol.2015.123