TY - JOUR
T1 - Loss of histone H3 lysine 36 trimethylation is associated with an increased risk of renal cell carcinoma-specific death
AU - Ho, Thai H.
AU - Kapur, Payal
AU - Joseph, Richard W.
AU - Serie, Daniel J.
AU - Eckel-Passow, Jeanette E.
AU - Tong, Pan
AU - Wang, Jing
AU - Castle, Erik P.
AU - Stanton, Melissa L.
AU - Cheville, John C.
AU - Jonasch, Eric
AU - Brugarolas, James
AU - Parker, Alexander S.
N1 - Funding Information:
We thank the support provided by the Gloria A and Thomas J Dutson, Jr Kidney Research Endowment. This work was supported by the Mayo Clinic Center for Individualized Medicine Epigenomics Program (to THH); a Kathryn H and Roger Penske Career Development Award to Support Medical Research (to THH); Gerstner Family Career Development Award (to THH), the National Cancer Institute at the National Institutes of Health (K12CA90628 to THH, R01CA134466 to ASP, R01CA175754 to JB); Cancer Prevention Research Institute of Texas (RP130603 to JB). This publication was made possible by CTSA Grant Number UL1 TR000135 from the National Center for Advancing Translational Sciences, a component of the National Institutes of Health. Its contents are solely the responsibility of the authors and do not necessarily represent the official view of the National Institutes of Health.
Publisher Copyright:
© 2016 USCAP, Inc All rights reserved.
PY - 2016/1/1
Y1 - 2016/1/1
N2 - 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<0.0001. After stratifying for the SSIGN score, H3K36me3-negative tumors in the low-risk SSIGN group had a worse renal cell carcinoma-specific survival (hazard ratio, 2.18; 95% confidence interval, 1.09-4.36); P=0.03. Although SETD2 DNA and mRNA alterations are not associated with overall survival, we provide evidence that deregulation of the H3K36me3 axis is associated with a higher risk of renal cell carcinoma-specific death. This association remains significant after stratifying for the SSIGN score, particularly among those patients with low-risk tumors.
AB - 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<0.0001. After stratifying for the SSIGN score, H3K36me3-negative tumors in the low-risk SSIGN group had a worse renal cell carcinoma-specific survival (hazard ratio, 2.18; 95% confidence interval, 1.09-4.36); P=0.03. Although SETD2 DNA and mRNA alterations are not associated with overall survival, we provide evidence that deregulation of the H3K36me3 axis is associated with a higher risk of renal cell carcinoma-specific death. This association remains significant after stratifying for the SSIGN score, particularly among those patients with low-risk tumors.
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U2 - 10.1038/modpathol.2015.123
DO - 10.1038/modpathol.2015.123
M3 - Article
C2 - 26516698
AN - SCOPUS:84952719241
SN - 0893-3952
VL - 29
SP - 34
EP - 42
JO - Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc
JF - Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc
IS - 1
ER -