title: Loss of histone H3 lysine 36 trimethylation is associated with an increased risk of renal cell carcinoma-specific death.
abstract: 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.
authors.affiliation: Division of Hematology and Medical Oncology, Mayo Clinic, Scottsdale, AZ, USA.|Epigenomics Program, Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA.
authors.forename: Thai H
authors.identifier: http://orcid.org/0000-0003-0023-2939
authors.initials: TH
authors.lastname: Ho
authors.affiliation: Departments of Pathology and Urology, University of Texas Southwestern Medical Center, Dallas, TX, USA.|Kidney Cancer Program, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Payal
authors.initials: P
authors.lastname: Kapur
authors.affiliation: Division of Hematology and Medical Oncology, Mayo Clinic, Jacksonville, FL, USA.
authors.forename: Richard W
authors.initials: RW
authors.lastname: Joseph
authors.affiliation: Department of Health Sciences Research, Mayo Clinic, Jacksonville, FL, USA.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Serie
authors.affiliation: Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, USA.
authors.forename: Jeanette E
authors.initials: JE
authors.lastname: Eckel-Passow
authors.affiliation: Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Pan
authors.initials: P
authors.lastname: Tong
authors.affiliation: Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Urology, Mayo Clinic Hospital, Phoenix, AZ, USA.
authors.forename: Erik P
authors.initials: EP
authors.lastname: Castle
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic, Scottsdale, AZ, USA.
authors.forename: Melissa L
authors.initials: ML
authors.lastname: Stanton
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
authors.forename: John C
authors.initials: JC
authors.lastname: Cheville
authors.affiliation: Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Jonasch
authors.affiliation: Kidney Cancer Program, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA.|Division of Hematology-Oncology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: James
authors.initials: J
authors.lastname: Brugarolas
authors.affiliation: Department of Health Sciences Research, Mayo Clinic, Jacksonville, FL, USA.
authors.forename: Alexander S
authors.initials: AS
authors.lastname: Parker
mesh_terms: D002292:Carcinoma, Renal Cell / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D019175:DNA Methylation; D018572:Disease-Free Survival; D006657:Histones / Q000378:metabolism*; D006801:Humans; D007680:Kidney Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D009154:Mutation; D012307:Risk Factors; D015996:Survival Rate
chemical_list: D006657:Histones