title: High-resolution profiling of histone h3 lysine 36 trimethylation in metastatic renal cell carcinoma.
abstract: Mutations in SETD2, a histone H3 lysine trimethyltransferase, have been identified in clear cell renal cell carcinoma (ccRCC); however it is unclear if loss of SETD2 function alters the genomic distribution of histone 3 lysine 36 trimethylation (H3K36me3) in ccRCC. Furthermore, published epigenomic profiles are not specific to H3K36me3 or metastatic tumors. To determine if progressive SETD2 and H3K36me3 dysregulation occurs in metastatic tumors, H3K36me3, SETD2 copy number (CN) or SETD2 mRNA abundance was assessed in two independent cohorts: metastatic ccRCC (n=71) and the Cancer Genome Atlas Kidney Renal Clear Cell Carcinoma data set (n=413). Although SETD2 CN loss occurs with high frequency (>90%), H3K36me3 is not significantly impacted by monoallelic loss of SETD2. H3K36me3-positive nuclei were reduced an average of ~20% in primary ccRCC (90% positive nuclei in uninvolved vs 70% positive nuclei in ccRCC) and reduced by ~60% in metastases (90% positive in uninvolved kidney vs 30% positive in metastases) (P<0.001). To define a kidney-specific H3K36me3 profile, we generated genome-wide H3K36me3 profiles from four cytoreductive nephrectomies and SETD2 isogenic renal cell carcinoma (RCC) cell lines using chromatin immunoprecipitation coupled with high-throughput DNA sequencing and RNA sequencing. SETD2 loss of methyltransferase activity leads to regional alterations of H3K36me3 associated with aberrant RNA splicing in a SETD2 mutant RCC and SETD2 knockout cell line. These data suggest that during progression of ccRCC, a decline in H3K36me3 is observed in distant metastases, and regional H3K36me3 alterations influence alternative splicing in ccRCC.
authors.affiliation: Division of Hematology and Medical Oncology, Mayo Clinic, Scottsdale, AZ, USA.|Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA.
authors.forename: T H
authors.initials: TH
authors.lastname: Ho
authors.affiliation: Center for Translational Cancer Research, Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, TX, USA.
authors.forename: I Y
authors.initials: IY
authors.lastname: Park
authors.affiliation: Department of Bioinformatics and Computational Biology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: H
authors.initials: H
authors.lastname: Zhao
authors.affiliation: Department of Bioinformatics and Computational Biology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: P
authors.initials: P
authors.lastname: Tong
authors.affiliation: Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA.|Department of Biomedical Statistics and Informatics, Mayo Clinic, Scottsdale, AZ, USA.
authors.forename: M D
authors.initials: MD
authors.lastname: Champion
authors.affiliation: Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA.|Department of Biomedical Statistics and Informatics, Rochester, MN, USA.
authors.forename: H
authors.initials: H
authors.lastname: Yan
authors.affiliation: Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX, USA.
authors.forename: F A
authors.initials: FA
authors.lastname: Monzon
authors.affiliation: Department of Genitourinary Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: A
authors.initials: A
authors.lastname: Hoang
authors.affiliation: Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: P
authors.initials: P
authors.lastname: Tamboli
authors.affiliation: Department of Health Sciences Research, Mayo Clinic, Jacksonville, FL, USA.
authors.forename: A S
authors.initials: AS
authors.lastname: Parker
authors.affiliation: Division of Hematology and Medical Oncology, Mayo Clinic, Jacksonville, FL, USA.
authors.forename: R W
authors.initials: RW
authors.lastname: Joseph
authors.affiliation: Division of Quantitative Sciences, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: W
authors.initials: W
authors.lastname: Qiao
authors.affiliation: Center for Cancer Genomics and Computational Biology, Van Andel Institute, Grand Rapids, MI, USA.
authors.forename: K
authors.initials: K
authors.lastname: Dykema
authors.affiliation: Department of Genitourinary Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: N M
authors.initials: NM
authors.lastname: Tannir
authors.affiliation: Department of Urology, Mayo Clinic, Scottsdale, AZ, USA.
authors.forename: E P
authors.initials: EP
authors.lastname: Castle
authors.affiliation: Department of Urology, Mayo Clinic, Scottsdale, AZ, USA.
authors.forename: R
authors.initials: R
authors.lastname: Nunez-Nateras
authors.affiliation: Center for Cancer Genomics and Computational Biology, Van Andel Institute, Grand Rapids, MI, USA.
authors.forename: B T
authors.initials: BT
authors.lastname: Teh
authors.affiliation: Department of Bioinformatics and Computational Biology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: J
authors.initials: J
authors.lastname: Wang
authors.affiliation: Center for Translational Cancer Research, Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, TX, USA.
authors.forename: C L
authors.initials: CL
authors.lastname: Walker
authors.affiliation: Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.|Center for Molecular Medicine and Graduate Institute of Cancer Biology, China Medical University, Taichung, Taiwan.
authors.forename: M-C
authors.initials: MC
authors.lastname: Hung
authors.affiliation: Department of Genitourinary Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: E
authors.initials: E
authors.lastname: Jonasch
mesh_terms: D002292:Carcinoma, Renal Cell / Q000378:metabolism* / Q000473:pathology; D047369:Chromatin Immunoprecipitation; D015331:Cohort Studies; D006657:Histones / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D007680:Kidney Neoplasms / Q000378:metabolism* / Q000473:pathology; D008239:Lysine / Q000378:metabolism*; D008745:Methylation; D009362:Neoplasm Metastasis
chemical_list: D006657:Histones; D008239:Lysine