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

被引：51

作者：

Ho, Thai H. ^{[1
,2
]}

Kapur, Payal ^{[3
,4
,5
]}

Joseph, Richard W. ^{[6
]}

Serie, Daniel J. ^{[7
]}

Eckel-Passow, Jeanette E. ^{[8
]}

Tong, Pan ^{[9
]}

Wang, Jing ^{[9
]}

Castle, Erik P. ^{[10
]}

Stanton, Melissa L. ^{[11
]}

Cheville, John C. ^{[12
]}

Jonasch, Eric ^{[13
]}

Brugarolas, James ^{[5
,14
]}

Parker, Alexander S. ^{[7
]}

机构：

[1] Mayo Clin, Div Hematol & Med Oncol, Scottsdale, AZ 85259 USA

[2] Mayo Clin, Ctr Individualized Med, Epigen Program, Rochester, MN USA

[3] Univ Texas SW Med Ctr Dallas, Dept Pathol, Dallas, TX 75390 USA

[4] Univ Texas SW Med Ctr Dallas, Dept Urol, Dallas, TX 75390 USA

[5] Univ Texas SW Med Ctr Dallas, Simmons Comprehens Canc Ctr, Kidney Canc Program, Dallas, TX 75390 USA

[6] Mayo Clin, Div Hematol & Med Oncol, Jacksonville, FL 32224 USA

[7] Mayo Clin, Dept Hlth Sci Res, Jacksonville, FL 32224 USA

[8] Mayo Clin, Div Biomed Stat & Informat, Rochester, MN USA

[9] Univ Texas MD Anderson Canc Ctr, Dept Bioinformat & Computat Biol, Houston, TX 77030 USA

[10] Mayo Clin Hosp, Dept Urol, Phoenix, AZ USA

[11] Mayo Clin, Dept Lab Med & Pathol, Scottsdale, AZ 85259 USA

[12] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN USA

[13] Univ Texas MD Anderson Canc Ctr, Dept Genitourinary Med Oncol, Houston, TX 77030 USA

[14] Univ Texas SW Med Ctr Dallas, Dept Internal Med, Div Hematol Oncol, Dallas, TX 75390 USA

来源：

MODERN PATHOLOGY | 2016年 / 29卷 / 01期

基金：

美国国家卫生研究院;

关键词：

MUTATIONS; HETEROGENEITY; EVOLUTION; GENES; SETD2; GRADE; TUMOR;

D O I：

10.1038/modpathol.2015.123

中图分类号：

R36 [病理学];

学科分类号：

100104 ;

摘要：

Sequencing of clear cell renal cell carcinomas identified loss-of-function mutations of SETD2, a gene that encodes a nonredundant methytransferase responsible for histone 113 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, 223; 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.

引用

页码：34 / 42

页数：9

共 25 条

[21] The impact of genetic heterogeneity on biomarker development in kidney cancer assessed by multiregional sampling [J].

Sankin, Alexander ;

Hakimi, Abraham A. ;

Mikkilineni, Nina ;

Ostrovnaya, Irina ;

Silk, Mikhail T. ;

Liang, Yupu ;

Mano, Roy ;

Chevinsky, Michael ;

Motzer, Robert J. ;

Solomon, Stephen B. ;

Cheng, Emily H. ;

Durack, Jeremy C. ;

Coleman, Jonathan A. ;

Russo, Paul ;

Hsieh, James J. .

CANCER MEDICINE, 2014, 3 (06) :1485-1492

[22] Variation in chromatin accessibility in human kidney cancer links H3K36 methyltransferase loss with widespread RNA processing defects [J].

Simon, Jeremy M. ;

Hacker, Kathryn E. ;

Singh, Darshan ;

Brannon, A. Rose ;

Parker, Joel S. ;

Weiser, Matthew ;

Ho, Thai H. ;

Kuan, Pei-Fen ;

Jonasch, Eric ;

Furey, Terrence S. ;

Prins, Jan F. ;

Lieb, Jason D. ;

Rathmell, W. Kimryn ;

Davis, Ian J. .

GENOME RESEARCH, 2014, 24 (02) :241-250

[23]

The Cancer Genome Atlas Research Network, 2013, NATURE, V499, P43

[24] Quantitative Interaction Proteomics and Genome-wide Profiling of Epigenetic Histone Marks and Their Readers [J].

Vermeulen, Michiel ;

Eberl, H. Christian ;

Matarese, Filomena ;

Marks, Hendrik ;

Denissov, Sergei ;

Butter, Falk ;

Lee, Kenneth K. ;

Olsen, Jesper V. ;

Hyman, Anthony A. ;

Stunnenberg, Henk G. ;

Mann, Matthias .

CELL, 2010, 142 (06) :967-980

[25] External Validation of the Mayo Clinic Stage, Size, Grade, and Necrosis (SSIGN) Score for Clear-Cell Renal Cell Carcinoma in a Single European Centre Applying Routine Pathology [J].

Zigeuner, Richard ;

Hutterer, Georg ;

Chromecki, Thomas ;

Imamovic, Arvin ;

Kampel-Kettner, Karin ;

Rehak, Peter ;

Langner, Cord ;

Pummer, Karl .

EUROPEAN UROLOGY, 2010, 57 (01) :102-109

← 1 2 3 →