Global Levels of Specific Histone Modifications and an Epigenetic Gene Signature Predict Prostate Cancer Progression and Development

被引：112

作者：

Bianco-Miotto, Tina ^{[2
]}

Chiam, Karen ^{[2
]}

Buchanan, Grant ^{[2
,3
]}

Jindal, Shalini ^{[2
]}

Day, Tanya K. ^{[2
]}

Thomas, Mervyn ^{[4
]}

Pickering, Marie A. ^{[2
]}

O'Loughlin, Melissa A. ^{[2
,3
]}

Ryan, Natalie K. ^{[2
]}

Raymond, Wendy A. ^{[5
,6
]}

Horvath, Lisa G. ^{[7
]}

Kench, James G. ^{[7
]}

Stricker, Phillip D. ^{[8
,9
]}

Marshall, Villis R. ^{[10
,11
]}

Sutherland, Robert L. ^{[7
,9
]}

Henshall, Susan M. ^{[7
,9
]}

Gerald, William L. ^{[12
]}

Scher, Howard I. ^{[13
]}

Risbridger, Gail P. ^{[14
]}

Clements, Judith A. ^{[15
,16
]}

Butler, Lisa M. ^{[2
]}

Tilley, Wayne D. ^{[2
]}

Horsfall, David J. ^{[2
]}

Ricciardelli, Carmela ^{[1
,2
]}

机构：

[1] Univ Adelaide, Discipline Obstet & Gynaecol, Sch Paediat & Reprod Hlth, Res Ctr Reprod Hlth,Robinson Inst, Adelaide, SA 5005, Australia

[2] Univ Adelaide, Discipline Med, Dame Roma Mitchell Canc Res Labs, Brisbane, Qld, Australia

[3] Univ Adelaide, Discipline Med, Freemasons Fdn Ctr Mens Hlth, Mol Ageing Lab, Brisbane, Qld, Australia

[4] Emphron Informat, Brisbane, Qld, Australia

[5] Flinders Med Ctr, Bedford Pk, SA, Australia

[6] Gribbles Pathol, Bedford Pk, SA, Australia

[7] St Vincents Hosp, Garvan Inst Med Res, Canc Res Program, Sydney, NSW 2010, Australia

[8] St Vincents Hosp, Dept Urol, Sydney, NSW 2010, Australia

[9] Univ New S Wales, Fac Med, St Vincents Clin Sch, Kensington, NSW 2033, Australia

[10] Royal Adelaide Hosp, Surg Serv, New York, NY USA

[11] Royal Adelaide Hosp, Specialty Serv, New York, NY USA

[12] Mem Sloan Kettering Canc Ctr, Dept Pathol, New York, NY 10021 USA

[13] Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, New York, NY 10021 USA

[14] Monash Univ, Dept Anat & Dev Biol, Prostate & Breast Canc Res Grp, Clayton, Vic, Australia

[15] Queensland Univ Technol, Australian Prostate Canc Res Centre Queensland, Discipline Mol Biosci, Kelvin Grove, Qld, Australia

[16] Queensland Univ Technol, Inst Hlth & Biomed Innovat, Kelvin Grove, Qld, Australia

来源：

CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION | 2010年 / 19卷 / 10期

基金：

英国医学研究理事会;

关键词：

VIDEO IMAGE-ANALYSIS; ANDROGEN RECEPTOR; DNA METHYLATION; BREAST-CANCER; RADICAL PROSTATECTOMY; ABERRANT EXPRESSION; TRIMETHYLATION; RECURRENCE; METHYLTRANSFERASE; COACTIVATOR;

D O I：

10.1158/1055-9965.EPI-10-0555

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 [肿瘤学];

摘要：

Background: Epigenetic alterations are common in prostate cancer, yet how these modifications contribute to carcinogenesis is poorly understood. We investigated whether specific histone modifications are prognostic for prostate cancer relapse, and whether the expression of epigenetic genes is altered in prostate tumorigenesis. Methods: Global levels of histone H3 lysine-18 acetylation (H3K18Ac) and histone H3 lysine-4 dimethylation (H3K4diMe) were assessed immunohistochemically in a prostate cancer cohort of 279 cases. Epigenetic gene expression was investigated in silico by analysis of microarray data from 23 primary prostate cancers (8 with biochemical recurrence and 15 without) and 7 metastatic lesions. Results: H3K18Ac and H3K4diMe are independent predictors of relapse-free survival, with high global levels associated with a 1.71-fold (P < 0.0001) and 1.80-fold (P = 0.006) increased risk of tumor recurrence, respectively. High levels of both histone modifications were associated with a 3-fold increased risk of relapse (P < 0.0001). Epigenetic gene expression profiling identified a candidate gene signature (DNMT3A, MBD4, MLL2, MLL3, NSD1, and SRCAP), which significantly discriminated nonmalignant from prostate tumor tissue (P = 0.0063) in an independent cohort. Conclusions: This study has established the importance of histone modifications in predicting prostate cancer relapse and has identified an epigenetic gene signature associated with prostate tumorigenesis. Impact: Our findings suggest that targeting the epigenetic enzymes specifically involved in a particular solid tumor may be a more effective approach. Moreover, testing for aberrant expression of epigenetic genes such as those identified in this study may be beneficial in predicting individual patient response to epigenetic therapies. Cancer Epidemiol Biomarkers Prev; 19(10); 2611-22. (C) 2010 AACR.

引用

页码：2611 / 2622

页数：12

共 58 条

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Global histone modifications predict prognosis of resected non-small-cell lung cancer [J].