Characterizing the DNA methylomes of indolent and aggressive prostate cancers

惰性和侵袭性前列腺癌 DNA 甲基化组的特征

基本信息

批准号：
8875628
负责人：
Angela H Ting
金额：
$ 32.58万
依托单位：
CLEVELAND CLINIC LERNER COM-CWRU
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-01 至 2017-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8875628
关键词：
Accounting Adverse effects Affect Aggressive behavior Area Base Pairing Benign Binding Sites Biochemical Biological Biological Assay Biological Markers Brachytherapy Candidate Disease Gene Categories Cells Cessation of life Chemicals Clinical Code DNA DNA Methylation DNA Modification Process Data Detection Development Diagnosis Disease Erectile dysfunction External Beam Radiation Therapy Future Gene Silencing Genes Genome Genomic Instability Gleason Grade for Prostate Cancer Goals Hypermethylation Incidence Indolent Laboratories Malignant - descriptor Malignant Neoplasms Malignant neoplasm of prostate Maps Methods Methylation MicroRNAs Molecular Morbidity - disease rate Nature Neoplasm Metastasis Outcome PSA screening Patients Prostate Prostate-Specific Antigen Radical Prostatectomy Recurrence Regulation Repetitive Sequence Resolution Sampling Screening for Prostate Cancer Site Specimen Techniques Testing Tumor Suppressor Genes Urinary Incontinence Urine base bisulfite sequencing cancer therapy cohort cost design effective therapy genome sequencing genome-wide men methylation biomarker methylation pattern methylome mortality new therapeutic target prevent promoter prostate carcinogenesis software development therapeutic target tool tumor

项目摘要

DESCRIPTION (provided by applicant): In the era of PSA screening, the incidence of prostate cancer has increased more than two fold with a concomitant rise in the number of radical prostatectomies performed. However, there has been only a modest decrease in cause-specific mortality. Thus, we are subjecting many patients with biologically indolent cancers to the morbidities of prostate cancer treatments such as radical prostatectomy, brachytherapy, and external beam radiation therapy. One of the strongest predictors of clinically aggressive behavior is high Gleason grade. However, we do not understand at a molecular level what differentiates low grade from high grade cancers. Using a candidate gene approach, differences in DNA methylation patterns have been shown between benign prostate and prostate cancer. More importantly, our preliminary data indicate that there are extensive DNA methylation differences between low and high Gleason grade cancers. Therefore, we hypothesize that DNA methylation differences underlie biological differences between indolent and aggressive prostate cancer. In Aim 1, we will perform a genome-wide mapping of DNA methylation patterns in benign prostate, low grade, and high grade cancers to identify areas of hypo- and hyper- methylation. In aim 2, we will subsequently validate these differences in additional, independent cohorts of clinical specimens. The goal is to utilize methylation differences as biomarkers that can distinguish between indolent and aggressive forms of the disease. Ultimately, these discoveries will help us understand the fundamental biological differences between indolent and aggressive prostate cancer, identify new biomarkers to distinguish them, and provide therapeutic targets for effective treatments.

描述（由申请人提供）：在PSA筛查时代，前列腺癌的发病率增加了两倍以上，同时进行的根治性前列腺切除术的数量也随之增加。然而，特定原因死亡率仅略有下降。因此，我们让许多患有生物学惰性癌症的患者接受前列腺癌治疗，例如根治性前列腺切除术、近距离放射治疗和外束放射治疗。临床攻击行为的最强预测因素之一是高格里森等级。然而，我们不知道在分子水平上如何区分低级别癌症和高级别癌症。使用候选基因方法，良性前列腺癌和前列腺癌之间的 DNA 甲基化模式存在差异。更重要的是，我们的初步数据表明，低格里森级别癌症和高格里森级别癌症之间存在广泛的 DNA 甲基化差异。因此，我们假设 DNA 甲基化差异是惰性前列腺癌和侵袭性前列腺癌之间生物学差异的基础。在目标 1 中，我们将对良性前列腺癌、低级别癌症和高级别癌症的 DNA 甲基化模式进行全基因组图谱分析，以确定低甲基化和高甲基化区域。在目标 2 中，我们随后将在额外的独立临床样本队列中验证这些差异。目标是利用甲基化差异作为生物标志物，可以区分疾病的惰性形式和侵袭性形式。最终，这些发现将帮助我们了解惰性前列腺癌和侵袭性前列腺癌之间的基本生物学差异，识别新的生物标志物来区分它们，并为有效治疗提供治疗靶点。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

WOMEN IN CANCER THEMATIC REVIEW: Diverse functions of DNA methylation: implications for prostate cancer and beyond.

DOI：
10.1530/erc-16-0306
发表时间：
2016-11
期刊：
Endocrine-related cancer
影响因子：
3.9
作者：
Thomas J. Sweet;A. Ting
通讯作者：
Thomas J. Sweet;A. Ting

Methylome-wide Sequencing Detects DNA Hypermethylation Distinguishing Indolent from Aggressive Prostate Cancer.

DOI：
10.1016/j.celrep.2015.10.078
发表时间：
2015-12-15
期刊：
Cell reports
影响因子：
8.8
作者：
Bhasin JM;Lee BH;Matkin L;Taylor MG;Hu B;Xu Y;Magi-Galluzzi C;Klein EA;Ting AH
通讯作者：
Ting AH

WOMEN IN CANCER PROFILE: Dude, where's my band?

癌症女性概况：伙计，我的乐队在哪里？