Pathogenetics of a Clinically-favorable Prostate Cancer Subtype

临床上有利的前列腺癌亚型的发病机制

• 批准号: 7740168
• 负责人: JONATHAN R POLLACK
• 金额: $ 20.62万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-12-01 至 2011-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7740168
• 关键词: 5q21; Aberrant DNA Methylation; Address; Behavior; Chromosomes; Classification; Clinical; Clinical Management; DNA; Diagnosis; Disease; Exhibits; Future; Gene Expression; Gene Mutation; Genes; Genetic; Genomics; Goals; Hybridization Array; Hypermethylation; Indolent; Knowledge; Lead; Location; Malignant Neoplasms; Malignant neoplasm of prostate; Molecular; Morbidity - disease rate; Mutation; Oncogenes; Pathogenesis; Patients; Pattern; Prostate-Specific Antigen; Prostatic Neoplasms; Publishing; Recurrence; Research; Screening procedure; Specimen; Stratification; Therapeutic Intervention; Tumor Suppressor Genes; United States; base; bisulfite; cancer diagnosis; comparative genomic hybridization; improved; men; novel; promoter; tumor

DESCRIPTION (provided by applicant): Prostate cancer is the most frequently diagnosed cancer among men in the United States. Yet, the vast majority of men with prostate cancer will not die from their disease, reflecting the clinically-indolent behavior of their tumors. Indeed, most clinicians now agree that prostate cancer is both over-diagnosed and over-treated, a situation exacerbated by widespread prostate specific antigen (PSA) screening, and leading to significant treatment-associated morbidity. A key clinical question then is which men with prostate cancer could be spared unnecessary and potentially harmful therapy. Addressing this question requires a more detailed molecular understanding of clinically-indolent prostate cancer. In prior published studies, we identified three previously unrecognized molecular subtypes of prostate cancer based on distinct patterns of gene expression. Notably, one of these subtypes, subtype-1 , exhibited clinically-favorable behavior, and we speculate might represent a class of indolent tumors not requiring therapeutic intervention. Our more recent studies using array-based comparative genomic hybridization (array CGH) now indicate a distinct genetic basis underlying the different subtypes, including specific deletion within chromosome cytobands 5q21 and 6q15 in the clinically-favorable subtype-1 tumors. These findings at once implicate novel tumor suppressor genes (TSGs) in the pathogenesis of clinically-favorable prostate cancer, and define their location. The goal of our proposed research is to discover the pathogenic TSGs at 5q21 and 6q15 underlying a clinically-favorable prostate cancer subtype. The specific aims are (1) To delimit the boundaries of recurrent deletion at 5q21 and 6q15 by array CGH; and (2) To screen remaining candidate TSGs for DNA mutations and promoter hypermethylation. These studies will further our knowledge of the molecular pathogenesis of prostate cancer. Our findings may also suggest novel gene-based markers for the diagnosis of clinically- favorable tumors, leading to improved treatment stratification and clinical management of men with prostate cancer.

描述（由申请人提供）：前列腺癌是美国男性中最常诊断出的癌症。然而，绝大多数患有前列腺癌的男性不会死于这种疾病，这反映了他们的肿瘤的临床惰性行为。事实上，大多数临床医生现在都认为前列腺癌被过度诊断和过度治疗，广泛的前列腺特异性抗原（PSA）筛查加剧了这种情况，并导致显着的治疗相关发病率。那么一个关键的临床问题是哪些患有前列腺癌的男性可以免受不必要且可能有害的治疗。解决这个问题需要对临床惰性前列腺癌有更详细的分子了解。在之前发表的研究中，我们根据不同的基因表达模式确定了三种以前未被识别的前列腺癌分子亚型。值得注意的是，这些亚型之一，亚型1，表现出临床上有利的行为，我们推测可能代表一类不需要治疗干预的惰性肿瘤。我们最近使用基于阵列的比较基因组杂交（阵列 CGH）进行的研究现在表明了不同亚型背后的独特遗传基础，包括临床上有利的 1 型肿瘤中染色体细胞带 5q21 和 6q15 内的特异性缺失。这些发现立即表明新的肿瘤抑制基因（TSG）与临床有利的前列腺癌的发病机制有关，并确定了它们的位置。我们提出的研究的目标是发现临床上有利的前列腺癌亚型的 5q21 和 6q15 致病性 TSG。具体目标是（1）通过阵列CGH界定5q21和6q15重复缺失的边界； (2) 筛选剩余候选 TSG 的 DNA 突变和启动子高甲基化。这些研究将进一步加深我们对前列腺癌分子发病机制的了解。我们的研究结果还可能为诊断临床上有利的肿瘤提出新的基于基因的标记，从而改善前列腺癌男性的治疗分层和临床管理。