Pathogenetics of a Clinically-favorable Prostate Cancer Subtype

描述（由申请人提供）：前列腺癌是美国男性中最常诊断的癌症。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，这种情况因广泛的前列腺特异性抗原（PSA）筛查而加剧，并导致显著的治疗相关发病率。一个关键的临床问题是，哪些前列腺癌患者可以避免不必要的和潜在的有害治疗。解决这个问题需要对临床惰性前列腺癌进行更详细的分子理解。在先前发表的研究中，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，表现出临床有利的行为，我们推测可能代表一类惰性肿瘤，不需要治疗干预。我们最近使用基于阵列的比较基因组杂交（阵列CGH）的研究表明，不同亚型的遗传基础不同，包括在临床上有利的亚型1肿瘤中染色体细胞带5 q21和6 q15内的特异性缺失。这些发现立刻暗示新的肿瘤抑制基因（TSGs）在临床上有利的前列腺癌的发病机制，并确定其位置。我们提出的研究的目标是发现5 q21和6 q15的致病性TSGs潜在的临床有利的前列腺癌亚型。具体目的是（1）通过阵列CGH来划定5 q21和6 q15复发性缺失的边界;（2）筛选剩余的候选TSGs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认识。我们的研究结果还可能提示新的基于基因的标记物用于诊断临床上有利的肿瘤，从而改善前列腺癌男性的治疗分层和临床管理。项目叙述： 拟议的研究旨在确定前列腺癌临床有利亚型的癌症基因。我们的研究结果将进一步了解前列腺癌的发病机制，并可能提出新的基于基因的标记物，以改善前列腺肿瘤的分类和前列腺癌患者的管理。

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. PROJECT NARRATIVE: The proposed studies aim to identify the cancer genes underlying a clinically-favorable subtype of prostate cancer. Our findings will further our understanding of the pathogenesis of prostate cancer, and may suggest novel gene-based markers for an improved classification of prostate tumors and management of patients with prostate cancer.