Pathogenetics of a Clinically-favorable Prostate Cancer Subtype

描述(申请人提供)：前列腺癌是美国男性中最常被诊断出的癌症。然而，绝大多数患有前列腺癌的男性不会死于他们的疾病，这反映了他们的肿瘤在临床上的懒惰行为。事实上，大多数临床医生现在都同意前列腺癌既被过度诊断又被过度治疗，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。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于不必要的、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理解。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，这些亚型中的一种，亚型-1，表现出临床上有利的行为，我们推测可能代表了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)的研究表明，不同亚型背后有明显的遗传基础，包括在临床有利的亚型1肿瘤中染色体细胞带5q21和6q15内的特异性缺失。这些发现立即暗示了新的肿瘤抑制基因(TSG)与临床上有利的前列腺癌的发病机制有关，并确定了它们的位置。我们建议的研究的目标是发现5q21和6q15的致病TSGs，这些TSGs是临床上有利的前列腺癌亚型的基础。其具体目的是(1)通过阵列CGH来划定5q21和6q15的重复缺失的边界；以及(2)筛选剩余的候选TSG以检测DNA突变和启动子超甲基化。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。我们的发现还可能为诊断临床上有利的肿瘤提供新的基于基因的标记物，从而改善前列腺癌患者的治疗分层和临床管理。项目说明： 拟议中的研究旨在确定一种临床上有利的前列腺癌亚型背后的癌症基因。我们的发现将进一步加深我们对前列腺癌发病机制的理解，并可能为改进前列腺癌的分类和前列腺癌患者的治疗提供新的基于基因的标记物。

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.