Identifying the tumor suppressor gene at 6q15 indolent prostate cancer

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。患前列腺癌的风险是六分之一，但绝大多数男性不会死于癌症，许多临床医生现在同意前列腺癌被过度治疗。一个关键的临床问题仍然是如何确定哪些患者患有临床上不重要的疾病，因此可以避免不必要的和潜在的有害治疗。为了识别临床惰性肿瘤的标志物，需要更好地了解临床惰性前列腺癌的分子机制。我们以前曾报道过3种基于不同基因表达模式的未识别的前列腺癌分子亚型，其中一种与临床惰性特征相关。进一步的基于阵列的比较基因组杂交（阵列CGH）分析显示，染色体细胞带6q15内的特异性缺失与临床惰性肿瘤相关。本研究的总体目标是了解临床惰性前列腺癌的分子发病机制。我们的具体目标是确定和功能特征的致病性肿瘤抑制基因（TSG）在6q15与惰性前列腺癌。将使用全基因组寡核苷酸阵列上的阵列CGH对另外50个临床惰性肿瘤标本进行基因组分析，以将6q15缺失核心内的基因数量缩小至10个以下。将通过对肿瘤标本中具有单拷贝缺失的剩余等位基因进行测序，筛选剩余候选TSGs的DMA突变，并通过对肿瘤标本中CpG岛区域的亚硫酸氢盐修饰DNA进行测序，筛选启动子超甲基化。然后通过在具有缺失的前列腺癌细胞系中重新表达候选TSG并测定对癌细胞活性（包括增殖、侵袭和凋亡）的影响来初步表征候选TSG的功能。这项研究将进一步加深我们对临床惰性前列腺癌分子发病机制的认识，并可能为临床惰性肿瘤的诊断提供新的基于基因的标记物。这可能会为医生提供更好的临床管理能力，并为前列腺癌患者选择最佳治疗方法。

DESCRIPTION (provided by applicant): Prostate cancer is the most frequently diagnosed cancer in men in the United States. The risk of prostate cancer is 1 in 6, but the vast majority of men will not die from their cancer and many clinicians now agree that prostate cancer is over-treated. A key clinical question that remains is how to determine which patients have clinically-insignificant disease and could therefore be spared unnecessary and potentially harmful therapy. In order to identify markers for clinically-indolent tumors, a better understanding of the molecular mechanisms of clinically-indolent prostate cancer is needed. We had previously reported 3 unrecognized molecular subtypes of prostate cancer based on distinct patterns of gene expression, one of which was associated with clinically-indolent features. Further analysis with array-based comparative genomic hybridization (array CGH) has revealed a specific deletion within chromosome cytoband 6q15to be associated with clinically-indolent tumors. The overall goal of this study is to gain understanding of the molecular pathogenesis of clinically-indolent prostate cancer. Our specific objective is to identify and functionally characterize the pathogenic tumor suppressor gene (TSG)at 6q15associated with indolent- prostate cancer. Array CGH on whole-genome oligonucleotide arrays will be used to genomically profile 50 additional clinically-indolent tumor specimens to narrow down the number of genes within the 6q15deletion core to less than 10. Remaining candidate TSGs will be screened for DMA mutation by sequencing the remaining allele of tumor specimens with a single-copy deletion, and for promoter hypermethylation by sequencing the bisulfite-modified DNA from the CpG island region from tumor specimens. The functions of candidate TSGs will then be preliminarily characterized by re-expressing them in prostate cancer cell lines with the deletion and assaying the effect on cancer cell activities, including proliferation, invasiveness, and apoptosis. This study will further our knowledge of the molecular pathogenesis of clinically-indolent prostate cancer and may suggest novel gene-based markers for the diagnosis of clinically-indolent tumors. This may provide doctors with an improved ability to clinically manage and choose the best treatment for men with prostate cancer.