"Molecular Signatures of Lethal and Indolent Prostate Cancer"

前列腺癌(PCa)的预后和临床处理是最复杂和 当代肿瘤学中有争议的问题。我们的首要目标是开发基于组织的分子 在治疗前进行测试，以区分惰性和攻击性前列腺癌。我们的提案将解决以下几个关键问题 与发展与临床相关的PCa分子特征有关的问题：(1)我们使用PCa 以特定死亡为临床终点；(2)我们将从瑞典雇佣3个明确的患者群体 有长期、完整的临床随访；(3)采用激光捕获等肿瘤增厚方法 显微解剖(LCM)是由于PCa细胞的异质性。 这些指导原则被组织为三个具体目标：在目标1中，我们使用10OK单核苷酸 多态(SNP)阵列检测杂合性缺失(LOH)、纯合缺失和 基因扩增事件，以9Kb的分辨率生成全基因组遗传图谱。将这一点结合起来 96例连续冰冻的前列腺癌活检标本的分子特征数据与临床数据 瑞典奥雷布罗确诊为临床局限性前列腺癌的男性，其中40人死于前列腺癌，30人死于其他疾病 原因，我们将开发一个分子特征来区分好斗和懒惰的前列腺癌。在目标2中，我们测试 并使用基于珠子的纳米技术来验证这一分子图谱，以评估 可以应用于福尔马林固定的石蜡包埋样本的DNA来自全国范围内的队列 瑞典的前列腺切除术(n=600)和两个有警惕的等待队列(n=620)，预计有200和120 分别为PCa特异性死亡。在目标3中，我们将使用瑞典的组织微阵列 前列腺切除术和警惕的等待队列并通过定量评估生物标记物的组合 免疫组织化学、免疫荧光、原位杂交或荧光分析 原位杂交(FISH)。 我们预计将开发可移植到其他实验室进行临床验证的现场测试。在 总结这项建议，我们期望有完善的和充分验证的PCa死亡的分子预测指标 以及适合于进一步临床发展的惰性PCA。

Prognostication and clinical management of prostate cancer (PCA) is one the most complex and controversial issues in contemporary oncology. Our overarching goal is to develop tissue based molecular tests to distinguish indolent from aggressive PCA prior to treatment. Our proposal will address several critical issues related to the development of a clinically relevant molecular signature of PCA: (1) We use PCA specific death as the clinical endpoint; (2) We will employ 3 well defined patient populations from Sweden with long term and complete clinical follow up; (3) We use tumor enriching methods such as laser capture microdissection (LCM) due to the cellular heterogeneity of PCA. These guiding principles have been organized into 3 Specific Aims: In Aim 1, we use 10OK single nucleotide polymorphism (SNP) arrays for the detection of Loss of Heterozygosity (LOH), homozygous deletions and gene amplification events to generate genome-wide genetic maps at a resolution of 9Kb. Combining this molecular signature data with clinical data on PCA biopsy samples from 96 consecutive frozen samples from men diagnosed in Orebro, Sweden with clinically localized PCA of whom 40 died of PCA and 30 of other causes, we will develop a molecular signature to distinguish aggressive from indolent PCA. In Aim 2, we test and validate this molecular profile using a bead-based nanotechnology to assess for somatic alterations in the DNA that can be applied on formalin-fixed paraffin embedded samples from the nationwide cohort of prostatectomies in Sweden (n=600) and two Watchful Waiting cohorts (n=620) with a projected 200 and 120 PCA specific deaths, respectively. In Aim 3, we will employ tissue microarrays from the Swedish Prostatectomy and the Watchful Waiting cohorts and evaluate combinations of biomarkers by quantitative analysis of immunohistochemistry, immunofluorescence (AQUA), in situ hybridization (ISH)or fluorescence in situ hybridization(FISH). We expect to develop in situ tests that will be transportable to other laboratories for clinical validation. At the conclusion of this proposal, we expect to have refined and fully validated molecular predictors of PCA death as well as indolent PCA that is appropriate for further clinical development.