Prostate Fusion Gene Variants as a Cancer Biomarker

描述(申请人提供)：前列腺癌是美国男性癌症死亡的第二大原因。前列腺特异性抗原(PSA)是一种肿瘤标志物，已被用于疾病的各个方面，包括筛查、治疗计划和监测。然而，PSA充满了许多不确定因素，并不断受到讯问。因此，迫切需要开发一种新的肿瘤标志物。最近，在大约一半的前列腺癌中发现了TMPRSS2：ERG融合基因。这种反复出现的基因组重排很可能与前列腺癌的发生有关。我们已经建立了一种基于微阵列的检测方法，可以筛选范围广泛的融合变种。我们假设TMPRSS2：ERG可以作为生物标记物，并且特定融合连接的鉴定可以用于设计定量PCR分析来评估尿液和血液中的“肿瘤负荷”。这种生物标记物是PSA的一个很好的替代品，因为这些融合基因是真正的癌症特异性基因，似乎与前列腺癌的发病机制有关。此外，我们还将研究融合变异体的转化活性，以更好地了解它们在前列腺癌发生中的作用。我们的具体目标是：(1)确定原发前列腺癌和相应尿液中TMPRSS2：ERG融合变异体；(2)确定原发肿瘤和尿液中特异性TMPRSS2：ERG融合变异体的存在与否与临床预后的关系；(3)表征各种TMPRSS2：ERG蛋白产物的转化活性。一种真正的癌症特异性生物标记物可以反映“肿瘤负荷”(类似于管理艾滋病毒患者的“病毒负荷”)，这将非常有助于评估疾病的侵袭性和对治疗的反应。这项提案的成功将显著改善前列腺癌患者的决策。 公共卫生相关性：迫切需要开发前列腺癌的替代肿瘤标记物，前列腺癌是美国男性癌症死亡的第二大原因。目前使用的生物标记物前列腺特异性抗原(PSA)充满了许多不确定性，并受到不断的询问，这使得我们建立了一种灵敏的用于临床应用的前列腺癌特异性融合基因的检测方法。这项提案的成功将显著改善前列腺癌患者的决策。

DESCRIPTION (provided by applicant): Prostate cancer is the second leading cause of cancer death in men in the United States. Prostate specific antigen (PSA) is a tumor marker that has been used in every aspect of the disease, including screening, treatment planning and surveillance. However, PSA is fraught with many uncertainties and is under constant interrogation. Therefore, there is a critical need for the development of an alternative tumor marker. Recently, the presence of the TMPRSS2:ERG fusion gene has been demonstrated in approximately half of all prostate cancers. This recurrent genomic rearrangement is very likely associated with prostate cancer development. We have established a microarray-based assay that can screen a broad range of fusion variants. We hypothesize that TMPRSS2:ERG can be used as a biomarker and that identification of the specific fusion junction can be used for designing quantitative PCR assays to assess "tumor load" in the urine and blood. This biomarker is an excellent alternative to PSA, as these fusion genes are truly cancer specific and appear to be associated with the pathogenesis of prostate cancer. Furthermore, we will also study the transformation activity of the fusion variants to better understand their role in prostate cancer development. Our specific aims are (1) Determine TMPRSS2:ERG fusion variants in primary prostate tumor and corresponding urine; (2) Correlate the presence/absence of specific TMPRSS2:ERG fusion variants in primary tumor and urine with clinical outcome; (3) Characterize the transformation activities of various TMPRSS2:ERG protein products. A true cancer-specific biomarker that mirrors "tumor load" (an analog to "viral load" for managing HIV patients) will be very useful for assessing aggressiveness of disease and response to therapy. The success of this proposal will significantly improve decision making for patients with prostate cancer. PUBLIC HEALTH RELEVANCE: There is a critical need for the development of an alternative tumor marker for prostate cancer, the second leading cause of cancer death in men in the United States. The currently used biomarker, prostate specific antigen (PSA), is fraught with many uncertainties and is under constant interrogation, leading us to establish a sensitive assay on a true prostate cancer-specific fusion gene for clinical application. The success of this proposal will significantly improve decision making for patients with prostate cancer.