Prostate Fusion Gene Variants as a Cancer Biomarker

描述（由申请人提供）：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，已被用于该疾病的各个方面，包括筛查、治疗计划和监测。然而，PSA充满了许多不确定性，并不断受到质疑。因此，迫切需要开发一种替代肿瘤标志物。最近，TMPRSS2:ERG融合基因在大约一半的前列腺癌中被证实存在。这种复发性的基因组重排很可能与前列腺癌的发展有关。我们已经建立了一种基于微阵列的检测方法，可以筛选广泛的融合变异。我们假设TMPRSS2:ERG可以作为一种生物标志物，并且鉴定特定的融合连接可以用于设计定量PCR检测来评估尿液和血液中的“肿瘤负荷”。这种生物标志物是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，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展中的作用。我们的具体目标是：(1)确定原发性前列腺肿瘤和相应尿液中的TMPRSS2:ERG融合变异；(2)原发肿瘤和尿液中特异性TMPRSS2:ERG融合变异的存在/缺失与临床结果的相关性；(3)表征各种TMPRSS2:ERG蛋白产物的转化活性。反映“肿瘤负荷”（类似于管理HIV患者的“病毒负荷”）的真正的癌症特异性生物标志物将对评估疾病的侵袭性和对治疗的反应非常有用。这项建议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.