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充满了许多不确定性，并不断受到质疑。因此，迫切需要开发替代肿瘤标志物。最近，TMPRSS 2：ERG融合基因的存在已被证明在大约一半的前列腺癌中。这种复发性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体。我们假设TMPRSS 2：ERG可用作生物标志物，并且特异性融合连接的鉴定可用于设计定量PCR测定以评估尿液和血液中的“肿瘤负荷”。这种生物标志物是PSA的极好替代品，因为这些融合基因确实具有癌症特异性，并且似乎与前列腺癌的发病机制相关。此外，我们还将研究融合变体的转化活性，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TMPRSS 2：ERG融合变体;（2）将原发性肿瘤和尿液中特异性TMPRSS 2：ERG融合变体的存在/不存在与临床结果相关联;（3）表征各种TMPRSS 2：ERG蛋白产物的转化活性。一个真正的癌症特异性生物标志物，反映了“肿瘤负荷”（一个类似于“病毒负荷”的管理艾滋病患者）将是非常有用的评估疾病的侵略性和对治疗的反应。该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志物，前列腺癌是美国男性癌症死亡的第二大原因。目前使用的生物标志物，前列腺特异性抗原（PSA），充满了许多不确定性，并在不断的询问下，导致我们建立一个敏感的检测真正的前列腺癌特异性融合基因的临床应用。该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.