Guanylyl Cyclase C in Blood and Colorectal Cancer

描述（由申请人提供）：在美国，50%的结直肠癌患者接受了“治愈性”切除术，但仍会复发。这部分反映了缺乏在临床明显复发前检测隐匿性微转移的技术。鸟苷酸环化酶C（GC-C）在正常粘膜和结直肠癌细胞中特异性表达，但在胃肠道外组织和肿瘤中不表达。GC-C似乎是一种敏感和特异的标记物，可用于检测肠外部位的结直肠癌细胞。初步研究表明，GC-C RT-PCR可以检测所有（34）例转移性结直肠癌患者血液中的转移性结直肠癌细胞。此外，通过RT-PCR测量的GC-C mRNA表达检测到组织病理学检查无疾病的淋巴结中存在隐性微转移。与淋巴结不表达GC-C的患者相比，淋巴结GC-C阳性的患者发生癌症相关死亡的风险更大。这些观察结果表明，对于接受结直肠癌术后监测的患者，GC-C RT-PCR可能有助于比其他方法更早地检测微转移和复发疾病。该应用程序将把我们实验室的基本观察结果转化为新的诊断工具，用于结直肠癌的管理。在具体目标1中，将检查来自未患有GI恶性肿瘤的对照患者（年龄范围为40岁至90岁）的血液中的GC-C表达，以确定处于发生结直肠癌风险的广泛人群中血液中GC-C RT-PCR的基线值。在具体目标2中，将定义血液中GC-C RT-PCR分析与转移性结直肠癌之间的关系。预计与无转移性疾病的患者相比，GC-C RT-PCR在转移性结直肠癌患者的血液中更常呈阳性。在特定目标3中，将临床明显复发与阳性GC-C RT-PCR之间的时间关系与从接受术后监测的结直肠癌患者前瞻性采集的系列血液样本中的血清癌胚抗原（CEA）进行比较。GC-C RT-PCR的预后价值将与本研究期间复发患者的血清CEA水平进行比较。预计GC-C RT-PCR在复发患者的血液中比CEA更早和更频繁地呈阳性。拟议的研究将把关于人体组织和血液中GC-C表达特异性的初步观察结果转化为临床数据，这些数据定义了这种新型标记物在术后监测期间管理结直肠癌患者的诊断效用。这些研究将为未来利用GC-C确定可能从治疗干预中受益的复发风险患者的试验奠定基础。

DESCRIPTION (provided by applicant): In the U.S., 50% of patients who undergo "curative" resection for colorectal cancer suffer recurrent disease. In part, this reflects the absence of techniques to detect occult micrometastases prior to clinically evident recurrence. Guanylyl cyclase C (GC-C) is specifically expressed by normal mucosal and colorectal cancer cells, but not by extra-gastrointestinal tissues and tumors. GC-C appears to be a sensitive and specific marker that can be employed to detect colorectal cancer cells in extra-intestinal sites. Preliminary studies demonstrated that GC-C RT-PCR could detect metastatic colorectal cancer cells in blood from all (34) patients examined with metastatic colorectal cancer. In addition, GC-C mRNA expression measured by RT-PCR detected occult micrometastases in lymph nodes that were free of disease by histopathology. Patients with lymph nodes positive for GC-C were at greater risk for cancer-related mortality compared to patients with lymph nodes that did not express GC-C These observations suggest that for patients undergoing post-operative surveillance for colorectal cancer, GC-C RT-PCR may be useful to detect micrometastases and recurrent disease earlier than other methods. This application will translate basic observations from our laboratory into new diagnostic tools for the management of colorectal cancer. In Specific Aim 1, GC-C expression will be examined in blood from control patients who do not have GI malignancies, with ages ranging from 40 yo to 90 yo, to establish the baseline value for GC-C RT-PCR in blood in the broad population of individuals at risk to develop colorectal cancer. In Specific Aim 2, the relationship between GC-C RT-PCR analysis in blood and metastatic colorectal cancer will be defined. It is expected that GC-C RT-PCR will be positive more often in the blood of patients with metastatic colorectal cancer compared to patients without metastatic disease. In Specific Aim 3, the temporal relationship between clinically evident recurrence and a positive GC-C RT-PCR will be compared to that of serum carcinoembryonic antigen (CEA) in serial blood samples collected prospectively from colorectal cancer patients undergoing post-operative surveillance. The prognostic value of GC-C RT-PCR will be compared to serum CEA levels in patients who recur during this study. It is anticipated that GC-C RT-PCR will be positive earlier and more frequently than CEA in the blood of patients who recur. The studies proposed will translate preliminary observations concerning the specificity of GC-C expression in human tissues and blood into clinical data which define the diagnostic utility of this novel marker for managing colorectal cancer patients during post-operative surveillance. These studies will form the foundation for future trials utilizing GC-C to identify patients at risk for recurrence who might benefit from therapeutic intervention.