Biomarker validation for intraductal papillary mucinous neoplasms of the pancreas

项目摘要/摘要：乳腺导管内乳头状黏液性肿瘤 胰腺是囊性肿瘤，表现为放射学上可识别的前驱病变。 胰腺癌。目前，IPMN是我们进行干预的最佳机会--和 拦截--在患上不治之症之前。然而，挑战是当前的。 实验室、内窥镜和成像技术无法区分IPMN 低风险(低级别异型增生)或高风险(高级别异型增生)成为侵袭性 癌症。此外，我们提高诊断准确性的能力-特别是通过生物标记物 开发-一直很困难，因为IPMN非常不同，具有多个组织学亚单位 同一病变内存在不典型增生的类型和级别。在过去的18个月里，我们有 以一种新的空间转录学平台为手段，设计并执行了先导性研究 在空间上识别高级别异型增生的精确的、亚型特异性的上皮标志物。 来自IPMN切除患者的组织。这些研究发现了基因上的显著差异 低级别和高度不典型增生之间的表达--而且是第一次--有明显的 明确肠和胰胆管亚型IPMN的基因表达差异。 后一项发现的重要性无论怎么强调都不为过，肠道IPMN亚型将 通常进展为浸润性胶质癌，这是一种侵袭性较弱的恶性肿瘤。 此外，我们还鉴定了不同肠道间囊肿液蛋白丰度的差异。 以及反映这些基因表达差异的胰胆管亚型IPMN。在这 项目，我们将利用这个空间平台来扩大我们的工作，并确定具体的子类型 高度不典型增生的上皮标志物。然后我们将评估囊液中的这些蛋白质 一个新的蛋白质组学平台(Olink Focus)，并进一步开发高风险预测模型 疾病(在之前的项目期内验证，AUC约为0.8)。最后，我们会 尝试通过将模型(S)应用于两个不同的囊液来快速验证该模型(S 我们小组开发的包含数百名患者囊液的储存库 已对胰腺囊肿进行了治疗--并有成熟的随访。我们相信，这种方法将 使我们能够识别非常特定的囊液蛋白标记物，包括上皮亚型和分级 并开发一种非常准确的检测高危IPMN的方法。患有IPMN的患者表现为 高级别异型增生的准确标记物的识别将允许 在发生不治之症之前进行根治性干预(切除)，同时保守治疗 那些具有低级别病变的患者的发病率--甚至死亡率--与手术相同。

PROJECT SUMMARY/ABSTRACT: Intraductal papillary mucinous neoplasms (IPMN) of the pancreas are cystic tumors that represent a radiographically identifiable precursor lesion of pancreatic cancer. Currently, IPMN represent our best opportunity for intervention - and interception - prior to the development of an incurable cancer. The challenge however, is current laboratory, endoscopic, and imaging technologies are unable to distinguish between IPMN that is at low-risk (low-grade dysplasia) or at high-risk (high-grade dysplasia) of becoming an invasive cancer. In addition, our ability to improve diagnostic accuracy - particularly through biomarker development - has been difficult, as IPMN is very heterogeneous with multiple histologic sub- types and grades of dysplasia existing within the same lesion. Over the past 18 months we have designed and performed pilot studies utilizing a novel spatial transcriptomics platform as a means to spatially identify precise, sub-type specific, epithelial markers of high-grade dysplasia in the tissue from patients resected for IPMN. These studies have found significant differences in gene expression between both low-grade and high-grade dysplasia - and for the first time - have clearly defined gene expression differences between intestinal and pancreaticobiliary sub-type IPMN. The importance of this latter finding cannot be overemphasized, as intestinal sub-type IPMN will typically progress to invasive colloid cancer, which is a much less aggressive malignancy. Furthermore, we have identified differences in cyst fluid protein abundances between intestinal and pancreaticobiliary sub-type IPMN that mirror these gene expression differences. In this project, we will utilize this spatial platform to expand our work and identify sub-type specific epithelial markers of high-grade dysplasia. We will then assess cyst fluid for these proteins using a novel proteomics platform (Olink Focus), and further develop a prediction model for high-risk disease (validated during the previous project period, AUC approximately 0.8). Finally, we will attempt to rapidly validate this model(s) by applying the model(s) to two separate cyst fluid repositories developed by our group that contain cyst fluid from hundreds of patients who have been managed for pancreatic cysts - and have mature follow-up. We believe this approach will allow us to identify very specific cyst fluid protein markers to both epithelial sub-type and grade of dysplasia and develop a very accurate test for high-risk IPMN. Patients with IPMN represent a population in which the identification of accurate markers of high-grade dysplasia will allow for curative intervention (resection) prior to the development of an incurable disease, while sparing those with low-grade lesions the morbidity – and even mortality – of operation.