TARGETS FOR SCREENING IN PANCREATIC NEOPLASIA

胰腺癌通常出现在临床晚期，不适合 手术切除。即使进行了切除，这种疾病通常最终也会 致命的。 胰腺浸润性腺癌的前驱病变是 胰腺上皮内肿瘤，通常称为“增生性”。它 可能非常常见，在高达60%的老年人中存在 人口。只有一部分在组织学上是先进的，还有一小部分 藏匿它们的人会患上癌症。因此，有必要 将胰腺癌发生重新解释为胰腺癌的进展 上皮内瘤变。具体地说，我们需要知道哪些标记 定义一种“高风险”的上皮内病变 侵入性的。K-ras基因突变在大量此类病变中的发现 建议需要应用更多的遗传标记。重要 问题仍然没有得到回答，比如导管病变的多灶性， 它们沿着胰管的物理延伸，哪些基因发生了变化 在病变的不同阶段，无论是一种 癌症可以追溯到特定的起源管道，以及标志物 高危病变的情况可能适用于筛查策略。 沿着两条主线的初步研究已经汇聚到一起，以便能够研究 上皮内病变。首先，一些基因改变已经被 在浸润性胰腺癌中定义，提供候选基因 用于研究前驱物质。第二，小细胞的研究技术 种群，包括显微操作器解剖，以获得个体 细胞，已经被开发出来。使用这些，我们演示了 K-ras基因突变与组织学进展的上皮内病变 扩散。此外，我们观察到有K-ras和p16的导管病变。 与由此产生的癌症完全相同的变化-分子 证实了这一肿瘤进展模型，并提示p16 突变标志着一些高风险的导管病变。 这个项目的具体目的是研究特定基因的时序 突变，表征了不同类型的导管病变的范围和数量 种群亚群，识别和研究特定的管道，这些管道给出 上升为浸润性癌。这项工作的总体目标是 因此，定义生物学上的“高风险”损害，并探索 基因检测作为临床筛查工具的适用性。

Pancreatic carcinoma usually presents at a clinical stage too advanced for surgical resection. Even with resection, the disease is usually eventually fatal. The precursor lesion for infiltrating adenocarcinoma of the pancreas is the pancreatic intraepithelial neoplasm, commonly termed a "hyperplasia". It is probably very common, being present in up to 60% of the older population. Only a subset are histologically advanced, and a small minority of persons harboring them will develop a cancer. Therefore, there is a need to reinterpret pancreatic carcinogenesis as a progression of intraepithelial neoplasia. Specifically, we need to know which markers define a "high risk" intraepithelial lesion that is likely to become invasive. The finding of K-ras mutations in a large number of these lesions has suggested that additional genetic markers need to be applied. Important questions remain unanswered, such as the multifocality of duct lesions, their physical extension along pancreatic ducts, which genes are altered in various stages of the lesions, whether the exact genetic changes in a cancer can be traced to a particular duct of origin, and whether markers of high risk lesions might be adapted for screening strategies. Preliminary studies along two lines have converged to allow the study of intraepithelial lesions. First, a number of genetic alterations have been defined in infiltrating pancreatic carcinomas, providing candidate genes for study of the precursors. Second, techniques for the study of small cell populations, including micromanipulator dissection to obtain individual cells, have been developed. Using these, we demonstrated an association of K-ras mutations with histologically advanced intraepithelial proliferations. Furthermore, we observed duct lesions having K-ras and p16 alterations identical to those of the resultant carcinomas - molecular confirmation for this tumor-progression model and suggestive that p16 mutations mark some high risk duct lesions. The specific aims of this project are to study the timing of specific gene mutations, characterize the extent and number of duct lesions among various population subgroups, identify and study the particular ducts which give rise to infiltrating carcinomas. The overall goal of this effort is therefore to define biologically "high risk" lesions, and explore the applicability to gene detection as a clinical screening tool.