Molecular Differences Predicting Tumor Progression in Colorectal Cancer (PQ #14)

描述（申请人提供）：结直肠肿瘤有不同的命运。Kim和他的同事证明，通过虚拟结肠镜的纵向监测，人类早期腺瘤可以生长，保持不变，甚至自发消退（中华医学杂志，357(14):1403- 12,2007）。我们发现小鼠早期腺瘤具有相同的命运（Acad Radiol. 16(12):1475- 82,2009）。此外，很大比例的腺瘤最终发展为侵袭性腺癌，偶尔会转移到局部淋巴结（Cancer Res. 69(14):5768- 75,2009）。由于最近显微成像技术的进步，肿瘤从良性到恶性的进展现在可以非常详细地描述。我们计划监测肿瘤的进展，收集活检进行组织病理学评估和分子分析（目的1）。与进展相关的转录变化可以用DNA微阵列来阐明。将进展为侵袭性腺癌的腺瘤与不进展的腺瘤进行比较（目的2）。这种类型的实验在人类身上是不可行的，因为任何肿瘤的临床结果都是不可知的。在小鼠模型中识别预测性生物标志物是识别人类感兴趣基因的重要的第一步。我们目前对导致人类结直肠癌（CRC）的遗传事件的了解还不够详细，无法为患者提供复杂的预后信息

DESCRIPTION (provided by applicant): Colorectal tumors have different fates. Kim and colleagues demonstrated that early adenomas in humans could grow, remain static, or even spontaneously regress as determined by longitudinally monitoring via virtual colonography (N Engl J Med. 357(14):1403-12, 2007). We found that early adenomas in the mouse had the same fates (Acad Radiol. 16(12):1475-82, 2009). Moreover, a significant percentage of adenomas eventually progress to invasive adenocarcinomas that occasionally metastasize to regional lymph nodes (Cancer Res. 69(14):5768-75, 2009). The progression of tumors from a benign to malignant state can now be meticulously detailed because of recent advances in micro-imaging. We plan to monitor tumors as they progress, collecting biopsies for histopathological assessment and molecular analysis (Aim 1). Transcriptional changes associated with progression can then be elucidated with DNA microarrays. The profile of adenomas that progress to invasive adenocarcinomas will be compared to the profile of adenomas that do not progress (Aim 2). This type of experiment is not feasible in humans because the clinical outcome of any tumor is unknowable. Identifying predictive biomarkers in a mouse model is an important first step towards identifying genes of interest in humans. Our current understanding of the genetic events leading to human colorectal cancer (CRC) is not sufficiently detailed to allow us to provide sophisticated prognostic information to patients based on the molecular characteristics of their tumors. More detailed information would lead to personalized risk stratification and screening recommendations for patients based on genetic changes present within their tumors. This approach would minimize the risks garnered by unnecessary screening tests, while maximizing the chances that high-risk patients undergo more appropriately timed surveillance. It could also guide novel strategies for chemoprevention and treatment of CRC.