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

描述（由申请人提供）：结直肠肿瘤有不同的结局。Kim及其同事证明，人类早期腺瘤可以生长、保持静止或甚至自发消退，如通过虚拟结肠造影纵向监测所确定的（N Engl J Med.357（14）：1403-12，2007）。我们发现小鼠中的早期腺瘤具有相同的命运（Acad Radiol.16（12）：1475-82，2009）。此外，显著百分比的腺瘤最终进展为偶尔转移至区域淋巴结的侵袭性腺癌（Cancer Res.69（14）：5768-75，2009）。由于显微成像技术的最新进展，肿瘤从良性到恶性的进展现在可以被细致地描述。我们计划监测肿瘤的进展，收集活检组织病理学评估和分子分析（目标1）。然后可以用DNA微阵列阐明与进展相关的转录变化。将进展为浸润性腺癌的腺瘤的特征与未进展的腺瘤的特征进行比较（目的2）。这种类型的实验在人类中是不可行的，因为任何肿瘤的临床结果都是不可知的。在小鼠模型中鉴定预测性生物标志物是鉴定人类感兴趣基因的重要第一步。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，无法为患者提供基于基因的复杂预后信息。 他们肿瘤的分子特征。更详细的信息将导致个性化的风险分层和筛查建议的基础上存在于他们的肿瘤内的遗传变化的患者。这种方法将最大限度地减少不必要的筛查测试带来的风险，同时最大限度地增加高风险患者接受更适当的定时监测的机会。它还可以指导CRC的化学预防和治疗的新策略。

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.