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，通过虚拟结肠造影术进行纵向监测，人类早期的腺瘤可以生长、保持静止，甚至可以自发消退(N Engl J Med.357(14)：1403-12,2007)。我们发现小鼠早期的腺瘤有相同的命运(Acad Radiol。16(12)：1475-82,2009)。此外，相当大比例的腺瘤最终进展为侵袭性腺癌，偶尔转移到区域淋巴结(癌症研究69(14)：5768-75,2009)。由于显微成像的最新进展，肿瘤从良性状态到恶性状态的进展现在可以被仔细地详细描述。我们计划监测肿瘤的进展，收集活检以进行组织病理学评估和分子分析(目标1)。然后，与进展相关的转录变化可以用DNA微阵列来阐明。进展为浸润性腺癌的腺瘤的概况将与没有进展的腺瘤的概况进行比较(目标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未知的。在小鼠模型中识别预测性生物标记物是识别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)的基因事件的了解还不够详细，不能为患者提供复杂的预后信息 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，并根据患者肿瘤内存在的基因变化为患者提供筛查建议。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危患者接受更适当的时机监测的机会。它还可以指导化学预防和治疗结直肠癌的新战略。

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.