Molecular Phenotype of Polyps in Serrated Polyposis Syndrome

描述（由申请人提供）：在美国，每年有超过50,000人死于结肠癌，使其成为男性和女性癌症死亡的第二大原因。结肠息肉通常是结肠癌的前兆。锯齿状息肉在普通人群中发病率很高（20-30%），以前被认为是无害的。然而，最近的研究提供证据表明，20-35%的结肠癌是由一部分锯齿状息肉引起的。锯齿状息肉分为两种主要亚型：无柄锯齿状腺瘤/息肉（SSA/Ps）和传统的增生性息肉。SSA/Ps似乎有发展为结肠癌的最大风险，而传统的增生性息肉被认为是良性的。一个主要的挑战是通过内镜或组织学检查将SSA/Ps与传统的增生性息肉区分开来。此外，我们对它们发展为结肠癌的机制知之甚少。我们预测，利用新技术确定SSA/Ps的基因表达表型，与传统的增生、腺瘤性息肉和对照组相比，将对SSA/Ps的肿瘤进展有重要的认识，提高SSA/Ps的诊断，并最终减少因SSA/Ps而患结肠癌的患者数量。我们首先将研究SSA/Ps患者的一个极端例子，即锯齿状息肉病综合征。患有锯齿状息肉病综合征的患者患结肠癌的几率很高，约为30-40%。这些患者中大量的SSA/Ps及其丰富的癌症风险为研究SSA/Ps及其与结肠癌的关系提供了一个很好的机会。我们的研究包括可获得的此类患者的最大队列之一。我们已经从这些患者和对照组中获得了SSA/Ps和邻近结肠活检标本，并应用了新的RNA分离和基因表达谱技术来研究它们。我们的方法以显著提高的分辨率检测RNA聚合酶II基因表达，以找到基因表达标记，并推进我们对SSA/Ps中改变的基因调控途径的了解。我们假设我们的方法和独特的患者队列将确定基因表达标记组，更准确地诊断SSA/Ps，预测其癌症风险，并使SSA/Ps向结肠癌进展的机制研究成为可能。我们拥有一支优秀的专家团队，包括博士。Randy Burt （APC基因的共同发现者），Curt Hagedorn （RNA分析和生物学），Mary Bronner （GI病理学），David Nix（生物信息学）和David Jones（结肠癌机制和表观遗传学）成功开展了SSA/Ps作为结肠癌前体的研究。

DESCRIPTION (provided by applicant): Over 50,000 people die from colon cancer each year in the USA, making it the second leading cause of cancer death for men and women alike. Colon polyps are the usual precursors of colon cancer. Serrated polyps, which occur at a high incidence (20-30%) in the general population, were previously considered harmless. However, recent studies provide evidence that 20-35% of colon cancers arise from a subset of serrated polyps. Serrated polyps are divided into two main subtypes: sessile serrated adenomas/polyps (SSA/Ps) and traditional hyperplastic polyps. SSA/Ps appear to have the greatest risk of progressing to colon cancer whereas traditional hyperplastic polyps are considered benign. A major challenge is differentiating SSA/Ps from traditional hyperplastic polyps by endoscopic or histological examination. Moreover, we know little about their mechanism of progression to colon cancer. We predict that using new technologies to define the gene expression phenotype of SSA/Ps, as compared to traditional hyperplastic, adenomatous polyps and controls, will lead to important insights into the neoplastic progression of SSA/Ps, improve the diagnosis of SSA/Ps and eventually decrease the number of patients suffering from colon cancer due to SSA/Ps. We initially will study an extreme example of patients with SSA/Ps, the serrated polyposis syndrome. Patients with the serrated polyposis syndrome have a high rate of colon cancer, approximately 30-40%. The numerous SSA/Ps in these patients and their enriched cancer risk provide an outstanding opportunity to study SSA/Ps and their relationship to colon cancer. Our study includes one of the largest cohorts of such patients available. We have already obtained SSA/Ps and adjacent colon biopsy specimens from these patients and controls and have applied new RNA isolation and gene expression profiling technologies to study them. Our approach examines RNA polymerase II gene expression, with a markedly enhanced resolution, to find gene expression markers and advance our knowledge of the gene regulatory pathways altered in SSA/Ps. We hypothesize that our approach and unique patient cohort will identify panels of gene expression markers that more accurately diagnose SSA/Ps, predict their cancer risk and enable mechanistic studies of the progression of SSA/Ps to colon cancer. We have an outstanding team of experts, including Drs. Randy Burt (co-discoverer of the APC gene), Curt Hagedorn (RNA analysis and biology), Mary Bronner (GI pathology), David Nix (bioinformatics) and David Jones (colon cancer mechanisms and epigenetics) to successfully conduct this study of SSA/Ps as precursors of colon cancer.