METHYLATION PROFILING AND RISK OF COLORECTAL CANCER

甲基化谱和结直肠癌风险

• 批准号: 6936549
• 负责人: Hassan Ashktorab
• 金额: $ 26.52万
• 依托单位: HOWARD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-01 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6936549
• 关键词: African American; adenomatous polyps; biomarker; biopsy; cancer risk; carcinoma; chromosome deletion; clinical research; colorectal neoplasms; endoscopy; gastrointestinal imaging /visualization; gel electrophoresis; gene induction /repression; gene mutation; genetic screening; human subject; immunocytochemistry; loss of heterozygosity; methylation; neoplasm /cancer classification /staging; neoplasm /cancer genetics; neoplastic transformation; p53 gene /protein; polymerase chain reaction; prognosis; tumor suppressor genes

DESCRIPTION (provided by applicant): Colorectal carcinoma (CRC) is the most common gastrointestinal malignancy in the U.S and the rate of CRC is 1.5 times higher in African Americans (AA) than Caucasians. Recent advances in the field of molecular medicine has led to the use of microsatellite instability (MSI), loss of heterozygosity (LOH), and methylation specific PCR techniques which permit detection of chromosomal and gene alterations of colonic mucosal cells. The use of markers has helped to predict disease progression and prognosis. Epigenetic changes are early in the sequence of genetic alterations leading to CRC. Subsequent changes often include the loss of portions or whole chromosomes. MSI in neoplasms accumulates mutations in microsatellites within the coding region of certain genes. These data suggest that MSI, LOH and methylation profiling may add an important layer of information in the molecular phenotyping of malignances for prognostic purposes. We postulate that MSI-H, gene silencing for DNA repair gene hMHL1, p16 and LOH of APC, p53 and deleted in colorectal cancer (DCC), which are known to modulate cellular proliferation in colonic mucosa, may alter chromosome behavior in the pathway of neoplastic transformation. MSI will be measured using five microsatellite loci, and the level of p53, APC and DCC protein will be determined by immunohistochemistry in mucosal biopsies. By determining the methylation and mutation/deletion profiles of 250 cases, we determine specifically (1) to elucidate the effect of p16 and hMLH1 gene methylation in the pathway of neoplastic transformation in normal and cancer tissue of AA patients with CRC, (2) to determine the induction of MSI in colonic mucosa that may be reflected in the expression of biomarkers of neoplastic transformation and cellular proliferation from AA patients history of colonic adenomas, those with no history of adenomas, and those with a history of resected CRC. These experiments may assist in identifying persons at risk of developing adenomas and/or CRC, (3) to determine whether LOH or allelic loss occurs in APC, p53, and DCC genes in normal and cancer tissue of CRC patients and identify persons at risk of developing additional adenomas and/or CRC, (4) to analyze tumor tissue in AA patients with stage III and high-risk stage II CRC who had been treated with fluorouracil, and the ability of MSI and LOH markers to predict survival and/or response to treatment. These studies will help in the detection and profiling of genetic changes in the pathway of CRC in AA.

描述（由申请人提供）：结直肠癌（CRC）是美国最常见的胃肠道恶性肿瘤，非洲裔美国人（AA）的CRC发生率是高加索人的1.5倍。分子医学领域的最新进展导致使用微卫星不稳定性（MSI），杂合性丧失（LOH）和甲基化特定的PCR技术，这些技术允许检测结肠粘膜细胞的染色体和基因改变。标记的使用有助于预测疾病的进展和预后。表观遗传变化是在导致CRC的遗传改变的早期。随后的变化通常包括部分或整个染色体的损失。肿瘤中的MSI在某些基因的编码区域内积累了微卫星突变。这些数据表明，MSI，LOH和甲基化谱分析可能在预后目的的恶性肿瘤分子表型中添加重要的信息层。我们假设MSI-H，用于DNA修复基因HMHL1，p16和apc，p53的LOH的基因沉默并在结直肠癌（DCC）中删除，已知可以调节结肠粘膜中的细胞增殖，可能会改变染色体的染色体行为。 MSI将使用五个微卫星基因座测量，p53，APC和DCC蛋白的水平将通过粘膜活检中的免疫组织化学确定。通过确定250例250例的甲基化和突变/缺失谱，我们确定（1）以阐明p16和hmlh1基因甲基在AA患者正常和癌症组织中的肿瘤转化途径中的影响，CRC患者的肿瘤组织和癌症组织的cRC（2），（2）可能会在Colonic Mucosa中诱导的ne培养基，以确定Colonic Mucosa诱导的ne ne ne ne ne ne。 AA患者的结肠腺瘤病史，没有腺瘤史的患者病史以及具有切除率的CRC史的人的扩散。这些实验可能有助于识别出患有腺瘤和/或CRC的风险的人，（3）确定在CRC患者正常和癌症组织中，LOH或等位基因损失是否发生在APC，p53和DCC基因中，并确定患有III阶段和/或CRC患者的额外腺瘤和/或CRC患者的风险（4）氟尿嘧啶，以及MSI和LOH标记预测生存和/或对治疗反应的能力。这些研究将有助于检测和分析AA中CRC途径的遗传变化。