Molecular Markers of BC

BC 分子标记

• 批准号: 7726888
• 负责人: SARASWATI SUKUMAR
• 金额: $ 22.54万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7726888
• 关键词: Accounting; Address; Age; Algorithms; Area; Azacitidine; Behavior; Benign; Biological; Biological Assay; Biological Markers; Breast; Breast Cancer Model; Carcinoma; Case-Control Studies; Cellularity; Characteristics; Clinical; Clinical Data; Clinical Trials; Colon Carcinoma; Derivation procedure; Detection; Development; Diagnosis; Disease; Disease Progression; Disease-Free Survival; Distant; End Point; Ensure; Epigenetic Process; Epithelial Cells; Event; Frequencies; Funding; Gene Expression; Gene Silencing; Genes; Genome; Goals; Histone Deacetylase Inhibitor; Histopathology; Hybridization Array; Hydroxamic Acids; Hypermethylation; Hyperplasia; Individual; Invasive; Laboratories; Lesion; Malignant Neoplasms; Mammography; Mastectomy; Methods; Methylation; Modeling; Molecular; Nested Case-Control Study; Noninfiltrating Intraductal Carcinoma; Normal Cell; Normal tissue morphology; Outcome; Paraffin Embedding; Pathology; Patients; Pattern; Polymerase Chain Reaction; Primary Neoplasm; Recurrence; Recurrent disease; Reproduction spores; Research Personnel; Resected; Risk; Sampling; Sensitivity and Specificity; Specificity; Specimen; Staging; Surgical margins; Techniques; Technology; Testing; Therapeutic; Tissues; Training; Woman; Work; base; breast cancer diagnosis; breast lesion; breast lumpectomy; cancer cell; cancer type; case control; cohort; disorder risk; ductal breast carcinoma; experience; follow-up; genome wide association study; improved; malignant breast neoplasm; promoter; size; tumor; tumor progression

Each year about 50,000 new cases of ductal carcinoma in situ (DCIS) are diagnosed in the US, and account for 17-34% of all mammographically detected cases. Disease recurs within 10 years in 20% of women treated for DCIS. Currently, no clinical or histopathological characteristics have been found that are consistently associated with recurrence. Promoter hypermethylation is a powerful epigenetic mechanism for suppression of gene expression and occurs in many types of cancers. Hypermethylated genes provide very sensitive and specific DMA markers for breast cancer. A quantitative method [Quantitative Multiplex- Methylation Specific PCR (QM-MSP)] was developed in the investigator's laboratory, which detects hypermethylation in multiple genes in very small biological samples of cancer cells in the presence of a vast excess of normal cells, with high sensitivity and specificity. This proposal is based upon the hypothesis that the hypermethylation of a specific set of genes in DCIS can be used to recognize those DCIS cases that will recur as invasive cancer. The goal of this proposal is to identify genes that are methylated in DCIS, study their behavior during tumor progression, and develop a recurrence model based on a DCISspecific gene methylation panel to test their utility as predictors of tumor recurrence in patients with long-term follow-up This goal will be achieved in three steps: In Aim 1, perform a genome-wide scan for genes silenced by hypermethylation using a modified array analysis on purified epithelial cells, isolated from 30 primary DCIS and treated with demethylating agents. In Aim 2, determine if the genes identified in Aim 1 support a model of progression from DCIS to invasive breast cancer. The genes, following verification, will be used for QM-MSP analysis of archival normal, benign, DCIS and invasive cancer samples, and in analogous samples obtained from 44 individual mastectomy specimens. In Aim 3, test the ability of the methylated gene marker panel derived in Aim 2 to prognosticate recurrence of DCIS as invasive ductal carcinoma, and thereby identify patients at risk. The most promising gene panel will be tested in training and test sets by QM-MSP in tumor samples from UCSF's DCIS case-control study. In this cohort of 1062 women treated only by lumpectomy, 200 cases recurred within 7 years, and are matched with 400 age-, grade-, size- and marginmatched control cases that did not recur. As a result of this work, we hope to derive an algorithm that will identify DCIS patients at risk for recurrence, and derive a molecular progression paradigm that will permit the development of a therapeutic strategy that will improve tumor-free survival among those patients, while minimizing excessive therapy in those unlikely to develop invasive disease.

每年在美国诊断出约50,000例现场导管癌（DCI），帐户 在所有乳房X线检查病例中，有17-34％。疾病在20％的妇女中在10年内复发 治疗了DCIS。目前，尚未发现尚无临床或组织病理学特征 一致与复发有关。启动子高甲基化是一种强大的表观遗传机制 抑制基因表达并发生在许多类型的癌症中。高甲基化基因提供非常 对乳腺癌的敏感和特异性DMA标记。一种定量方法[定量多路复用 在研究者的实验室中开发了甲基化特异性PCR（QM-MSP）]，该实验室检测 在很大 过多的正常细胞，具有高灵敏度和特异性。该提议基于以下假设 DCI中一组特定基因的高甲基化可用于识别这些DCIS病例 这将作为侵入性癌症复发。该提案的目的是鉴定在中甲基化的基因 DCIS，研究其在肿瘤进展过程中的行为，并基于Dcisspific开发复发模型 基因甲基化面板以测试其效用，作为长期患者肿瘤复发的预测指标 后续行动将通过三个步骤实现：在AIM 1中，对基因进行基因扫描进行沉默 通过使用对纯化的上皮细胞进行的修改阵列分析，通过超甲基化，从30个原发性分离 DCI并用脱甲基剂处理。在AIM 2中，确定AIM 1中鉴定的基因是否支持 从DCI到浸润性乳腺癌的进展模型。验证后的基因将用于 QM-MSP分析档案正常，良性，DCI和侵入性癌症样品以及类似样品的QM-MSP分析 从44个单独的乳房切除术标本获得。在AIM 3中，测试甲基化基因标记的能力 在AIM 2中得出的面板预测DCI的复发为侵入性导管癌，从而将 确定有危险的患者。最有希望的基因面板将在训练和测试集中测试QM-MSP UCSF的DCIS病例对照研究中的肿瘤样品。在这一队列中，只有1062名妇女 乳房切除术，200例在7年内重现，并与400岁，级，尺寸和边缘匹配 控制案件没有复发。由于这项工作，我们希望得出一种算法 识别出患有复发风险的DCIS患者，并得出一个分子进展范例，该范例将允许 制定一种治疗策略，该策略将改善这些患者的无肿瘤生存期，而 最大程度地减少不太可能发展入侵性疾病的人的过度治疗。