Multicenter Genetic, Epigenetic & Expression Analysis of DCIS outcome predictors

多中心遗传、表观遗传

• 批准号: 8108116
• 负责人: CHRISTOPHER B UMBRICHT
• 金额: $ 56.97万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8108116
• 关键词: Bioinformatics; Biological Assay; Biological Markers; Breast Diseases; Carcinoma; Case-Control Studies; Cataloging; Catalogs; Caucasians; Caucasoid Race; Clinical; Clinical Management; Clonal Evolution; Copy Number Polymorphism; DNA; DNA Methylation; Data; Development; Diagnosis; Diagnostic; Disease; Disease Progression; Disease-Free Survival; Ensure; Epigenetic Process; Ethnic group; Evaluation; Event; Excision; Experimental Designs; Formalin; Future; Gene Mutation; Genes; Genetic; Genetic Markers; Genomics; Goals; Hawaii; Housing; Intervention; Iowa; Location; Longevity; Loss of Heterozygosity; Malignant - descriptor; Malignant Neoplasms; Medical Surveillance; Methods; Methylation; Minority; Modeling; Molecular; Morbidity - disease rate; Mutation; National Cancer Institute; Neoplasm Metastasis; Noninfiltrating Intraductal Carcinoma; Operative Surgical Procedures; Outcome; Paraffin Embedding; Pathway interactions; Patients; Pattern; Performance; Phase; Population; Probability; Prognostic Marker; Progressive Disease; Quality of life; Recurrence; Recurrent disease; Residual state; Resolution; Sampling; Screening for cancer; Staging; Testing; Therapeutic; Time; Tissue Sample; Tissue-Specific Gene Expression; Tissues; Treatment Cost; Validation; Woman; Work; aggressive therapy; base; cancer cell; candidate marker; carcinogenesis; clinical material; cohort; cost; design; genome wide association study; genome-wide; genome-wide analysis; high risk; high throughput analysis; interest; killings; malignant breast neoplasm; novel strategies; patient population; performance tests; population based; prognostic; racial and ethnic; repository; success

DESCRIPTION (provided by applicant): The goal of this project is to identify the molecular alterations that occur in the progression from ductal carcinoma in situ (DCIS) to invasive breast cancer. This is of critical importance because it is only after the milestone of tissue invasion has been achieved that a cancer has the potential to metastasize and kill a patient. Invasive breast cancers harbor multiple molecular alterations that were sequentially acquired during progression from ADH to ductal carcinoma in situ (DCIS) to invasive breast cancer. We will identify the genetic alterations that may be specific to DCIS or may be cumulative with increasing malignant potential. 7Rationale: While the cure rate for ductal carcinoma in situ (DCIS) is over 90%, this comes at the cost of considerable treatment-related morbidity. We urgently need the prognostic markers that would identify key genetic alterations predictive of the long-term outcome of DCIS, since most DCIS never become invasive carcinomas, presumably because they lack critical genetic changes, the replicative lifespan, or simply the time necessary to do so. Our experimental design exploits recent technological developments that permit genome- wide testing of DNA samples for genetic and epigenetic alterations, even in the very limited material available from archival DCIS samples. DCIS may represent a stage at which various pathways of clonal evolution are attempted, until a particular combination of genetic and/or epigenetic changes allows tissue invasion. Indications are that genetic mutations and epigenetic silencing may both be operative in carcinogenesis, and that these alternatives may be used interchangeably, even in a complementary fashion in the same cancer cell. Therefore, a combined analysis of both types of alterations is necessary. 7Design: This study is designed as multicenter, longitudinal, case-control study of DCIS. We have identified unique cohorts of pure DCIS cases with known outcomes to enable a multicenter genome-wide screening study of 100 cases and 100 controls, which will be initially limited to patients of Caucasian origin in order to obtain a homogenous patient population and maximize the probability of successfully validating our hypothesis that prognostic markers exist in DCIS. Candidate markers of interest will be further characterized by quantitative PCR methods, with the goal of creating a single, prognostic multiplex PCR signature that can be used on the limited clinical material typically obtained in the diagnostic phase of the evaluation of DCIS. We will then validate the assay in an independent test cohort of 100 cases of DCIS with progressive disease vs. 100 cases of DCIS that remain disease free, obtained from the population-based repository provided by the Iowa SEER residual tissue repository (RTR). We will also use an additional population-based repository located in Hawaii, to test if the prognostic signature developed from Caucasian samples can be used successfully in a different ethnic group. This will guide future work, particularly regarding the necessity of exploring the predictive power of the multiplex assay in different populations. PUBLIC HEALTH RELEVANCE: The overarching goal of this project is to develop robust, DNA-based predictive genetic markers that will be useful in identifying the minority of cases of preinvasive breast cancer (DCIS), that do in fact progress to invasive disease, given the current lack of molecular guidance available to stratify patients with pure DCIS. Of the over 60,000 women currently diagnosed with pure DCIS per year, less than 30% will develop recurrent breast disease within 10 years of undergoing a surgical resection. With appropriate markers, many could be spared the cost and morbidity of aggressive therapy. Furthermore, the assessment of new approaches to better treat those patients at high risk of disease progression will remain problematic as long as most cases would do well regardless of intervention.

描述（由申请人提供）：该项目的目标是确定从导管原位癌 (DCIS) 发展为浸润性乳腺癌过程中发生的分子改变。这是至关重要的，因为只有在达到组织侵袭的里程碑之后，癌症才有可能转移并杀死患者。浸润性乳腺癌存在多种分子改变，这些改变是在从 ADH 到导管原位癌 (DCIS) 再到浸润性乳腺癌的进展过程中相继获得的。我们将鉴定可能是 DCIS 特有的基因改变，也可能是随着恶性潜力的增加而累积的基因改变。 7 理由：虽然导管原位癌 (DCIS) 的治愈率超过 90%，但这是以相当大的治疗相关发病率为代价的。我们迫切需要预后标志物来识别预测 DCIS 长期结果的关键基因改变，因为大多数 DCIS 永远不会成为浸润性癌，大概是因为它们缺乏关键的基因改变、复制寿命，或者仅仅是这样做所需的时间。我们的实验设计利用了最新的技术发展，允许对 DNA 样本进行全基因组测试，以了解遗传和表观遗传的改变，即使是在 DCIS 档案样本中可用的材料非常有限。 DCIS 可能代表尝试各种克隆进化途径的阶段，直到遗传和/或表观遗传变化的特定组合允许组织侵袭。有迹象表明，基因突变和表观遗传沉默可能都在致癌过程中起作用，并且这些替代方案可以互换使用，甚至在同一癌细胞中以互补的方式使用。因此，有必要对两种类型的改变进行综合分析。 7 设计：本研究被设计为 DCIS 的多中心、纵向、病例对照研究。我们已经确定了具有已知结果的独特的纯 DCIS 病例队列，以便能够对 100 例病例和 100 名对照进行多中心全基因组筛查研究，该研究最初将仅限于白种人血统的患者，以获得同质的患者群体并最大化概率成功验证了我们的假设，即 DCIS 中存在预后标志物。感兴趣的候选标志物将通过定量 PCR 方法进一步表征，目标是创建单一的、预后多重 PCR 特征，该特征可用于通常在 DCIS 评估的诊断阶段获得的有限临床材料。然后，我们将在一个独立的测试队列中验证该检测方法，该测试队列由 100 例患有进展性疾病的 DCIS 病例与 100 例无疾病的 DCIS 病例组成，这些病例是从爱荷华州 SEER 残留组织存储库 (RTR) 提供的基于人群的存储库中获得的。我们还将使用位于夏威夷的一个额外的基于人群的存储库，来测试从白种人样本中开发的预后特征是否可以成功地用于不同的种族群体。这将指导未来的工作，特别是关于探索多重检测在不同人群中的预测能力的必要性。 公共卫生相关性：该项目的总体目标是开发强大的、基于 DNA 的预测遗传标记，这些标记将有助于识别少数浸润前乳腺癌 (DCIS) 病例，考虑到这些病例实际上确实进展为浸润性疾病。目前缺乏可用于对纯 DCIS 患者进行分层的分子指导。目前每年有超过 60,000 名女性被诊断患有单纯 DCIS，其中不到 30% 的女性在接受手术切除后 10 年内会出现复发性乳腺疾病。有了适当的标志物，许多人就可以避免积极治疗的费用和发病率。此外，只要大多数病例无论采取何种干预措施都会表现良好，对更好地治疗疾病进展高风险患者的新方法的评估仍然存在问题。