Establishment of a novel genomic approach to non-invasive therapeutic response assessment & monitoring of minimal residual disease (MRD) in patients with Non-Hodgkin´s Lymphoma

建立一种新的基因组方法来评估非侵入性治疗反应

• 批准号: 249636657
• 负责人: Dr. Florian Paul Scherer
• 金额: --
• 依托单位: Division of Oncology
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2013
• 资助国家: 德国
• 起止时间: 2012-12-31 至 2015-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/249636657?language=en
• 关键词: Establishment; novel; genomic; approach; non

We propose to develop and apply a sensitive assay for response assessment including MRD (minimal residual disease) detection in patients with Non-Hodgkins Lymphomas (NHL), using a novel method for quantitation of tumor-derived DNA in circulation. Circulating tumor DNA represents a potential liquid biopsy, a promising biomarker for minimally invasive monitoring of tumor dynamics, since tumor DNA is continually released into the blood by cancer cells and can be detected as cell-free DNA (cfDNA). Advances in high throughput sequencing (HTS) technologies have enabled rapid sequencing of cancer whole genomes and revealed that most tumor genomes, including NHLs, contain thousands of previously unappreciated aberrations, which could serve as biomarkers in NHL patients. Through profiling of a select yet broad collection of somatic aberrations that are recurrent in NHL, we want to devise a sensitive method for early response assessment and MRD detection for future clinical studies and clinical use. A major hurdle in quantitating circulating tumor DNA using HTS is the relatively low level of tumor-derived cfDNA that must be detected, requiring extremely high (and therefore costly) sequencing depth. To overcome this problem a novel approach called CAncer Personalized Profiling by Deep Sequencing (CAPP-Seq) was devised. CAPP-Seq utilizes a custom designed solution-based hybridization method to capture genomic regions highly enriched for single nucleotide variants (SNVs), insertions/deletions (indels), or translocations in NHLs. Aim of this study is to fully develop and characterize a novel next generation sequencing (NGS) method for detecting tumor-derived cell-free DNA circulating in blood. We will expand CAPP-Seq using a collection of >230 diverse lymphoid malignancies studied by HTS. Furthermore, we want to compare the potential utility of CAPP-Seq with IgH-HTS and standardized radiographic criteria for NHL response assessment in NHL by prospectively establishing benchmarks for sensitivity and specificity.

我们建议开发和应用一种灵敏的方法来评估包括检测非霍奇金淋巴瘤(NHL)患者的微小残留病(MRD)在内的反应，使用一种新的方法来定量循环中的肿瘤来源DNA。循环的肿瘤DNA是一种潜在的液体活检，是一种很有前途的生物标志物，用于肿瘤动力学的微创监测，因为肿瘤DNA不断被癌细胞释放到血液中，并可被检测为无细胞DNA(CfDNA)。高通量测序(HTS)技术的进步使癌症全基因组的快速测序成为可能，并揭示了包括NHL在内的大多数肿瘤基因组包含数千种以前未被发现的异常，这些异常可以作为NHL患者的生物标志物。通过对NHL中反复出现的大量体细胞异常的分析，我们希望设计一种敏感的方法来进行早期反应评估和MRD检测，以供未来的临床研究和临床使用。使用HTS对循环肿瘤DNA进行定量的一个主要障碍是必须检测到相对较低的肿瘤来源cfDNA水平，这需要极高的(因此也是昂贵的)测序深度。为了克服这一问题，设计了一种新的方法，称为癌症个性化深度测序(CAPP-SEQ)。CAPP-SEQ利用定制设计的基于溶液的杂交方法来捕获NHL中高度丰富的单核苷酸变异(SNV)、插入/缺失(INDELs)或易位的基因组区域。本研究的目的是全面开发和表征一种新的检测血液中肿瘤来源的无细胞DNA的新的下一代测序(NGS)方法。我们将使用HTS研究的230种不同的淋巴系统恶性肿瘤的集合来扩展CAPP-Seq。此外，我们希望通过前瞻性地建立敏感性和特异性的基准，比较CAPP-SEQ与IGH-HTS和标准化放射学标准在评估NHL反应方面的潜在效用。