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

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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.