Journal Article

Multimodal analysis of cell-free DNA whole-genome sequencing for pediatric cancers with low mutational burden

Barreca, Daniele, Myklebost, Ola, Krumbholz, Manuela, Semper, Sabine, Ambros, Inge M., Bock, Christoph, Stütz, Adrian M., Tomazou, Eleni M., Pierron, Gaelle, Schleiermacher, Gudrun, Brennan, Bernadette, Boye, Kjetil, Peneder, Peter, Marec-Bérard, Perrine, Whelan, Jeremy, Ambros, Peter F., Bernkopf, Marie, Agaimy, Abbas, Tötzl, Marcus, Chicard, Mathieu, Burchill, Susan Ann, Ergüner, Bekir, Engstler, Gernot, Dirksen, Uta, Sheffield, Nathan C., Lapouble, Eve, Schaefer, Christiane, Boztug, Heidrun, Hutter, Caroline, Metzler, Markus, Surdez, Didier, Rendeiro, André F., Dworzak, Michael, Delattre, Olivier, Taschner-Mandl, Sabine, Strauss, Sandra J.

2021

Overview

Sequencing of cell-free DNA in the blood of cancer patients (liquid biopsy) provides attractive opportunities for early diagnosis, assessment of treatment response, and minimally invasive disease monitoring. To unlock liquid biopsy analysis for pediatric tumors with few genetic aberrations, we introduce an integrated genetic/epigenetic analysis method and demonstrate its utility on 241 deep whole-genome sequencing profiles of 95 patients with Ewing sarcoma and 31 patients with other pediatric sarcomas. Our method achieves sensitive detection and classification of circulating tumor DNA in peripheral blood independent of any genetic alterations. Moreover, we benchmark different metrics for cell-free DNA fragmentation analysis, and we introduce the LIQUORICE algorithm for detecting circulating tumor DNA based on cancer-specific chromatin signatures. Finally, we combine several fragmentation-based metrics into an integrated machine learning classifier for liquid biopsy analysis that exploits widespread epigenetic deregulation and is tailored to cancers with low mutation rates. Clinical associations highlight the potential value of cfDNA fragmentation patterns as prognostic biomarkers in Ewing sarcoma. In summary, our study provides a comprehensive analysis of circulating tumor DNA beyond recurrent genetic aberrations, and it renders the benefits of liquid biopsy more readily accessible for childhood cancers. Liquid biopsies enable minimally invasive applications for diagnosis and treatment monitoring. Here the authors analyse fragmentation patterns of circulating tumour DNA on multiple levels and develop a bioinformatic tool, LIQUORICE, to accurately detect and classify paediatric cancers with low mutational burden.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 38/22 / 45 / 45/23 / 631/114/794 / 631/208/177 / 631/67/69 / 692/4028/67/2332 / 692/53 / Adolescent / Adult / Algorithms / Biomarkers / Biomarkers, Tumor - blood / Biomarkers, Tumor - genetics / Biopsy / Blood circulation / Bone Neoplasms - blood / Bone Neoplasms - diagnosis / Bone Neoplasms - genetics / Bone Neoplasms - pathology / Cancer / Case-Control Studies / Child / Child, Preschool / Children / Chromatin / Circulating Tumor DNA - blood / Circulating Tumor DNA - genetics / Deoxyribonucleic acid / Depth profiling / Deregulation / Diagnosis / DNA / DNA fragmentation / DNA Mutational Analysis / DNA sequencing / Epigenetics / Ewing's sarcoma / Ewings sarcoma / Female / Fragmentation / Genetic analysis / Genomes / Health services / Humanities and Social Sciences / Humans / Infant / Learning algorithms / Liquid Biopsy - methods / Liquorice / Machine learning / Male / Middle Aged / Monitoring / multidisciplinary / Mutation / Mutation rates / Patients / Pediatrics / Peripheral blood / Sarcoma / Sarcoma, Ewing - blood / Sarcoma, Ewing - diagnosis / Sarcoma, Ewing - genetics / Sarcoma, Ewing - pathology / Science / Science (multidisciplinary) / Telemedicine / Tumors / Whole Genome Sequencing / Young Adult