Cell type signatures in cell-free DNA fragmentation profiles reveal disease biology

Abstract

Cell-free DNA fragmentation; Cancer

Fragmentación de ADN libre de células; Cáncer

Fragmentació d'ADN lliure de cèl·lules; Càncer

Circulating cell-free DNA (cfDNA) fragments have characteristics that are specific to the cell types that release them. Current methods for cfDNA deconvolution typically use disease tailored marker selection in a limited number of bulk tissues or cell lines. Here, we utilize single cell transcriptome data as a comprehensive cellular reference set for disease-agnostic cfDNA cell-of-origin analysis. We correlate cfDNA-inferred nucleosome spacing with gene expression to rank the relative contribution of over 490 cell types to plasma cfDNA. In 744 healthy individuals and patients, we uncover cell type signatures in support of emerging disease paradigms in oncology and prenatal care. We train predictive models that can differentiate patients with colorectal cancer (84.7%), early-stage breast cancer (90.1%), multiple myeloma (AUC 95.0%), and preeclampsia (88.3%) from matched controls. Importantly, our approach performs well in ultra-low coverage cfDNA datasets and can be readily transferred to diverse clinical settings for the expansion of liquid biopsy.

We would like to thank the patients and their families for agreeing to participate in this study. We would like to thank the Genomics Core at KU Leuven for the use of the sequencing facilities. Funding was received from the European Union’s Horizon 2020 research and innovation program under grant agreement No 824110 – EASI-Genomics (J.R.V.) and the Marie Skłodowska-Curie grant agreement No 813707 (MATER), from Kom Op Tegen Kanker (Stand up to Cancer) KOTK/2018/11468, from the Flemish cancer society (2016/10728/2603 to A.C.), and FWO-SBO grant S003422N, and from Agentschap Innoveren en Ondernemen (VLAIO; Flanders Innovation & Entrepreneurship grant HBC.2018.2108). S.T. was supported by FWO SB/1S74420N. Institutional support was received from the KU Leuven, C1- C14/18/092, C14/22/125, and C3/20/100 to J.R.V