Griffin: Framework for clinical cancer subtyping from nucleosome profiling of cell-free DNA

Cell-free DNA (cfDNA) has the potential to inform tumor subtype classification and help guide clinical precision oncology. Here we developed Griffin, a new method for profiling nucleosome protection and accessibility from cfDNA to study the phenotype of tumors using as low as 0.1x coverage whole genome sequencing (WGS) data. Griffin employs a novel GC correction procedure tailored to variable cfDNA fragment sizes, which improves the prediction of chromatin accessibility. Griffin achieved excellent performance for detecting tumor cfDNA in early-stage cancer patients (AUC=0.96). Next, we applied Griffin for the first demonstration of estrogen receptor (ER) subtyping in metastatic breast cancer from cfDNA. We analyzed 254 samples from 139 patients and predicted ER subtype with high performance (AUC=0.89), leading to insights about tumor heterogeneity. In summary, Griffin is a framework for accurate clinical subtyping and can be generalizable to other cancer types for precision oncology applications.