Cancer monitoring and stratification using somatic copy number alterations and epigenetic signatures

Our group has developed several methods for the analysis of circulating tumor DNA (ctDNA). To date, we have analyzed more than 4,000 plasma samples from patients with cancer (breast, prostate, colon, renal and lung carcinoma), which allowed us to estimate the dynamics of clonal evolution of tumor genomes and to identify mechanisms of resistance against given therapies. Using shallow whole-genome sequencing we observed in serial plasma analyses that focal amplifications represent frequent novel occurring changes driving progression of cancer.

Recently we leveraged the fact that plasma DNA is nucleosome protected DNA. Appropriate bioinformatics including support vector machines allowed the mapping of nucleosome positions based on the genomic sequencing coverage of plasma DNA fragments. For example, the genomic sequencing coverage of plasma DNA fragments around transcription start sites (TSSs) has a peculiar pattern allowing the identification of actively transcribed genes of cells releasing their DNA into the circulation. Furthermore, as deregulation of transcription factors (TFs) is an important driver of tumorigenesis we also assessed TF activity based on cell-free DNA sequencing and nucleosome footprint analysis. To this end, we analyzed whole genome sequencing data for >1,000 cell-free DNA samples from cancer patients and healthy controls using a newly developed bioinformatics pipeline that infers accessibility of TF binding sites from cell-free DNA fragmentation patterns. We observed patient-specific as well as tumor-specific patterns, including accurate prediction of tumor subtypes in prostate cancer, with important clinical implications for the management of patients. Furthermore, we show that cell-free DNA TF profiling is capable of detection of early-stage colorectal carcinomas.