Accelerating the Development and Validation of Liquid Biopsy Assays for Cancer

Liquid biopsies, such as blood plasma containing cell-free DNA, provide a non-invasive route to profile tumor genomes in precision medicine. Current research and clinical efforts have largely focused on detecting mutations in select cancer genes from circulating tumor DNA (ctDNA) found in cell-free DNA. However, solutions to characterize and integrate genome-wide alterations and epigenetic profiling can further improve the detection of ctDNA in cancer patients. We propose to develop novel computational approaches for high-sensitivity copy number and tissue-of-origin analysis from scalable low-pass whole genome sequencing of cell-free DNA. We will apply these approaches to study metastatic castration-resistant prostate cancer (mCRPC), a lethal disease with no curative treatment. Using the rich clinical annotations and serial blood samples collected during therapy, we will identify features and alterations in ctDNA that may be implicated in treatment resistance. These innovations will be critical to establishing an accurate clinical cfDNA diagnostic workflow and will accelerate the discovery of blood-based genomic biomarkers in cancer.

Final Report

The ICI Fund Grant has helped us pursue three projects leading to development of new computational methods for circulating tumor DNA analysis and insights into advanced prostate cancer.  Results from these projects have been used to secure additional grant funding and manuscripts are being prepared for publication. 

  1. A comprehensive analysis of linked-read and short-read whole genome sequencing (WGS) of tumors from advanced prostate cancer. We identified significant regions of structural variation (SV) breakpoint hotspots that helped to form nine distinct SV signatures. These signatures were associated with some known alterations in DNA damage repair genes and stratified patients with poorer prognosis that were not revealed by gene mutations alone. These results provide a closer view of complex SV patterns in metastatic prostate tumors and will help inform genomic analyses in circulating tumor DNA (ctDNA). 
  2. Development of Griffin, a method for profiling nucleosome occupancy from cell-free DNA (cfDNA). We developed a new computational framework and tool that employs a novel data processing procedure to correct cfDNA fragment coverage for improving analysis of nucleosome protection and accessibility. We applied Griffin to detect cancer, predict cancer tissue-of-origin, and study tumor cell plasticity in prostate cancer.
  3. Study of genomic copy number alteration signatures from low-coverage WGS (0.1-0.5x) and clinical targeted panel sequencing data from tissue and cfDNA of prostate cancer patients. We developed an approach to use off-target reads from panel sequencing data to predict genome-wide CNA profiles. We applied this to a large number of patients sequenced using the OncoPlex targeted cancer gene panel. We are finalizing the clinical correlation component of the study now. 
  4. New grants obtained using results as preliminary data: NCI R21, CDMRP/DoD Prostate Cancer Research Program Idea Development Award, Prostate Cancer Foundation Young Investigator Award.

Learn More

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

Github:
Griffin: A flexible framework for nucleosome profiling of cell-free DNA

Nature.com:
A framework for clinical cancer subtyping from nucleosome profiling of cell-free DNA

AACRjournals.org:
Nucleosome patterns in circulating tumor DNA reveal transcriptional regulation of advanced prostate cancer phenotypes

Insight.org:
Patterns of structural variation define prostate cancer across disease states