Researchers have developed and validated an artificial intelligence (AI)-powered liquid biopsy that accurately identified hepatocellular carcinoma (HCC) based on cell-free DNA (cfDNA) fragments in individuals from two distinct populations, according to research findings published in Cell Press Blue.
“Our earlier studies showed that fragmentome analyses could detect liver cancer and, more recently, chronic liver diseases that increase cancer risk,” said co-senior study author Victor Velculescu, MD, PhD, the Cancer Genetics and Epigenetics Professor, Co-Director of the Cancer Genetics and Epigenetics Program at Johns Hopkins. “This study demonstrates that the approach works with high performance across different patient populations while revealing the biological signals in the bloodstream that make this type of detection possible.”
Background and Study Methods
Previously, the research team developed the machine learning–based liquid biopsy platform DELFI (DNA Evaluation of Fragments for Early Interception), which was used for analyzing cfDNA fragmentation profiles for detection of lung and liver cancers. The approach demonstrated efficacy among individuals from Europe, the United States, and Hong Kong. They also found that the fragmentomics approach could be used to detect liver fibrosis and cirrhosis.
In this study, the researchers developed and validated an AI classifier to identify HCC in high-risk independent populations. The two cohorts consisted of patients with and without HCC carcinoma from Guatemala and Romania (n = 377), to represent possible different disease etiologies.
Key Findings
The researchers found that cfDNA fragmentome characteristics such as chromatin, genomic, methylome, mutational, and repeat element profiles were changed in patients with HCC of different etiologies.
They used a methylation-based tissue-of-origin algorithm, called MethID, on the cfDNA fragmentomes to identify changes that came from liver, vascular, or immune cells. They then developed and locked a cfDNA fragmentome classifier for identifying HCC across different stages and etiologies. The classifier outperformed alpha-fetoprotein in detecting HCC.
“[T]hese DNA fragments contain much more information than whether cancer is present,” said co-senior study author Zachariah Foda, MD, PhD, Assistant Professor of Medicine at the Johns Hopkins University School of Medicine. “It tells us where these fragments originate and how they change during cancer development, allowing us to better understand the biology of the disease and improve our ability to detect it.”
When cfDNA fragmentomes, alpha-fetoprotein, and clinical risk were all combined in one AI model, the model demonstrated higher sensitivity for detecting early- and late-stage HCC in the two geographic cohorts than conventional approaches to disease detection.
Going forward, the researchers plan to prospectively validate and refine multimodal liquid biopsy approaches using fragmentomics to improve the early detection of HCC.
DISCLOSURES: This research was supported by the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, the Commonwealth Foundation, the Cole Foundation, a research grant from Delfi Diagnostics, National Institutes of Health grants, and a Department of Defense grant. Drs. Phallen, Adleff, and Scharpf are co-founders of Delfi Diagnostics, and Adleff, Scharpf, and Foda are consultants. Drs. Phallen, Scharpf, and Foda are inventors on patent applications submitted by Johns Hopkins University related to cfDNA and cancer detection that have been licensed to Delfi Diagnostics. Dr. Velculescu is a founder of Delfi Diagnostics and Artemyx, serves on the board of directors and owns stock of both organizations. The Johns Hopkins University owns equity in Delfi Diagnostics. Dr. Velculescu divested his equity in Personal Genome Diagnostics (PGDx) to LabCorp in February 2022. He is an inventor on patent applications submitted by Johns Hopkins University related to cancer genomic and cell-free DNA analyses that have been licensed to one or more entities, including Delfi Diagnostics, Artemyx, LabCorp, Qiagen, Sysmex, Agios, Genzyme, Esoterix, Ventana, and ManaT Bio. Under the terms of these license agreements, the university and inventors are entitled to fees and royalty distributions. Velculescu is an adviser to Viron Therapeutics and Epitope. Drs. Annapragada, Phallen, Scharpf, and Foda are co-founders of Artemyx and hold equity in Artemyx.
