Detection and characterization of hepatocellular carcinoma using cfDNA fragmentomes

This is the authors' abstract. We don't add key points for this paper.

Hepatocellular carcinoma (HCC) is a leading cause of cancer death globally with increasing mortality due to emerging metabolic risk factors. Here, we show that in 377 individuals with and without HCC from two geographic cohorts, cell-free DNA (cfDNA) fragmentome characteristics, including chromatin, genomic, methylome, mutational, and repeat element profiles, were altered in patients with cancer of different etiologies, including metabolic risk factors and aflatoxin exposure. A novel methylation-based tissue-of-origin algorithm (MethID) identified cfDNA fragmentome changes originating from liver, vascular, and immune cells in cancer patients. A locked cfDNA fragmentome classifier detected HCC across stages and etiologies, outperforming alpha-fetoprotein (AFP). Combining cfDNA fragmentomes, AFP, and clinical risk achieved high sensitivity in early- and late-stage cancers in both cohorts and was more sensitive than conventional approaches for detecting early-stage disease. This study provides insights into cfDNA origins for populations at risk and validates a genome-wide fragmentome approach for non-invasive detection of HCC.