Sensitive biomarkers for early cancer detection remain largely lacking. Circulating telomere DNA may help.
A case-control study with hospital hepatocellular carcinoma (HCC) cases was conducted to identify potential biomarkers for HCC detection (Discovery). We used next generation sequencing method for circulating cell-free DNA (ccfDNA) analysis. We modeled telomere and end sequence in circulation (Telecon) to detect HCC in Discovery. We validated Telecon in a prospective cohort among hepatitis B virus (HBV)-seropositive participants with biannual blood collections from 2012 till 2019, using nested case-control design (Validation).
In Discovery, among short ccfDNA (25-60 nucleotides), telomere was more abundant in HCC patients than in controls (18.87-fold, P=6.4×10-18). Telomere contributed 91% of the variation of the Telecon model, which distinguished HCC cases from controls completely (AUC=1.0). In Validation, among 18,185 participants, 2,893 were HBV-seropositive and developed 81 incident HCC cases (incidence rate 382 per 100,000 person-years). Telecon showed increasing detection performance using pre-diagnosis samples collected ≥4 years (AUC=0.538), 3-4 years (0.741), 2-3 years (0.742), 1-2 years (0.786), and 0-1 year (0.930) before diagnosis. Within one year before diagnosis and at a specificity of 98%, Telecon had a sensitivity of 68.2% (95% CI=52.4-81.4%) in detecting early HCC, yielding an estimated positive predict value of 15.2% among HBV-seropositive population. High Telecon was also associated with a higher risk of death among hospital HCC patients (hazard ratio 3.22, 95% CI=1.49-7.0), independent of tumor stage.
Circulating short telomere may effectively detect early and aggressive hepatocellular carcinoma in high-risk populations.
The authors.
China Scholarship Council (201808440263); Lau Grant (LC230003); Swedish Research Council (202001418).
Z. Zheng: Financial Interests, Personal, Royalties: ArcherDX; Financial Interests, Personal, Advisory Role: Helitec, GenEditBio. All other authors have declared no conflicts of interest.