Prospective and longitudinal evaluations of telomere length of circulating DNA as a risk predictor of hepatocellular carcinoma in HBV patients

<span class="paragraphSection"><div class="boxTitle">Abstract</div>Prospective and longitudinal epidemiological evidence is needed to assess the association between telomere length and risk of hepatocellular carcinoma (HCC). In 323 cancer-free Korean-American HBV patients with 1-year exclusion window (followed for >1 year and did not develop HCC within 1 year), we measured the relative telomere length (RTL) in baseline serum DNAs and conducted extensive prospective and longitudinal analyses to assess RTL–HCC relationship. We found that long baseline RTL conferred an increased HCC risk compared to short RTL [hazard ratio (HR) = 4.93, <span style="font-style:italic;">P</span> = 0.0005). The association remained prominent when the analysis was restricted to patients with a more stringent 5-year exclusion window (HR = 7.51, <span style="font-style:italic;">P</span> = 0.012), indicating that the association was unlikely due to including undetected HCC patients in the cohort, thus minimizing the reverse-causation limitation in most retrospective studies. Adding baseline RTL to demographic variables increased the discrimination accuracy of the time-dependent receiver operating characteristic analysis from 0.769 to 0.868 (<span style="font-style:italic;">P =</span> 1.0 × 10⁻⁵). In a nested longitudinal subcohort of 16 matched cases–control pairs, using a mixed effects model, we observed a trend of increased RTL in cases and decreased RTL in controls along 5 years of follow-up, with a significant interaction of case/control status with time (<span style="font-style:italic;">P</span> for interaction=0.002) and confirmed the association between long RTL and HCC risk [odds ratio [OR] = 3.63, <span style="font-style:italic;">P</span> = 0.016]. In summary, serum DNA RTL may be a novel non-invasive prospective marker of HBV-related HCC. Independent studies are necessary to validate and generalize this finding in diverse populations and assess the clinical applicability of RTL in HCC prediction.</span>

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