Abstract 110: Prospective and longitudinal evaluations of telomere length in circulating serum DNA as a noninvasive risk factor of hepatocellular carcinoma in HBV patients.

Background: In a recent retrospective case-control study, we showed that patients with HBV-related hepatocellular carcinoma (HCC) had significantly longer telomeres in circulating serum DNA than cancer-free HBV patients, indicating that circulating DNA telomere length may be a novel HCC marker. Prospective and longitudinal evidence is needed to confirm this finding. Method: In a cohort of 323 cancer-free HBV patients who had been followed for >1 year and did not develop HCC within 1 year, we determined the relative telomere length (RTL) in baseline serum DNA samples and conducted prospective and longitudinal analyses to assess the relationships between RTL and HCC risk. Results: In a median follow-up of 4.5 years (range, 1.1-21.1), 37 patients developed HCC. Using the median baseline RTL as cut-off, long RTL conferred a significantly increased HCC risk compared to short RTL (HR=4.93, 95% CI 2.00-12.13, P=0.0005, Plog-rank=1.7x10-6). This association remained significant when the analysis was more stringently restricted to patients who had been followed for >5 years and did not develop HCC within 5 years (HR=7.51, 95% CI 1.56-36.18, P=0.012, Plog-rank=0.0024), indicating that the RTL-HCC association was unlikely due to the inclusion of undiagnosed HCC patients in the cancer-free HBV cohort, thus further minimizing the effect of the reverse-causation limitation that is inherent in most previous telomere length-related retrospective studies. The area under the curve (AUC) in the time-dependent ROC analysis increased from 0.769 (demographic variables only) to 0.868 (demographic variables and baseline RTL), with a statistically significant difference (P=1.0x10-5) assessed by 10,000-time bootstrap resampling. Finally, in a nested longitudinal sub-population of 22 matched cases-control pairs with multiple samples for each patient collected at different follow-up time points, we found a significant increase in RTL from baseline to HCC diagnosis in cases (slope=0.032, P=4.0x10-5), in contrast to a RTL decrease from baseline to last follow-up in controls (slope=-0.020, P=0.026). Using a mixed-effects model for longitudinal case-control analysis, we showed that long RTL conferred a significantly increased risk of HCC (OR=4.55, 95% CI 1.91-10.89, P=0.0007). Collectively, the longitudinal data were consistent with the prospective analysis results, indicating that telomere lengthening may be an important driving factor in hepatocarcinogenesis. Conclusions: To our best knowledge, this is one of the first prospective and longitudinal evaluations of RTL in cancer risk prediction. Our data suggests that RTL of circulating serum DNA may be a novel non-invasive prospective marker of HBV-related HCC. Future studies are needed to generalize this finding in broader populations and test its clinical applicability in HCC prevention. Citation Format: Hushan Yang, Hie-won Hann, Shaogui Wan, Yinzhi Lai, Kejin Zhang, Richard Hann, Ronald E. Myers. Prospective and longitudinal evaluations of telomere length in circulating serum DNA as a noninvasive risk factor of hepatocellular carcinoma in HBV patients. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 110. doi:10.1158/1538-7445.AM2013-110