Telomerase reverse transcriptase mutations in plasma DNA in patients with hepatocellular carcinoma or cirrhosis: Prevalence and risk factors

Abstract

Telomerase reverse transcriptase (<i>TERT</i>) mutation is the most frequent genetic alteration in hepatocellular carcinoma (HCC). Our aims were to investigate whether <i>TERT</i> mutations can be detected in circulating cell-free DNA (cfDNA) of patients with HCC and/or cirrhosis and characterize clinical parameters associated with these mutations. We retrieved data on <i>TERT</i> C228T and C250T promoter mutations in 196 HCCs from The Cancer Genome Atlas. We measured these <i>TERT</i> mutations in plasma cfDNA in 218 patients with HCC and 81 patients with cirrhosis without imaging evidence of HCC. The prevalence of <i>TERT</i> mutations in The Cancer Genome Atlas HCC specimens was 44.4%. <i>TERT</i> mutations were detected with similar prevalence (47.7%) in plasma cfDNAs from 218 patients with HCC. <i>TERT</i> mutations, either within the HCC or in cfDNA, were associated with male sex, hepatitis C virus (HCV), alcoholic cirrhosis, family history of cancer, and poor prognosis. The high prevalence of <i>TERT</i> mutations in HCCs in male patients with cirrhosis caused by HCV and/or alcohol was confirmed in an independent set of HCCs (86.6%). Finally, <i>TERT</i> mutations were detected in cfDNA of 7 out of 81 (8.6%) patients with cirrhosis without imaging evidence of HCC, including 5 male patients with cirrhosis due to HCV and/or alcohol. Genes involved in xenobiotic and alcohol metabolism were enriched in HCCs with <i>TERT</i> mutations, and vitamin K2 was identified as an upstream regulator. <i>Conclusion</i>: <i>TERT</i> mutations are detectable in plasma cfDNA. Long-term imaging surveillance of patients with cirrhosis with cfDNA TERT mutations without evidence of HCC is required to assess their potential as early biomarkers of HCC. (<i>Hepatology Communications</i> 2018;2:718-731).