Telomerase reverse transcriptase promoter mutation is an early somatic genetic alteration in the transformation of premalignant nodules in hepatocellular carcinoma on cirrhosis

Abstract

Genetic determinants of the early steps of carcinogenesis on cirrhosis are still poorly understood. We aimed to evaluate the occurrence of telomerase reverse transcriptase (TERT) promoter mutations in the transformation of cirrhotic nodules into hepatocellular carcinoma (HCC). We analyzed a series of 268 liver samples, including 96 nodules developed in 58 patients with cirrhosis and 114 additional cirrhosis. All samples were screened for TERT promoter mutations, and in 31 nodules, for 10 genes recurrently mutated in HCC. Immunohistochemistry (IHC) analyses were performed for glypican 3, glutamine synthase, and heat shock protein 70. Six liver pathologists reviewed all the samples. Among The 96 nodules, 88 were firmly diagnosed as low-grade dysplastic nodules (LGDNs; 32 cases), high-grade dysplastic nodules (HGDNs; 16 cases), early HCC (eHCC; 23 cases), or small and progressed HCC in 17 cases. The agreement between the initial diagnosis from pathological report and the final expert consensus report was moderate for the diagnosis of benign versus malignant nodules (weighted kappa 5 0.530). TERT promoter mutations were highly related to the step-wise hepatocarcinogenesis because mutations were identified in 6% of LGDNs, 19% of HGDNs, 61% of eHCCs, and 42% of small and progressed HCC. TERT promoter mutation is the most frequent molecular alteration in eHCC given that the IHC criteria for diagnosis of malignancy were found in only 39% of the cases. TERT promoter mutation was also the earliest genetic alteration because mutations in 10 other genes were only identified in 28% of the small and progressed HCC. Conclusion: Frequency of TERT promoter mutations rapidly increases during the different steps of the transformation of premalignant lesions into HCC on cirrhosis. Consequently, somatic TERT promoter mutation is a new biomarker predictive of transformation of premalignant lesions into HCC. (HEPATOLOGY 2014;60:1983-1992 M ore than 90% of hepatocellular carcinomas (HCCs) in Western countries develop on a cirrhotic background as a result of chronic hepatitis B or C infection, alcohol abuse, or metabolic syndrome. 1 The dissection of the early events of liver carcinogenesis is a major issue in order to understand the underlying pathogenesis of the disease, refine the diagnosis, and thus propose targeted chemopreventive agents and guide curative treatment. 2 HCC classically develops on cirrhosis through a multistep process of Abbreviations: ARID, AT-rich interactive domain; BCLC, Barcelona Clinic Liver Cancer; bp, base pairs; CDKN2A, cyclin-dependent kinase inhibitor 2A; CI, confidence interval; CTNNB1, catenin (cadherin-associated protein), beta 1,

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

“…We detected TERT promoter mutations in plasma cfDNA of 47.7% of these patients, a prevalence similar to the prevalence reported in tumors (44.4%‐65%) 6, 7, 9, 21. In this group of patients, we again found an association of circulating cfDNA TERT promoter mutations with male sex, cirrhosis (alcoholic cirrhosis in particular), HCV, and family history of cancer.…”

Reply

“…1 The authors note that their results are consistent with observations within a 48-week, randomized study that evaluated the potential benefit of enoxaparin, in which anticoagulation decreased cirrhosis disease progression far more markedly than the decreased incidence of PVT. 2 Together, the results of these studies suggest common, but not identical, mechanisms underlying the progression of liver disease and PVT occurrence and imply that activation of hemostasis within the microcirculation of the liver, rather than occlusion of larger portal vessels, is the primary driver of disease progression.…”

“…We thank Ko et al for their comments about our article 1 and their description of telomerase reverse transcriptase (TERT) promoter hypermethylation as a potential mechanism of TERT reactivation and a prognostic biomarker in a series of hepatocellular carcinoma (HCC) from Korea. Telomere shortening and absence of telomerase activity are involved in cirrhosis pathogenesis, but telomerase reactivation is required in tumor initiation and progression.…”

“…We read with great interest the article by Nery et al recently published in HEPATOLOGY. 1 The authors should be commended for the great effort in performing this study, which prospectively assessed the incidence of portal vein thrombosis (PVT) in patients with compensated and mildly decompensated cirrhosis, the risk factors for its occurrence, and its impact on disease history.…”

Nrf2, but not β‐catenin, mutation represents an early event in rat hepatocarcinogenesis

“…Although in humans NRF2/KEAP1 mutations have been identified in HCCs, 5,6 they were not found in dysplastic cirrhotic macronodules, where TERT mutation was the earliest identified event. 33 However, regulation of telomerase activity is different in humans and rodents. In fact, while telomerase activity is usually undetectable in adult human tissues, several organs of normal adult rodents display substantial amounts of telomerase activity; in particular, in the liver telomerase is expressed at a nearly constant level throughout life and decreases during liver regeneration.…”