High frequency of telomerase reverse-transcriptase promoter somatic mutations in hepatocellular carcinoma and preneoplastic lesions

Nault, Jean–Charles; Mallet, Maxime; Pilati, Camilla; Caldéraro, Julien; Bioulac‐Sage, Paulette; Laurent, Césari; Laurent, Alexis; Cherqui, Daniel; Balabaud, Charles; Zucman‐Rossi, Jessica

doi:10.1038/ncomms3218

Cited by 555 publications

(595 citation statements)

References 31 publications

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“…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.…”

Section: Discussionsupporting

confidence: 86%

“…TERT promoter mutations in tumors have been reported in HCC of all etiologies, including NAFLD,19 HBV,20 and HCV,21 and in HCC arising from both cirrhotic and noncirrhotic liver 7. Prior reports suggested that TERT promoter mutations were associated with older age, presence of HCV, absence of HBV, and poor overall survival 21.…”

Section: Discussionmentioning

confidence: 99%

“…Samples with a mutant TERT allele fraction ≥0.1% and with at least two visible mutant signals were considered positive for the mutation, as described 11, 12. Because the two TERT promoter mutations are mutually exclusive,6, 7 we measured TERT C250T mutation in samples that were negative for TERT C228T mutation.…”

Section: Methodsmentioning

confidence: 99%

“…TERT promoter mutation is the most frequent genetic alteration in HCC6, 7 and a central and ancestry‐independent node of hepatocarcinogenesis 4. Most importantly, TERT promoter mutations occur also in cirrhotic preneoplastic macronodules (25%) and in hepatocellular adenomas with malignant transformation to HCC (44%), therefore representing early recurrent genetic events in HCC in the cirrhotic and noncirrhotic liver 7, 8. In cirrhosis, TERT promoter mutations are highly related to stepwise hepatocarcinogenesis, with mutations identified in 6% of low‐grade dysplastic nodules, 19% of high‐grade dysplastic nodules, and 61% of early HCCs 9…”

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confidence: 99%

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

Jiao

Watt

Stevenson

et al. 2018

Hepatology Communications

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Telomerase reverse transcriptase (TERT) mutation is the most frequent genetic alteration in hepatocellular carcinoma (HCC). Our aims were to investigate whether TERT 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 TERT C228T and C250T promoter mutations in 196 HCCs from The Cancer Genome Atlas. We measured these TERT mutations in plasma cfDNA in 218 patients with HCC and 81 patients with cirrhosis without imaging evidence of HCC. The prevalence of TERT mutations in The Cancer Genome Atlas HCC specimens was 44.4%. TERT mutations were detected with similar prevalence (47.7%) in plasma cfDNAs from 218 patients with HCC. TERT 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 TERT 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, TERT 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 TERT mutations, and vitamin K2 was identified as an upstream regulator. Conclusion: TERT 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. (Hepatology Communications 2018;2:718‐731)

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Section: Discussionsupporting

confidence: 86%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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

Jiao

Watt

Stevenson

et al. 2018

Hepatology Communications

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“…We described somatic TERT promoter mutations in 60% of human HCCs leading to increased TERT expression. 2 However, other genetic and viral mechanisms can cause TERT reexpression. Insertional mutagenesis of hepatitis B virus (HBV) in the TERT promoter has been described in approximately 15%-20% of HBV-related HCC.…”

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confidence: 99%

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TERT C228T mutation in non‐malignant bladder urothelium is associated with intravesical recurrence for patients with non‐muscle invasive bladder cancer

et al. 2020

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Telomerase reverse transcriptase ( TERT ) promoter mutations are frequently found in tumors or urine from patients with urothelial carcinoma (UC). TERT promoter mutations are also detected in urine from patients with no evidence of cancer but are associated with subsequent UC development. Mutations in the TERT promoter are thought to be present in nonmalignant urothelium (NMU) during early stages of tumor formation prior to pathological change, but this has not been proven directly. In this proof‐of‐concept study, we investigated the clinical utility of TERT promoter mutation analysis in NMU of patients with non‐muscle‐invasive bladder cancer (NMIBC). This single‐institute study included 53 primary tumors and 428 systematic bladder biopsy specimens from 54 patients with NMIBC. All patients underwent systematic random biopsy and transurethral resection of the bladder tumor. Genomic DNA was analyzed for TERT C228T and C250T mutations using droplet digital PCR (ddPCR). The association between TERT promoter mutation of NMU and bladder recurrence was examined by the Kaplan–Meier method and Cox proportional hazards model. Of the 54 patients, 16 (29.6%) had a TERT C228T mutation and three (5.6%) had a TERT C250T mutation in NMU. Of 428 biopsy specimens, the TERT C228T mutation was detected in 9% (31/364) of normal urothelium, 27% (4/15) of urothelial dysplasia (UD), 50% (9/18) of UD suspicious for carcinoma in situ (CIS), and 58% (18/31) of CIS. During follow‐up (median: 3.7 years), 22 (40.7%) patients experienced bladder recurrence and five (9.3%) experienced disease progression. Cox proportional hazard analysis showed that TERT C228T mutation in NMU was significantly associated with bladder recurrence after adjustment for cofounding factors ( P = 0.0128). Thus, TERT C228T mutation was detected in NMU, which was a reliable independent prognostic factor of bladder tumor recurrence.

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High frequency of telomerase reverse-transcriptase promoter somatic mutations in hepatocellular carcinoma and preneoplastic lesions

Cited by 555 publications

References 31 publications

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

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

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TERT C228T mutation in non‐malignant bladder urothelium is associated with intravesical recurrence for patients with non‐muscle invasive bladder cancer

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