Telomerase reverse transcriptase promoter mutations in hepatocellular carcinogenesis

Ma, Zi-Xian; Yang, Chunmei; Li, Mengge; Tu, Hong

doi:10.20517/2394-5079.2018.104

Cited by 10 publications

(11 citation statements)

References 94 publications

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“…The major risk factors for HCC include liver cirrhosis, hepatitis B or C virus infection, alcohol abuse, nonalcoholic steatohepatitis, and metabolic disease. The mutation landscape in liver carcinogenesis is reportedly complicated, involving a number of pathways as well as somatic mutations in a multitude of genes [ 2 , 3 , 4 ]. Among the genetic alterations, telomerase reverse transcriptase ( TERT ) promoter mutations were reported to occur early and most frequently, affecting approximately 30–60% of all HCC patients [ 5 , 6 ].…”

Section: Introductionmentioning

confidence: 99%

“…However, embryonic stem cells and most cancer cells can maintain telomeres to overcome cell senescence or apoptosis. This process is controlled by TERT , the catalytic component of the telomerase complex that maintains telomere ends by addition of the telomere repeat TTAGGG [ 4 , 9 ]. Thus, TERT plays an important role in oncogenesis and the immortality of cancer cells.…”

Section: Introductionmentioning

confidence: 99%

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Significance of TERT Genetic Alterations and Telomere Length in Hepatocellular Carcinoma

Jang

Kim

et al. 2021

Cancers

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Telomerase reverse transcriptase (TERT) mutations are reportedly the most frequent somatic genetic alterations in hepatocellular carcinoma (HCC). An integrative analysis of TERT-telomere signaling during hepatocarcinogenesis is lacking. This study aimed to investigate the clinicopathological association and prognostic value of TERT gene alterations and telomere length in HCC patients undergoing hepatectomy as well as transarterial chemotherapy (TACE). TERT promoter mutation, expression, and telomere length were analyzed by Sanger sequencing and real-time PCR in 305 tissue samples. Protein–protein interaction (PPI) analysis was performed to identify a set of genes that physically interact with TERT. The PPI analysis identified eight key TERT-interacting genes, namely CCT5, TUBA1B, mTOR, RPS6KB1, AKT1, WHAZ, YWHAQ, and TERT. Among these, TERT was the most strongly differentially expressed gene. TERT promoter mutations were more frequent, TERT expression was significantly higher, and telomere length was longer in tumors versus non-tumors. TERT promoter mutations were most frequent in HCV-related HCCs and less frequent in HBV-related HCCs. TERT promoter mutations were associated with higher TERT levels and longer telomere length and were an independent predictor of worse overall survival after hepatectomy. TERT expression was positively correlated with tumor differentiation and stage progression, and independently predicted shorter time to progression after TACE. The TERT-telomere network may have a crucial role in the development and progression of HCC. TERT-telomere abnormalities might serve as useful biomarkers for HCC, but the prognostic values may differ with tumor characteristics and treatment.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Significance of TERT Genetic Alterations and Telomere Length in Hepatocellular Carcinoma

Jang

Kim

et al. 2021

Cancers

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“…It is widely accepted that the gene recurrently targeted by viral integration usually plays a role in carcinogenesis. TCGA analysis showed that TERT , MLL4 and CCNE1 have aberrant expressions in HCC, and their biological functions in hepatocarcinogenesis have been extensively studied 21,41,42 . On the contrary, except for TERT , the impacts of MLL4 and CCNE1 on NHL have never been documented.…”

Section: Discussionmentioning

confidence: 99%

Characterization of hepatitis B virus infection and viral DNA integration in non‐Hodgkin lymphoma

Shen

Chen

et al. 2020

Intl Journal of Cancer

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Hepatitis B virus (HBV) infection has been reported to be associated with non‐Hodgkin lymphoma (NHL). However, the evidence is limited to the seroepidemiological study. There is a lack of evidence showing the HBV infection and integration in NHL cells. Here, we reported that in the Shanghai area, the positive rates of serum HBsAg (OR: 3.11; 95% CI: 2.20‐4.41) and HBeAg (OR: 3.99; 95% CI: 1.73‐9.91) were significantly higher in patients with NHL. HBsAg, HBcAg and HBV DNA were detected in 34.4%, 45.2% and 47.0% of the NHL tissues, respectively. Furthermore, by using a high‐throughput viral integration detection approach (HIVID), integrated HBV DNA was identified from 50% (6/12) HBV‐related NHL tissues. There were a total of 313 HBV integration sites isolated from the NHL tissues, among which four protein‐coding genes (FAT2, SETX, ITGA10 and CD63) were interrupted by HBV DNA in their exons. Seven HBV preferential target genes (ANKS1B, HDAC4, EGFLAM, MAN1C1, XKR6, ZBTB38 and CCDC91) showed significantly altered expression levels in NHL, suggesting a potential role of these genes in NHL development. Taken together, HBV integration is a common phenomenon in NHL. This finding opens up a new direction of research into the mechanistic link between HBV infection and NHL.

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“…TERT activation is shown in 85-90% of all human cancers. 34,35 TERT is the most frequently integrated gene by HBV-DNA in HCC. To date, 19 independent studies have identified a total of 435 integrations of HBV-DNA in the TERT gene, and 62.99% (274/435) of HBV-DNA integration occurs in the promoter region of TERT.…”

Section: Discussionmentioning

confidence: 99%

Characterization of hepatitis B virus DNA integration patterns in intrahepatic cholangiocarcinoma

Cong

et al. 2020

Hepatology Research

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Aim: Hepatitis B virus (HBV) integration is one of the mechanisms contributing to hepatocellular carcinoma (HCC) development. However, the status of HBV integration in intrahepatic cholangiocarcinoma (ICC) is poorly understood. This study aims to characterize the viral integration in HBV-related ICC. Methods: The presence of HBV S and C gene in ICCs and the paratumor tissue was determined by polymerase chain reaction direct sequencing. Hepatitis B virus integration was detected by a high-throughput capture sequencing method. The expression analysis of the genes targeted by HBV in ICC was undertaken in The Cancer Genome Atlas dataset. Results: Hepatitis B virus S and/or C gene fragments were detected in 71.43% (10/14) ICCs and 57.14% (8/14) paratumor tissues. Using the high-throughput capture sequencing approach, 139 and 183 HBV integration breakpoints were identified from seven ICC and seven paired paratumor tissues, respectively. Seven genes (TERT, CEACAM20, SPATA18, TRERF1, ZNF23, LINC01449, and LINC00486) were recurrently targeted by HBV-DNA in different ICC tissues or different cell populations of the same tissue. TERT, which is the most preferential HBV target gene in HCC, was found to be repeatedly interrupted by HBV-DNA in three different ICC tissues. Based on The Cancer Genome Atlas dataset, TERT, as well as three other HBV recurrently targeted genes (SPATA18, TRERF1, and ZNF23), showed differential expression levels between ICC and para-ICC tissues. Conclusions: Taken together, HBV integration is a common event in HBV-related ICC. The HBV recurrent integration genes identified from this study, such as TERT, provide new clues for further research on the causative link between HBV infection and ICC.

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Telomerase reverse transcriptase promoter mutations in hepatocellular carcinogenesis

Cited by 10 publications

References 94 publications

Significance of TERT Genetic Alterations and Telomere Length in Hepatocellular Carcinoma

Significance of TERT Genetic Alterations and Telomere Length in Hepatocellular Carcinoma

Characterization of hepatitis B virus infection and viral DNA integration in non‐Hodgkin lymphoma

Characterization of hepatitis B virus DNA integration patterns in intrahepatic cholangiocarcinoma

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