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TERT promoter mutations in primary liver tumors
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TERT promoter mutations in primary liver tumors Jean-Charles Nault a,b,c,d,e, Jessica Zucman-Rossi a,b,c,d,f,∗ a
Inserm, UMR-1162, Génomique fonctionnelle des Tumeurs solides, Équipe Labellisée Ligue Contre le Cancer, 75010 Paris, France b Université Paris Descartes, Labex Immuno-Oncology, Sorbonne Paris Cité, Faculté de Médecine, 75006 Paris, France c Université Paris 13, Sorbonne Paris Cité, UFR SMBH, 93000 Bobigny, France d Université Paris Diderot, 75013 Paris, France e AP—HP, Hôpitaux Universitaires Paris — Seine-Saint-Denis, Site Jean-Verdier, Pôle d’Activité Cancérologique Spécialisée, Service d’Hépatologie, 93143 Bondy, France f Assistance publique—Hôpitaux de Paris, Hôpital Européen Georges-Pompidou, 75015 Paris, France
Summary Next-generation sequencing has drawn the genetic landscape of hepatocellular carcinoma and several signaling pathways are altered at the DNA level in tumors: Wnt/catenin, cell cycle regulator, epigenetic modifier, histone methyltransferase, oxidative stress, ras/raf/map kinase and akt/mtor pathways. Hepatocarcinogenesis is a multistep process starting with the exposure to different risk factors, followed by the development of a chronic liver disease and cirrhosis precede in the vast majority of the cases the development of HCC. Several lines of evidence have underlined the pivotal role of telomere maintenance in both cirrhosis and HCC pathogenesis. TERT promoter mutations were identified as the most frequent genetic alterations in hepatocellular carcinoma with an overall frequency around 60%. Moreover, in cirrhosis, TERT promoter mutationsare observed at the early steps of hepatocarcinogenesis since they are recurrently identified in low-grade and high-grade dysplastic nodules. In contrast, acquisition of genomic diversity through mutations of classical oncogenes and tumor suppressor genes (TP53, CTNNB1, ARID1A. . .) occurred only in progressed HCC. In normal liver, a subset of HCC can derived from the malignant transformation of hepatocellular adenoma (HCA). In HCA, CTNNB1 mutations predispose to transformation of HCA in HCC and TERT promoter mutations are required in most of the cases as a second hit for a full malignant transformation. All these findings have refined our knowledge of HCC pathogenesis and have pointed telomerase as a target for tailored therapy in the future. © 2015 Elsevier Masson SAS. All rights reserved.
∗ Corresponding author at: Inserm U 1162, Génomique fonctionnelle des tumeurs solides, 27, rue Juliette-Dodu, 75010 Paris, France. Tel.: +33 1 53 72 51 66; fax: +33 1 53 72 51 92. E-mail address: [email protected] (J. Zucman-Rossi).
http://dx.doi.org/10.1016/j.clinre.2015.07.006 2210-7401/© 2015 Elsevier Masson SAS. All rights reserved.
Please cite this article in press as: Nault J-C, Zucman-Rossi J. TERT promoter mutations in primary liver tumors. Clin Res Hepatol Gastroenterol (2015), http://dx.doi.org/10.1016/j.clinre.2015.07.006
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Hepatocellular carcinoma (HCC) has emerged as an important health problem worldwide. The main etiologies of HCC are hepatitis B virus (HBV), hepatitis C virus (HCV), alcohol consumption, obesity (non-alcoholic steatohepatitis [NASH]) and rare metabolic disorder like hemochromatosis [1,2]. In area of low incidence of HCC-like in western countries, HCC develop mainly on cirrhosis related to HCV, high alcohol intake and NASH [1,2]. In Asia, the high incidence of HCC follows the huge number of patients with chronic HBV infection. During HBV infection, HCC could also arise in otherwise normal liver or in liver with limited fibrosis [3]. Moreover, a small percentage of HCC developed on normal liver and without chronic viral infection in both western and eastern countries. In clinical care, a limited number of patients with HCC are eligible to curative treatment (liver transplantation, radiofrequency ablation and liver resection) [1,4]. Most of the times, patients only benefit of palliative treatment (chemoembolization or sorafenib a tyrosine kinase inhibitor) or best supportive care [2,5]. From a basic point of view, HCC have a complex pathogenesis characterized by genomic diversity [6—8]. As other cancer, accumulation of somatic molecular alterations in malignant hepatocytes draws a unique profile in each HCC [9]. In this review, we will describe how the identification of telomerase reverse transcriptase (TERT) promoter mutations as the most frequent somatic genetics alterations in HCC has underlined the major role of telomere and telomerase in liver carcinogenesis.
The genetic landscape of hepatocellular carcinoma Recent technological breakthroughs have accelerated the exploration of the tumor genome and have increased our knowledge of HCC pathogenesis [9,10]. Whole exome (exploring the whole coding region of the genome), whole genome (exploring both coding and non-coding region) or RNA sequencing (exploring the whole-transcriptome sequence) allow to draw quickly the genetic portrait of a tumor [10]. Each tumor is a unique combination of somatic mutations in genes driver of the mechanism of tumorigenesis and in passenger genes. Driver genes mutated in HCC belong to several key signaling pathway of oncogenesis [11] and the genetic landscape of HCC includes recurrent somatic mutations in CTNNB1 and AXIN1 (WNT/-catenin pathway), TP53, RB1, CDKN2A inactivation (cell cycle gene), ARID1A and ARID2 mutations (chromatin remodeling gene), MLL2, MLL3 and MLL4 mutations (histone methyltransferase gene), NFE2L2 and KEAP1 mutations (stress oxidative pathway), RPS6KA3, PIK3CA, TSC1 and TSC2 mutations (AKT/MTOR and RAS/RAF/MAP kinase pathways) and VEGFA and CCND1/FGF19 amplification [12,13].
Telomere and telomerase in cirrhosis pathogenesis and liver carcinogenesis Telomeres are short repeated DNA sequences (TTAGGG) situated at the extremity of each chromosome [14,15]. Due to the replication end problem, telomere shortened at each round of cell division and when a critical point is
attained DNA damage protein are activated and lead to cell senescence [15,16]. The telomerase complex function is to maintain telomere length and to avoid senescence by adding repeat sequence at the extremity of the chromosome [17]. The telomerase complex is composed of the core catalytic enzyme named telomerase reverse transcriptase (TERT) and of the RNA template named TERC. Cirrhosis is characterized by senescent hepatocytes with short telomere and absence of telomerase activity [18]. Several lines of evidence have shown that telomere deficient mice have a high incidence of cirrhosis occurrence when the liver is exposed to chronic liver injury [19]. In contrast, in the same model, telomerase reactivation is required to promote full malignant transformation on a cirrhotic background [20]. The limiting factor of the complex is TERT and reactivation of telomerase is a widely observed phenomena in cancer [21,22]. It avoids senescence induced by telomere shortening during the uncontrolled proliferation of cancer cells [23—26]. In the same line, several studies have reported a frequent reactivation of TERT in HCC compared to normal liver or cirrhosis [26,27]. However, the mechanism leading to telomerase reactivation was poorly understood until recently.
TERT promoter mutations in hepatocellular carcinoma Activating mutations of the TERT promoter that increase TERT expression have been recently described in several types of tumors including melanoma, glioblastoma, hepatocellular carcinoma, bladder cancer or anaplastic thyroid cancer [28—31]. These mutations are substitutions located in two hot spots situated 124 and 146 base paired before the ATG start [28,29]. They created a new consensus binding sequence (CCGGAA or CCGGAT) that could bind ETS/TCF transcription factor and lead to an increase promoter activity. In HCC, we identified TERT promoter mutations in 59% of the tumors (Table 1) [32]. Other teams confirmed these results and the frequency of TERT promoter mutations is more frequent in western countries (54 to 60%) whereas 29 to 31% of HCC are mutated in eastern countries [12,13,30,33—36]. Almost all TERT promoter mutations in HCC (95%) occurred at the first hot spot -124G>A [32]. These mutations were not identified in the seminal whole exome studies of the HCC because this region of the genome was not included in the whole exome data. Consequently, TERT promoter mutations are the most frequent genetic alterations observed in HCC and these mutations are associated with an increase TERT expression. Interestingly, TERT promoter mutations were more frequent in old patients and were also significantly associated with activating mutations of catenin suggesting cooperation between these two pathways [13,32]. Moreover, insertion of HBV in the TERT gene, most frequently in the promoter, has been described as an alternative mechanism leading to telomerase expression [37,38]. TERT amplifications, is another mechanism of telomerase reactivation, they have been also described by two different teams in 5 to 6% of HCC [12,13]. Strikingly, TERT promoter mutations, TERT amplification and HBV insertion in the TERT promoter were exclusive together. All these data have underlined the pivotal role of telomere maintenance in liver carcinogenesis.
Please cite this article in press as: Nault J-C, Zucman-Rossi J. TERT promoter mutations in primary liver tumors. Clin Res Hepatol Gastroenterol (2015), http://dx.doi.org/10.1016/j.clinre.2015.07.006
% mut.
Hepatocellular carcinoma
305
59
94
Hepatocellular carcinoma Hepatocellular carcinoma
61 195
44 29
Hepatocellular carcinoma Hepatocellular carcinoma
78 469
Hepatocellular carcinoma Hepatocellular carcinoma Liver high-grade dysplastic nodule Liver low-grade dysplastic nodule Hepatocellular adenoma Hepatocellular adenoma Borderline HCC/HCA and HCC on HCA Hepatoblastoma Hepatocholangiocarcinoma Intrahepatic cholangiocarcinoma Gallbladder carcinoma Gallbladder carcinoma
44 35 16 32 223 15 27 15 30 52 10 154
124 hot spot (%)
146 hot spot (%)
Association
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Old age, CTNNB1 mutation, low tumor size, low AFP and low frequency in HBV infection
Nault et al., 2013 [32]
95
5
47 54
100 93
5
Old age, hepatitis C and low frequency in HBV infection High-grade of differentiation CTNNB1 mutation, low frequency in HBV infection
34 31 19 6 0 0 44 0 15 0 0 9
66
34
87 87
13 13
Hepatitis C
43
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TERT promoter and liver tumors
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Table 1
Killela et al., 2013 [30] Chen et al., 2014 [33] Quaas et al., 2014 [34] Totoki et al., 2015 [13] Cevik et al., 2015 [35] Huang et al., 2015 [36] Nault et al., 2014 [43] Nault et al., 2014 [43] Pilati et al., 2014 [52] Quaas et al., 2014 [34] Pilati et al., 2014 [52] Eichenmuller et al., 2014 [53] Fujimoto et al., 2015 [55] Quaas et al., 2014 [34] Killela et al., 2013 [30] Qu et al., 2014 [54]
TERT: telomerase reverse transcriptase; % mut.: percentage of mutations; HCC: hepatocellular carcinoma; HCA: hepatocellular adenoma; HBV: hepatitis B virus.
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TERT promoter mutations in premalignant lesions on cirrhosis On cirrhosis, liver carcinogenesis is a multistep process with the sequential development of low-grade dysplastic nodules, high-grade dysplastic macronodules, early HCC and small and progress HCC [39,40]. Usually, TERT is not expressed in mature hepatocytes and in cirrhotic liver however it is re-expressed in some cirrhotic premalignant lesions (as high-grade dysplastic nodules) in addition of the wellknown re-expression of TERT in HCC [27,41,42]. Recently, we have reported somatic recurrent mutations in the TERT promoter in 6% of low-grade dysplastic nodules and 19% of high-grade dysplastic nodules (Table 1) [32,43]. Other mutations in cancer genes like TP53, CTNNB1, ARID1A, ARID2, RPS6KA3 occurred only in small and progressed HCC [43]. It is the first report of recurrent genetic alterations in cirrhotic premalignant lesions and TERT promoter mutations could be considered as a gatekeeper gene like APC in the colorectal adenoma-carcinoma sequence [44]. These data underlined that reactivation of telomerase trough mutation of TERT promoter is required at the earlier step in order to bypass replicative senescence of cirrhotic hepatocytes. In contrast, acquisition of genomic diversity appears to be a late event in liver carcinogenesis on cirrhosis [9].
TERT promoter mutations in hepatocellular adenomas A subset of HCC developed on normal liver derived from a malignant transformation of HCA. HCA are rare liver tumors composed of benign proliferation of hepatocytes [45]. The description of the genetic landscape of HCA is a paradigm of genotype/phenotype classification in liver tumors. Four groups of HCA have been identified [46,47]. The first one is composed of HCA with bi-allelic inactivating mutations of HNF1A and is characterized by steatosis at pathological reviewing [48]. The second group is HCA with activating mutations of CTNNB1 (coding for -catenin). Male are overrepresented in this subgroup and cholestasis and pseudoglandular formation are frequently observed. CTNNB1 mutations were associated with an increased risk of malignant transformation [47]. The third group is composed of inflammatory HCA characterized by inflammatory infiltrate, sinusoidal dilatation and dystrophic arteries. In this subgroups, recurrent somatic activating mutations of IL6ST (coding for gp130), STAT3, FRK, JAK1 and GNAS lead to the JAK/STAT pathway activation [49—51]. Interestingly, IL6ST and CTNNB1 mutations could be associated whereas HNF1A are exclusive from CTNNB1 and the inflammatory mutations activating the JAK/STAT pathway. Finally, the last group is composed of the remaining unclassified HCA. In a series of 250 ‘‘classical’’ HCA without any signs of malignant transformation, we did not identify any TERT promoter mutations and these results were confirmed by an independent group [32,34,52]. Recently, in the subset of HCA with malignant transformation we identified TERT promoter mutations in 44% (Table 1) [32,52]. Moreover, TERT promoter mutations were associated with mutations of CTNNB1, suggesting again a cooperation between telomerase maintenance and
Wnt/-catenin pathway [32,52]. To summarize, CTNNB1 mutations with or without IL6ST mutations lead to HCA initiation and TERT promoter mutations is required at the last step of malignant transformation into HCC. As HCA arise on normal liver with hepatocytes having their full renewal ability, reactivation of telomerase is required later in the process to bypass oncogene-induced senescence and increase the proliferative ability of tumor hepatocytes [9].
TERT promoter mutations in other primary liver cancers As in other pediatric cancers, TERT promoter mutations were not identified in hepatoblastoma (Table 1) [53]. Quaas et al. have analyzed 52 intrahepatic cholangiocarcinoma and found no mutations of the TERT promoter [34]. TERT promoter mutations were observed in 0 to 9% of gallbladder cancer [30,54]. In contrast, among 30 hepatocholangiocarcinoma, 15% of the tumors were mutated in the TERT promoter [55]. Consequently, TERT promoter mutations were not recurrently involved in the pathogenesis of cholangiocarcinoma and of hepatoblastoma and were observed only in a subset of hepatocholangiocarcinoma. It suggests that acquisition of TERT promoter mutations during carcinogenesis is dependent of the cell of origins of the tumor in the liver.
Conclusion Reactivation of telomerase is a major event of malignant transformation of hepatocytes in either normal or cirrhotic liver. TERT promoter mutations, the leading somatic genetic defect in HCC, are one of the main mechanisms leading to telomerase re-expression. TERT amplification and insertion of HBV virus in the TERT promoter are alternative mechanism explaining telomerase reactivation. However, 5% of HCC lack telomerase expression; in these tumors an alternative mechanisms of telomere lengthening could exist, its mechanism remains to be elucidate [56]. Moreover, telomerase is a potential therapeutic target and telomerase inhibitors (including small molecule inhibitor, G-quadruplex stabilizer and antisense oligonucleotide) or telomerase vaccine are currently in development to treat cancer harboring high telomerase expression [57,58]. These molecules are promising drugs that should be tested in HCC in the next future.
Disclosure of interest The authors declare that they have no conflicts of interest concerning this article.
Acknowledgements The team is supported by grants from Ligue Nationale Contre le Cancer (équipe Labllisée), Inserm and INCa (PRTK14).
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MINI REVIEW
TERT promoter mutations in primary liver tumors Jean-Charles Nault a,b,c,d,e, Jessica Zucman-Rossi a,b,c,d,f,∗ a
Inserm, UMR-1162, Génomique fonctionnelle des Tumeurs solides, Équipe Labellisée Ligue Contre le Cancer, 75010 Paris, France b Université Paris Descartes, Labex Immuno-Oncology, Sorbonne Paris Cité, Faculté de Médecine, 75006 Paris, France c Université Paris 13, Sorbonne Paris Cité, UFR SMBH, 93000 Bobigny, France d Université Paris Diderot, 75013 Paris, France e AP—HP, Hôpitaux Universitaires Paris — Seine-Saint-Denis, Site Jean-Verdier, Pôle d’Activité Cancérologique Spécialisée, Service d’Hépatologie, 93143 Bondy, France f Assistance publique—Hôpitaux de Paris, Hôpital Européen Georges-Pompidou, 75015 Paris, France
Summary Next-generation sequencing has drawn the genetic landscape of hepatocellular carcinoma and several signaling pathways are altered at the DNA level in tumors: Wnt/catenin, cell cycle regulator, epigenetic modifier, histone methyltransferase, oxidative stress, ras/raf/map kinase and akt/mtor pathways. Hepatocarcinogenesis is a multistep process starting with the exposure to different risk factors, followed by the development of a chronic liver disease and cirrhosis precede in the vast majority of the cases the development of HCC. Several lines of evidence have underlined the pivotal role of telomere maintenance in both cirrhosis and HCC pathogenesis. TERT promoter mutations were identified as the most frequent genetic alterations in hepatocellular carcinoma with an overall frequency around 60%. Moreover, in cirrhosis, TERT promoter mutationsare observed at the early steps of hepatocarcinogenesis since they are recurrently identified in low-grade and high-grade dysplastic nodules. In contrast, acquisition of genomic diversity through mutations of classical oncogenes and tumor suppressor genes (TP53, CTNNB1, ARID1A. . .) occurred only in progressed HCC. In normal liver, a subset of HCC can derived from the malignant transformation of hepatocellular adenoma (HCA). In HCA, CTNNB1 mutations predispose to transformation of HCA in HCC and TERT promoter mutations are required in most of the cases as a second hit for a full malignant transformation. All these findings have refined our knowledge of HCC pathogenesis and have pointed telomerase as a target for tailored therapy in the future. © 2015 Elsevier Masson SAS. All rights reserved.
∗ Corresponding author at: Inserm U 1162, Génomique fonctionnelle des tumeurs solides, 27, rue Juliette-Dodu, 75010 Paris, France. Tel.: +33 1 53 72 51 66; fax: +33 1 53 72 51 92. E-mail address: [email protected] (J. Zucman-Rossi).
http://dx.doi.org/10.1016/j.clinre.2015.07.006 2210-7401/© 2015 Elsevier Masson SAS. All rights reserved.
Please cite this article in press as: Nault J-C, Zucman-Rossi J. TERT promoter mutations in primary liver tumors. Clin Res Hepatol Gastroenterol (2015), http://dx.doi.org/10.1016/j.clinre.2015.07.006
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Hepatocellular carcinoma (HCC) has emerged as an important health problem worldwide. The main etiologies of HCC are hepatitis B virus (HBV), hepatitis C virus (HCV), alcohol consumption, obesity (non-alcoholic steatohepatitis [NASH]) and rare metabolic disorder like hemochromatosis [1,2]. In area of low incidence of HCC-like in western countries, HCC develop mainly on cirrhosis related to HCV, high alcohol intake and NASH [1,2]. In Asia, the high incidence of HCC follows the huge number of patients with chronic HBV infection. During HBV infection, HCC could also arise in otherwise normal liver or in liver with limited fibrosis [3]. Moreover, a small percentage of HCC developed on normal liver and without chronic viral infection in both western and eastern countries. In clinical care, a limited number of patients with HCC are eligible to curative treatment (liver transplantation, radiofrequency ablation and liver resection) [1,4]. Most of the times, patients only benefit of palliative treatment (chemoembolization or sorafenib a tyrosine kinase inhibitor) or best supportive care [2,5]. From a basic point of view, HCC have a complex pathogenesis characterized by genomic diversity [6—8]. As other cancer, accumulation of somatic molecular alterations in malignant hepatocytes draws a unique profile in each HCC [9]. In this review, we will describe how the identification of telomerase reverse transcriptase (TERT) promoter mutations as the most frequent somatic genetics alterations in HCC has underlined the major role of telomere and telomerase in liver carcinogenesis.
The genetic landscape of hepatocellular carcinoma Recent technological breakthroughs have accelerated the exploration of the tumor genome and have increased our knowledge of HCC pathogenesis [9,10]. Whole exome (exploring the whole coding region of the genome), whole genome (exploring both coding and non-coding region) or RNA sequencing (exploring the whole-transcriptome sequence) allow to draw quickly the genetic portrait of a tumor [10]. Each tumor is a unique combination of somatic mutations in genes driver of the mechanism of tumorigenesis and in passenger genes. Driver genes mutated in HCC belong to several key signaling pathway of oncogenesis [11] and the genetic landscape of HCC includes recurrent somatic mutations in CTNNB1 and AXIN1 (WNT/-catenin pathway), TP53, RB1, CDKN2A inactivation (cell cycle gene), ARID1A and ARID2 mutations (chromatin remodeling gene), MLL2, MLL3 and MLL4 mutations (histone methyltransferase gene), NFE2L2 and KEAP1 mutations (stress oxidative pathway), RPS6KA3, PIK3CA, TSC1 and TSC2 mutations (AKT/MTOR and RAS/RAF/MAP kinase pathways) and VEGFA and CCND1/FGF19 amplification [12,13].
Telomere and telomerase in cirrhosis pathogenesis and liver carcinogenesis Telomeres are short repeated DNA sequences (TTAGGG) situated at the extremity of each chromosome [14,15]. Due to the replication end problem, telomere shortened at each round of cell division and when a critical point is
attained DNA damage protein are activated and lead to cell senescence [15,16]. The telomerase complex function is to maintain telomere length and to avoid senescence by adding repeat sequence at the extremity of the chromosome [17]. The telomerase complex is composed of the core catalytic enzyme named telomerase reverse transcriptase (TERT) and of the RNA template named TERC. Cirrhosis is characterized by senescent hepatocytes with short telomere and absence of telomerase activity [18]. Several lines of evidence have shown that telomere deficient mice have a high incidence of cirrhosis occurrence when the liver is exposed to chronic liver injury [19]. In contrast, in the same model, telomerase reactivation is required to promote full malignant transformation on a cirrhotic background [20]. The limiting factor of the complex is TERT and reactivation of telomerase is a widely observed phenomena in cancer [21,22]. It avoids senescence induced by telomere shortening during the uncontrolled proliferation of cancer cells [23—26]. In the same line, several studies have reported a frequent reactivation of TERT in HCC compared to normal liver or cirrhosis [26,27]. However, the mechanism leading to telomerase reactivation was poorly understood until recently.
TERT promoter mutations in hepatocellular carcinoma Activating mutations of the TERT promoter that increase TERT expression have been recently described in several types of tumors including melanoma, glioblastoma, hepatocellular carcinoma, bladder cancer or anaplastic thyroid cancer [28—31]. These mutations are substitutions located in two hot spots situated 124 and 146 base paired before the ATG start [28,29]. They created a new consensus binding sequence (CCGGAA or CCGGAT) that could bind ETS/TCF transcription factor and lead to an increase promoter activity. In HCC, we identified TERT promoter mutations in 59% of the tumors (Table 1) [32]. Other teams confirmed these results and the frequency of TERT promoter mutations is more frequent in western countries (54 to 60%) whereas 29 to 31% of HCC are mutated in eastern countries [12,13,30,33—36]. Almost all TERT promoter mutations in HCC (95%) occurred at the first hot spot -124G>A [32]. These mutations were not identified in the seminal whole exome studies of the HCC because this region of the genome was not included in the whole exome data. Consequently, TERT promoter mutations are the most frequent genetic alterations observed in HCC and these mutations are associated with an increase TERT expression. Interestingly, TERT promoter mutations were more frequent in old patients and were also significantly associated with activating mutations of catenin suggesting cooperation between these two pathways [13,32]. Moreover, insertion of HBV in the TERT gene, most frequently in the promoter, has been described as an alternative mechanism leading to telomerase expression [37,38]. TERT amplifications, is another mechanism of telomerase reactivation, they have been also described by two different teams in 5 to 6% of HCC [12,13]. Strikingly, TERT promoter mutations, TERT amplification and HBV insertion in the TERT promoter were exclusive together. All these data have underlined the pivotal role of telomere maintenance in liver carcinogenesis.
Please cite this article in press as: Nault J-C, Zucman-Rossi J. TERT promoter mutations in primary liver tumors. Clin Res Hepatol Gastroenterol (2015), http://dx.doi.org/10.1016/j.clinre.2015.07.006
% mut.
Hepatocellular carcinoma
305
59
94
Hepatocellular carcinoma Hepatocellular carcinoma
61 195
44 29
Hepatocellular carcinoma Hepatocellular carcinoma
78 469
Hepatocellular carcinoma Hepatocellular carcinoma Liver high-grade dysplastic nodule Liver low-grade dysplastic nodule Hepatocellular adenoma Hepatocellular adenoma Borderline HCC/HCA and HCC on HCA Hepatoblastoma Hepatocholangiocarcinoma Intrahepatic cholangiocarcinoma Gallbladder carcinoma Gallbladder carcinoma
44 35 16 32 223 15 27 15 30 52 10 154
124 hot spot (%)
146 hot spot (%)
Association
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95
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47 54
100 93
5
Old age, hepatitis C and low frequency in HBV infection High-grade of differentiation CTNNB1 mutation, low frequency in HBV infection
34 31 19 6 0 0 44 0 15 0 0 9
66
34
87 87
13 13
Hepatitis C
43
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TERT promoter and liver tumors
Please cite this article in press as: Nault J-C, Zucman-Rossi J. TERT promoter mutations in primary liver tumors. Clin Res Hepatol Gastroenterol (2015), http://dx.doi.org/10.1016/j.clinre.2015.07.006
Table 1
Killela et al., 2013 [30] Chen et al., 2014 [33] Quaas et al., 2014 [34] Totoki et al., 2015 [13] Cevik et al., 2015 [35] Huang et al., 2015 [36] Nault et al., 2014 [43] Nault et al., 2014 [43] Pilati et al., 2014 [52] Quaas et al., 2014 [34] Pilati et al., 2014 [52] Eichenmuller et al., 2014 [53] Fujimoto et al., 2015 [55] Quaas et al., 2014 [34] Killela et al., 2013 [30] Qu et al., 2014 [54]
TERT: telomerase reverse transcriptase; % mut.: percentage of mutations; HCC: hepatocellular carcinoma; HCA: hepatocellular adenoma; HBV: hepatitis B virus.
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TERT promoter mutations in premalignant lesions on cirrhosis On cirrhosis, liver carcinogenesis is a multistep process with the sequential development of low-grade dysplastic nodules, high-grade dysplastic macronodules, early HCC and small and progress HCC [39,40]. Usually, TERT is not expressed in mature hepatocytes and in cirrhotic liver however it is re-expressed in some cirrhotic premalignant lesions (as high-grade dysplastic nodules) in addition of the wellknown re-expression of TERT in HCC [27,41,42]. Recently, we have reported somatic recurrent mutations in the TERT promoter in 6% of low-grade dysplastic nodules and 19% of high-grade dysplastic nodules (Table 1) [32,43]. Other mutations in cancer genes like TP53, CTNNB1, ARID1A, ARID2, RPS6KA3 occurred only in small and progressed HCC [43]. It is the first report of recurrent genetic alterations in cirrhotic premalignant lesions and TERT promoter mutations could be considered as a gatekeeper gene like APC in the colorectal adenoma-carcinoma sequence [44]. These data underlined that reactivation of telomerase trough mutation of TERT promoter is required at the earlier step in order to bypass replicative senescence of cirrhotic hepatocytes. In contrast, acquisition of genomic diversity appears to be a late event in liver carcinogenesis on cirrhosis [9].
TERT promoter mutations in hepatocellular adenomas A subset of HCC developed on normal liver derived from a malignant transformation of HCA. HCA are rare liver tumors composed of benign proliferation of hepatocytes [45]. The description of the genetic landscape of HCA is a paradigm of genotype/phenotype classification in liver tumors. Four groups of HCA have been identified [46,47]. The first one is composed of HCA with bi-allelic inactivating mutations of HNF1A and is characterized by steatosis at pathological reviewing [48]. The second group is HCA with activating mutations of CTNNB1 (coding for -catenin). Male are overrepresented in this subgroup and cholestasis and pseudoglandular formation are frequently observed. CTNNB1 mutations were associated with an increased risk of malignant transformation [47]. The third group is composed of inflammatory HCA characterized by inflammatory infiltrate, sinusoidal dilatation and dystrophic arteries. In this subgroups, recurrent somatic activating mutations of IL6ST (coding for gp130), STAT3, FRK, JAK1 and GNAS lead to the JAK/STAT pathway activation [49—51]. Interestingly, IL6ST and CTNNB1 mutations could be associated whereas HNF1A are exclusive from CTNNB1 and the inflammatory mutations activating the JAK/STAT pathway. Finally, the last group is composed of the remaining unclassified HCA. In a series of 250 ‘‘classical’’ HCA without any signs of malignant transformation, we did not identify any TERT promoter mutations and these results were confirmed by an independent group [32,34,52]. Recently, in the subset of HCA with malignant transformation we identified TERT promoter mutations in 44% (Table 1) [32,52]. Moreover, TERT promoter mutations were associated with mutations of CTNNB1, suggesting again a cooperation between telomerase maintenance and
Wnt/-catenin pathway [32,52]. To summarize, CTNNB1 mutations with or without IL6ST mutations lead to HCA initiation and TERT promoter mutations is required at the last step of malignant transformation into HCC. As HCA arise on normal liver with hepatocytes having their full renewal ability, reactivation of telomerase is required later in the process to bypass oncogene-induced senescence and increase the proliferative ability of tumor hepatocytes [9].
TERT promoter mutations in other primary liver cancers As in other pediatric cancers, TERT promoter mutations were not identified in hepatoblastoma (Table 1) [53]. Quaas et al. have analyzed 52 intrahepatic cholangiocarcinoma and found no mutations of the TERT promoter [34]. TERT promoter mutations were observed in 0 to 9% of gallbladder cancer [30,54]. In contrast, among 30 hepatocholangiocarcinoma, 15% of the tumors were mutated in the TERT promoter [55]. Consequently, TERT promoter mutations were not recurrently involved in the pathogenesis of cholangiocarcinoma and of hepatoblastoma and were observed only in a subset of hepatocholangiocarcinoma. It suggests that acquisition of TERT promoter mutations during carcinogenesis is dependent of the cell of origins of the tumor in the liver.
Conclusion Reactivation of telomerase is a major event of malignant transformation of hepatocytes in either normal or cirrhotic liver. TERT promoter mutations, the leading somatic genetic defect in HCC, are one of the main mechanisms leading to telomerase re-expression. TERT amplification and insertion of HBV virus in the TERT promoter are alternative mechanism explaining telomerase reactivation. However, 5% of HCC lack telomerase expression; in these tumors an alternative mechanisms of telomere lengthening could exist, its mechanism remains to be elucidate [56]. Moreover, telomerase is a potential therapeutic target and telomerase inhibitors (including small molecule inhibitor, G-quadruplex stabilizer and antisense oligonucleotide) or telomerase vaccine are currently in development to treat cancer harboring high telomerase expression [57,58]. These molecules are promising drugs that should be tested in HCC in the next future.
Disclosure of interest The authors declare that they have no conflicts of interest concerning this article.
Acknowledgements The team is supported by grants from Ligue Nationale Contre le Cancer (équipe Labllisée), Inserm and INCa (PRTK14).
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