Telomere shortening correlates with increasing aneuploidy of chromosome 8 in human hepatocellular carcinoma

Plentz, Ruben R.; Schlegelberger, Brigitte; Flemming, Peer; Gebel, M.; Kreipe, Hans; Manns, Michael P.; Rudolph, K. Lenhard; Wilkens, Ludwig

doi:10.1002/hep.20847

Cited by 59 publications

(39 citation statements)

References 29 publications

(43 reference statements)

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“…The initiation of human hepatocellular carcinoma (HCC) is associated with telomere shortening at precancerous disease stages and in early tumors (10)(11)(12). However, telomerase reactivation occurs in the vast majority of human HCCs during tumor progression (10,11).…”

Section: Introductionmentioning

confidence: 99%

Transient telomere dysfunction induces chromosomal instability and promotes carcinogenesis

Begus‐Nahrmann¹,

Hartmann²,

Kraus³

et al. 2012

J. Clin. Invest.

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Telomere shortening limits the proliferative capacity of a cell, but perhaps surprisingly, shortening is also known to be associated with increased rates of tumor initiation. A current hypothesis suggests that telomere dysfunction increases tumor initiation by induction of chromosomal instability, but that initiated tumors need to reactivate telomerase for genome stabilization and tumor progression. This concept has not been tested in vivo, since appropriate mouse models were lacking. Here, we analyzed hepatocarcinogenesis in a mouse model of inducible telomere dysfunction on a telomerase-proficient background, in telomerase knockout mice with chronic telomere dysfunction (G3 mTerc -/-), and in WT mice with functional telomeres and telomerase. Transient or chronic telomere dysfunction enhanced the rates of chromosomal aberrations during hepatocarcinogenesis, but only telomerase-proficient mice exhibited significantly increased rates of macroscopic tumor formation in response to telomere dysfunction. In contrast, telomere dysfunction resulted in pronounced accumulation of DNA damage, cell-cycle arrest, and apoptosis in telomerase-deficient liver tumors. Together, these data provide in vivo evidence that transient telomere dysfunction during early or late stages of tumorigenesis promotes chromosomal instability and carcinogenesis in telomerase-proficient mice.

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Section: Introductionmentioning

confidence: 99%

Transient telomere dysfunction induces chromosomal instability and promotes carcinogenesis

Begus‐Nahrmann¹,

Hartmann²,

Kraus³

et al. 2012

J. Clin. Invest.

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“…These results represent a significant extension of previous studies showing that telomere shortening characterizes the cirrhosis stage 25 and that further telomere shortening coincides with the evolution of CIN in HCC. 18,19 High levels of p21 expression in cirrhotic liver have previously been correlated with an increased cancer risk. 38 That telomere shortening and consequent activation of cell cycle checkpoints repress liver regeneration at the cirrhosis stage and that in this molecular context loss of p16/p21-expression represents a selective advantage allowing clonal expansion of hepatocytes with dysfunctional telomeres seem possible.…”

Section: Discussionmentioning

confidence: 99%

“…13,14 Whether both of these lesions represent true precursor lesions and which of these precursors is more closely related to HCC are intensely debated. [7][8][9][10][11][12] On the molecular level, HCC are characterized by massive chromosomal instability (CIN) in more than 95% of cases, [15][16][17] and telomere shortening 18,19 and loss of p53-checkpoint function in more than 70% of the cases. 3,20 Experimental data from telomerase-deficient mice show that telomere shortening represents one mechanism that leads to induction of CIN and increasing initiation of various cancer types 21,22 including HCC.…”

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confidence: 99%

Telomere shortening and inactivation of cell cycle checkpoints characterize human hepatocarcinogenesis

et al. 2007

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Telomere shortening and inactivation of cell cycle checkpoints characterize carcinogenesis. Whether these molecular features coincide at specific stages of human hepatocarcinogenesis is unknown. The preneoplasia-carcinoma sequence of human HCC is not well defined. Small cell changes (SCC) and large cell changes (LCC) are potential precursor lesions. We analyzed hepatocellular telomere length, the prevalence of DNA damage, and the expression of p21 and p16 in biopsy specimens of patients with chronic liver disease (n ‫؍‬ 27) that showed different precursor lesions and/or HCC: liver cirrhosis (n ‫؍‬ 25), LCC (n ‫؍‬ 26), SCC (n ‫؍‬ 13), and HCC (n ‫؍‬ 13). The study shows a decrease in telomere length in nondysplastic cirrhotic liver compared with normal liver and a further significant shortening of telomeres in LCC, SCC, and HCC. HCC had the shortest telomeres, followed by SCC and LCC. Hepatocytes showed an increased p21 labeling index (p21-LI) at the cirrhosis stage, which remained elevated in most LCC. In contrast, most SCC and HCC showed a strongly reduced p21-LI. Similarly, p16 was strongly expressed in LCC but reduced in SCC and not detectable in HCC. ␥H2AX-DNA-damage-foci were not detected in LCC but were present in SCC and more frequently in HCC. These data indicate that LCC and SCC represent clonal expansions of hepatocytes with shortened telomeres. Conclusion: The inactivation of cell cycle checkpoints coincides with further telomere shortening and an accumulation of DNA damage in SCC and HCC, suggesting that SCC represent more advanced precursor lesions compared with LCC. (HEPATOLOGY 2007;45:968-976.) H CC represents the fifth most common neoplasm in humans. 1 Treatment options for HCC patients are limited, and the disease is often diagnosed at an advanced stage. 2 The molecular pathogenesis of hepatocarcinogenesis is poorly understood, 3 thus impairing the development of molecular markers, efficient screening procedures, and molecular therapies.HCC rarely evolve in noncirrhotic liver but the risk sharply increases at the cirrhosis stage of chronic liver diseases, with the yearly incidence of HCC ranging from Gastroenterology, Hepatology, and Endocrinology, Medical School Hannover, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany. E-mail: Rudolph.Lenhard@MH-hannover.de; fax: 0049-511-532-6998, or to: Massimo Roncalli, Department of Pathology, University of Milan and IRCCS Humanitas Clinical Institute, Via Manzoni 56, 20089 Rozzano (Milan), Italy. E-mail: massimo.roncalli@unimi.it; fax: 0039-02-82244791. Copyright © 2007 (2) small cell changes/dysplasia (SCC). 13,14 Whether both of these lesions represent true precursor lesions and which of these precursors is more closely related to HCC are intensely debated. [7][8][9][10][11][12] On the molecular level, HCC are characterized by massive chromosomal instability (CIN) in more than 95% of cases, 15-17 and telomere shortening 18,19 and loss of p53-checkpoint function in more than 70% of the cases. 3,20 Experimental data from telomerase-deficient mic...

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“…Moreover, hepatocyte aging, as assessed by relative nuclear size, was found to be associated with hepatocarcinogenesis in patients with non-HBV non-HCV non-alcoholic chronic liver injury (22). Although the mechanisms underlying age-related hepatocarcinogenesis have not been fully elucidated, aging is associated with telomere shortening, which in turn results in chromosomal instability and the inactivation of cell cycle checkpoints (23,24). In addition, aging is known to enhance DNA hypermethylation of tumor suppressor genes, which is associated with the onset of HCC (25).…”

Section: Discussionmentioning

confidence: 99%

Time trends of clinical characteristics in hepatocellular carcinoma patients with chronic hepatitis B virus infection: A field survey between 2000 and 2012

Amano

Kawaguchi

Kuromatsu

et al. 2014

Molecular and Clinical Oncology

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Abstract. The hepatitis B virus (HBV) carrier rate has decreased in Japan; however, the incidence of HBV infection among hepatocellular carcinoma (HCC) patients has not decreased accordingly. In this study, we aimed to assess the time trends of the clinical characteristics in HCC patients with chronic HBV infection. Between 2000 and 2012, we enrolled a total of 156 HCC patients with chronic HBV infection in our field survey. The HCC risk was evaluated using the HCC prediction score, which is constructed from the characteristics of age, presence of liver cirrhosis and serum levels of albumin, bilirubin and HBV DNA. Lifestyle factors and the presence of diabetes mellitus were also evaluated. The time trends of patient characteristics were analyzed using the Jonckheere-Terpstra proportion trend test. Among HCC patients with chronic HBV infection, the proportion of patients at high risk according to the HCC prediction score significantly decreased during the study period (P=0.0005). Similarly, the proportion of patients with liver cirrhosis, ≤3.5 g/dl serum albumin level, >4 log copies/ml serum HBV DNA level and ≥60 g/day alcohol intake were also significantly decreased. The proportion of male and obese patients was not significantly altered, whereas the proportion of elderly (≥65 years) and diabetic patients tended to increase during the study period (P=0.0654 and P=0.0528, respectively). In this study, we analyzed the time trends of the clinical characteristics in HCC patients with chronic HBV infection and demonstrated that aging and diabetes mellitus may be involved in the hepatocarcinogenesis in patients with chronic HBV infection.

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Telomere shortening correlates with increasing aneuploidy of chromosome 8 in human hepatocellular carcinoma

Cited by 59 publications

References 29 publications

Transient telomere dysfunction induces chromosomal instability and promotes carcinogenesis

Transient telomere dysfunction induces chromosomal instability and promotes carcinogenesis

Telomere shortening and inactivation of cell cycle checkpoints characterize human hepatocarcinogenesis

Time trends of clinical characteristics in hepatocellular carcinoma patients with chronic hepatitis B virus infection: A field survey between 2000 and 2012

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