Hepatocellular telomere shortening correlates with chromosomal instability and the development of human hepatoma

Abstract

The telomere hypothesis of cancer initiation indicates that telomere shortening initiates cancer by induction of chromosomal instability. To test whether this hypothesis applies to human hepatocellular carcinoma (HCC), we analyzed the telomere length of hepatocytes in cytological smears of fine-needle biopsies of liver tumors from patients with cirrhosis (n ‫؍‬ 39). The tumors consisted of 24 HCC and 15 regenerative nodules as diagnosed by combined histological and cytological diagnostics. In addition, we analyzed the telomere length of hepatocytes in HCC and surrounding noncancerous liver tissue within individual patients in another cohort of 10 patients with cirrhosis. Telomere length analysis of hepatocytes was correlated with tumor pathology and ploidy grade of the tumors, which was analyzed by cytophotometry. Telomeres were significantly shortened in hepatocytes of HCC compared to hepatocytes in regenerative nodules or surrounding noncancerous liver tissue. Hepatocyte telomere shortening in HCC was independent of the patient's age. There was no overlap in mean telomere lengths of individual samples when comparing HCC with regenerative nodules or noncancerous surrounding liver. Within the HCC group, telomeres were significantly shorter in hepatocytes of aneuploid tumors compared to diploid tumors. In conclusion, our data suggest that the telomere hypothesis of cancer initiation applies to human HCC and that cell type-specific telomere length analysis might indicate the risk of HCC development. (HEPATOLOGY 2004;40:80 -86.) L iver cirrhosis is the major risk factor for the development of hepatocellular carcinoma (HCC), and the incidence of HCC in cirrhotic patients is 3% to 6% annually. 1-3 One of the common features of human epithelial cancer is the prevalence of chromosomal instability (CIS). 4 As in other epithelial cancers, HCCs show a high incidence of CIS. 5 A current hypothesis is that telomere shortening and loss of telomere function play a role in the induction of CIS. 6,7 The main function of telomeres is the capping of chromosomal ends. 8 Due to the "end-replication problem" of DNA polymerase, telomeres shorten during each round of cell division. 9 Telomere shortening limits the proliferative capacity of primary human cells to a finite number of cell divisions 10 and appears to restrain the regenerative capacity of tissues and organs in aging and chronic diseases. 7 In the liver, hepatocyte telomere shortening has been linked to cirrhosis formation. 11 When telomeres reach a critically short length, they lose capping function, resulting in chromosomal fusions. 12 When cells with fused chromosomes enter the cell cycle, these fusions will be disrupted during mitosis, resulting in the breakage of chromosomes and chromosomal gains and losses. 13 This phenomenon has been termed the fusion-bridge-breakage cycle and might contribute to the induction of CIS and cancer in the aged. 13 In line with this hypothesis, the initiation of cancer is increased by telomere shortening in telomerase-deficient mice. 1...

Benign metastasizing leiomyoma: clonality, telomere length and clinicopathologic analysis

“…However, the meaning of telomere length is a complicated subject. While it has been shown that telomere length correlates inversely, and telomerase activity directly, with malignancy in epithelial tumors, [6][7][8][9] only a couple of studies address this question in soft tissue tumors. 22,23 Bonatz et al measured telomere length in 107 uterine leiomyomas using a Southern blot method and found that telomeres were significantly shorter in tumoral tissue compared to adjacent uterine smooth muscle.…”

“…However, since there is a 50% chance that the same X-inactivation could occur incidentally between two tumors, more cases should be analyzed using this method. Telomere shortening, a possible crucial event leading to chromosomal instability and development of malignancy, has been reported in multiple types of human cancer [6][7][8][9] and can be demonstrated with telomerespecific fluorescence in situ hybridization (FISH) probes.…”

Frequent changes in subtelomeric DNA methylation patterns and its relevance to telomere regulation during human hepatocarcinogenesis

“…17 Telomere length becomes shorter in the early stages of human hepatocarcinogenesis, 18,19 and these short telomeres are thought to be one of the factors that can induce chromosomal instability, an important mechanism of HBV-related hepatocarcinogenesis. 20,21 Epigenetic modification has been implicated as a critical event in carcinogenesis. 22 Aberrant DNA methylation of proto-oncogenes and tumor suppressor genes has frequently been found in human cancers.…”

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

“…3 We have recently demonstrated that telomere shortening characterizes hepatocytes of HCC compared with hepatocytes in regenerative nodules or surrounding noncancerous liver tissue. 8 Whether telomere shortening simply leads to random genomic instability or whether it leads to specific cytogenetic changes reflecting the cytogenetic fingerprint of a specific tumor type remains to be determined. In more than 90% of all HCC, chromosomal aberrations can be detected by using centromere-specific chromosome probes for chromosomes 1 and 8, indicating the significant role of CIN in the development of HCC.…”