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...
Purpose: A comparative quantitative methylation profiling of hepatocellular carcinoma and the most frequent benign liver tumor, hepatocellular adenoma, was set up for the identification of tumor-specific methylation patterns. Experimental Design: The quantitative methylation levels of nine genes (RASSF1A, cyclinD2, p16INK4a, DAP-K, APC, RIZ-1, HIN-1, GSTp1, SOCS-1) were analyzed in hepatocellular carcinoma and adjacent normal tissue (n = 41), hepatocellular adenoma and adjacent normal tissue (n = 26), focal nodular hyperplasia (n = 10), and unrelated normal liver tissue (n = 28). Accumulated methylation data were analyzed using various statistical algorithms, including hierarchical clustering, to detect tumor-specific methylation patterns. Results: Cluster analysis revealed that hepatocellular adenoma displays a methylation profile much more similar to that found in normal liver tissue and focal nodular hyperplasia than to that found in hepatocellular carcinoma. Many characteristic differences were not detected when using mere qualitative methylation assays. The cyclinD2 gene was identified as a new and frequent target for aberrant hypermethylation in hepatocellular carcinoma (68%). In the control group of 28 liver specimens from healthy donors, a clear correlation between age of patient and frequency and level of aberrant methylation was seen, which could not be detected in the group of hepatocellular carcinoma specimens. Conclusions: Methylation profiling can clearly contribute to the unequivocal classification of suspicious lesions, but only if done in a quantitative manner applying cell type and gene-specific thresholds. In hepatocellular carcinoma, the altered methylation patterns accompanying malignant transformation override the age-dependent increase in gene methylation.
The data underscore the importance and prognostic value of the UICC tumour classification for cholangiocellular carcinoma. The prognosis of mixed tumours is no different. Liver resection remains the treatment of choice; transplantation offers no solution for otherwise unresectable tumours.
ObjectiveThis article describes the experience with liver transplantation in patients with irresectable neuroendocrine hepatic metastases. Summary Background DataLiver transplantation has become an established therapy in primary liver cancer. On contrast, there is little experience with liver transplantation in secondary hepatic tumors. So far, in the majority of patients being transplanted for irresectable liver metastases, long-term results have been disappointing because of early tumor recurrence. Because of their biologically less aggressive nature, the metastases of neuroendocrine tumors could represent a justified indication for liver grafting. MethodsIn a retrospective study, the data of 12 patients who underwent liver transplantation for irresectable neuroendocrine hepatic metastases were analyzed regarding survival, tumor recurrence, and symptomatic relief. ResultsNine of 12 patients currently are alive with a median survival of 55 months (range, 1 1.0 days to 103.5 months). The operative mortality was 1 of 12, 2 patients died because of septic complications or tumor recurrences or both 6.5 months and 68.0 months after transplantation. All patients had good symptomatic relief after hepatectomy and transplantation. Four of the nine patients who are alive have no evidence of tumor with a follow-up of 2.0, 57.0, 58.0, and 103.5 months after transplantation. ConclusionsIn selected patients, liver transplantation for irresectable neuroendocrine hepatic metastases may provide not only long-term palliation but even cure. Regarding the shortage of donor organs, liver grafting for neuroendocrine metastases should be considered solely in patients without evidence of extrahepatic tumor manifestation and in whom all other treatment methods are no longer effective. 347
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