Abstract
The role of telomere dysfunction and aberrant telomerase activities in hepatocellular carcinoma (HCC) has been overlooked for many years. This study aimed to delineate the variation and prognostic value of telomere length in HCC. Telomere‐specific fluorescence in situ hybridization (FISH) and qPCR were used to evaluate telomere length in HCC cell lines, tumor tissues, and isolated non‐tumor cells within the tumor. Significant telomere attrition was found in tumor cells and cancer‐associated fibroblasts (CAFs) compared to their normal counterparts, but not in intratumor leukocytes or bile duct epithelial cells. Clinical relevance and prognostic value of telomere length were investigated on tissue microarrays of 257 surgically treated HCC patients. Reduced intensity of telomere signals in tumor cells or CAFs correlated with larger tumor size and the presence of vascular invasion (p < 0.05). Shortened telomeres in tumor cells or CAFs associated with reduced survival and increased recurrence, and were identified as independent prognosticators for HCC patients (p < 0.05). These findings were validated in an independent HCC cohort of 371 HCC patients from The Cancer Genome Atlas (TCGA) database, confirming telomere attrition and its prognostic value in HCC. We also showed that telomerase reverse transcriptase promoter (TERTp) mutation correlated with telomere shortening in HCC. Telomere variation in tumor cells and non‐tumor cells within the tumor microenvironment of HCC was a valuable prognostic biomarker for this fatal malignancy. © 2017 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
Highlights
Hepatocellular carcinoma (HCC) is the third most common cause of cancer deaths and the fourth most common cancer worldwide [1]
Telomere attrition was found in tumor cells and cancer-associated fibroblasts (CAFs), but not in tumor-infiltrating lymphocyte (TIL) or BDECs
Telomere shortening has been reported in various human cancers using fluorescence in situ hybridization (FISH) [28,29,30,31]
Summary
Hepatocellular carcinoma (HCC) is the third most common cause of cancer deaths and the fourth most common cancer worldwide [1] Chronic liver damage, such as that caused by chronic hepatitis, liver cirrhosis, and fatty liver disease, is closely associated with the occurrence of HCC [2]. Recent advances in sequencing technologies have enabled the identification of multiple driver genetic alterations and pathways implicated in hepatocarcinogenesis and tumor progression [3]. This may help us to develop new targets and biomarkers that improve clinical decision-making and patient outcomes.
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