Telomerase Activity in Periampullary Tumors Correlates With Aggressive Malignancy

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Abstract
To determine the presence of telomerase activity in a variety of periampullary malignancies and pancreatic diseases and quantify its activity to establish any association with the stage or aggressiveness of malignancy. Progressive shortening of telomeres, repetitive DNA sequences at the ends of chromosomes, plays a role in cell senescence. Telomerase catalyzes conservation of telomeric repeats and may promote cell immortality and hence malignancy. It is absent in normal tissues but upregulated in more than 80% of cancers. Fresh specimens of 62 periampullary tumors were snap-frozen in liquid nitrogen and adjacent tissue was formalin-fixed for histopathology. The telomerase repeat amplification protocol (TRAP) was used to obtain telomerase DNA products. These were separated with gel electrophoresis, stained with SYBR green, and quantified by densitometry. Findings were confirmed with a fluorometric TRAP assay in which fluorescent primers specific for telomerase were selectively amplified in its presence. Telomerase activity was upregulated in 26 of 33 periampullary malignancies (79%): 17 of 21 pancreatic adenocarcinomas (81%), 2 of 2 cholangiocarcinomas, 2 of 2 duodenal carcinomas, and 5 of 8 ampullary carcinomas (63%). Poorly differentiated periampullary tumors had significantly higher telomerase activity than well-differentiated tumors, and tumors larger than 2 cm had significantly higher telomerase activity than those 2 cm or smaller. Pancreatic ductal adenocarcinomas with lymph node metastases had significantly greater activity than node-negative cancers. Two of 11 intraductal papillary mucinous tumors were positive for telomerase activity, but only in foci of invasive carcinoma. Chronic pancreatitis (n = 7), serous cystadenomas (n = 5), benign mucinous cystic neoplasms (n = 4), neuroendocrine cancer (n = 1), and acinar cell carcinoma (n = 1) had no detectable telomerase activity. Telomerase activity is common in periampullary carcinomas. The magnitude of activity correlates with aggressiveness in pancreatic adenocarcinoma and may prove useful as a molecular index for biologic staging.