Telomeres are shortened in acinar-to-ductal metaplasia lesions associated with pancreatic intraepithelial neoplasia but not in isolated acinar-to-ductal metaplasias

Telomeres protect against chromosomal breakage, fusion, and interchromosome bridges during cell division. Shortened telomeres have been observed in the lowest grade of pancreatic intraepithelial neoplasia. Genetically engineered mouse models of pancreatic neoplasia develop acinar-to-ductal metaplasia prior to the development of pancreatic intraepithelial neoplasia suggesting that acinar-to-ductal metaplasias can be an early precursor lesion to pancreatic cancer. Some human pancreatic intraepithelial neoplasias are associated with acinar-to-ductal metaplasias, and it has been suggested that these acinar-to-ductal metaplasias arise as a consequence of growth of adjacent pancreatic intraepithelial neoplasias. Since the earliest known genetic lesions of pancreatic intraepithelial neoplasias is shortened telomeres we compared the telomere lengths of acinar-to-ductal metaplasia lesions, pancreatic intraepithelial neoplasias and adjacent normal cells of human pancreata to determine if acinar-to-ductal metaplasias could be precursors to pancreatic intraepithelial neoplasia. We used quantitative fluorescent in situ hybridization to measure the telomere length of cells from pancreatic lesions and adjacent normal pancreata from 22 patients, including 20 isolated acinar-to-ductal metaplasias, 13 pancreatic intraepithelial neoplasias associated with acinar-to-ductal metaplasias, and 12 pancreatic intraepithelial neoplasias. Normalized mean telomere fluorescence was significantly different among the cell types analyzed; 12.6±10.2 units in normal acinar cells, 10.2±6.4 in ductal cells, 8.4±5.9 in fibroblasts, 9.4±7.3 in isolated acinar-to-ductal metaplasias, 4.1±2.9 in pancreatic intraepithelial neoplasia-associated acinar-to-ductal metaplasias, and 1.6±1.9 in pancreatic intraepithelial neoplasias, respectively (p<0.001, ANOVA with randomized block design). Telomeres were significantly shorter in pancreatic intraepithelial neoplasia-associated acinar-to-ductal metaplasias (p<0.05, post-hoc Duncan test) and in pancreatic intraepithelial neoplasias (p<0.05), than in normal cells, or isolated acinar-to-ductal metaplasias. Thus, shortened telomeres are found in pancreatic intraepithelial neoplasia-associated acinar-to-ductal metaplasias, but not in isolated acinar-to-ductal metaplasia lesions. These results indicate that isolated acinar-to-ductal metaplasias are not a precursor to pancreatic intraepithelial neoplasia, and support the hypothesis that pancreatic intraepithelial neoplasia-associated acinar-to-ductal metaplasias arise secondary to pancreatic intraepithelial neoplasia lesions.