Telomeres Are Shortened in Acinar to Ductal Metaplasia (ADM) Lesions Associated with Pancreatic Intraepithelial Neoplasias (PanINs) but Not in Isolated ADMs
S-M Hong, CM Heaphy, C Shi, HJ Cho, AK Meeker, JR Eshleman, RH Hruban, M Goggins. Johns Hopkins Medical Institutions, Baltimore, MD; Korea University, Seoul, Republic of Korea
Background: Telomeres protect against chromosomal breakage, fusion, and interchromosome bridges during cell division. Shortened telomeres have been observed in the earliest grade of pancreatic intraepithelial neoplasia (PanIN). Recent studies with genetically engineered mouse models suggested acinar ductal metaplasias (ADMs) could be an early precursor lesion to pancreatic cancer. However, studies in human tissues have suggested that ADM lesions may represent retrograde extension of PanINs. Telomere length of ADM lesions arising in the context of noninvasive precursor lesions has not been elucidated.
Design: We assessed telomere length using fluorescent in situ hybridization from multiple non-invasive precursor lesions from 22 patients, including lesions from 20 isolated ADMs, 13 ADM associated with PanINs, and12 PanINs and normal regions, including 22 areas with acinar cells, 12 with ductal cells, and 22 with fibroblasts. Quantitative image analyses were performed to measure relative telomere length.
Results: Relative telomere length was significantly different among non-invasive lesions; 15.5+22.0 in normal acinar cells, 10.7+8.3 in ductal cells, 10.0+13.0 in fibroblasts, 10.4+12.4 in isolated ADMs, 5.5+9.3 in ADM with PanINs, and 2.5+4.9 in PanINs, respectively (p=0.006, Unbalanced 1-way ANOVA). Telomeres are significantly shorter in ADM lesions associated with PanINs (p=0.04,T-test) and in PanINs (p=0.004, T-test), than they are in acinar cells. However there was no significant difference of relative telomere length among other cell types.
Conclusions: Shortened telomeres are found in ADM lesions associated with PanINs suggesting that most isolated ADMs are not genetically unstable and are not a precursor to PanIN, as defined by telomere length. Further investigation is required to determine if ADMs associated with PanIN are a precursor of PanINs or if such ADMs arise as a consequence of retrograde neoplastic growth of PanIN cells with shortened telomeres.
Tuesday, March 23, 2010 9:30 AM
Poster Session III # 130, Tuesday Morning