Telomere Shortening Is Nearly Universal in Pancreatic Intraepithelial Neoplasia

Abstract

A multistep model of carcinogenesis has recently been proposed for pancreatic ductal adenocarcinomas. In this model, noninvasive precursor lesions in the pancreatic ductules accumulate genetic alterations in cancer-associated genes eventually leading to the development of an invasive cancer. The nomenclature for these precursor lesions has been standardized as pancreatic intraepithelial neoplasia or PanIN. Despite the substantial advances made in understanding the biology of invasive pancreatic adenocarcinomas, little is known about the initiating genetic events in the pancreatic ductal epithelium that facilitates its progression to cancer. Telomeres are distinctive structures at the ends of chromosomes that protect against chromosomal breakage-fusion-bridge cycles in dividing cells. Critically shortened telomeres can cause chromosomal instability, a sine qua non of most human epithelial cancers. Although evidence for telomeric dysfunction has been demonstrated in invasive pancreatic cancer, the onset of this phenomenon has not been elucidated in the context of noninvasive precursor lesions. We used a recently de- The 5-year survival rate of patients with ductal adenocarcinoma of the pancreas is 4%, one of the lowest of any neoplasm. Each year, nearly 29,000 patients are diagnosed with pancreatic cancer in the United States, and almost all will succumb to their disease.

Telomere length variation in biliary tract metaplasia, dysplasia, and carcinoma

“…17,18,30 Shortened telomeres have been identified in a variety of invasive cancers and preinvasive lesions of the pancreas and prostate, and telomere shortening may be a critical early event in the development of epithelial neoplasms. 13,14,31,32 In addition to telomere shortening observed in dysplastic and carcinoma specimens, the majority of metaplastic lesions of the gallbladder in this study also demonstrated telomere shortening, supporting prior genetic evidence that metaplastic change in the gallbladder represents an early neoplastic alteration. 7 Specifically, in the study of Wistuba et al, 7 gallbladder metaplasias showed loss of heterozygosity in at least one cancer-associated locus in four of five cases.…”

“…[10][11][12] For example, telomere shortening appears to be an early and common event in precursors to invasive prostatic and pancreatic cancer. 13,14 Telomeres consist of DNA-protein structures, which serve as 'caps' on the ends of linear chromosomes that allow cells to distinguish between double-stranded breaks in the DNA and normal chromosome ends. 15,16 In humans, telomeric DNA sequences consist of 1000-2000 tandem repeats of TTAGGG, which generally shorten following cell division owing to incomplete replication of telomere repeats during DNA synthesis (the 'end-replication problem').…”

CpG island methylation profile of pancreatic intraepithelial neoplasia

“…In addition, telomere shortening is a common genetic abnormality observed in all stages of PanINs including the vast majority of earliest lesions (PanIN-1A). 10 PanIN lesions may be particularly important in patients with a strong family history of pancreatic cancer. [11][12][13] Pancreata in patients with a strong family history of pancreatic cancer are remarkable for the presence of multifocal PanIN lesions, and these PanIN lesions are characteristically associated with a distinctive form of lobular parenchymal atrophy and are closely associated with the subtle EUS abnormalities seen in this group.…”

Concordant loss of MTAP and p16/CDKN2A expression in pancreatic intraepithelial neoplasia: evidence of homozygous deletion in a noninvasive precursor lesion

“…3 Telomere shortening and activating point mutations in the KRAS2 oncogene occur early in PanIN-1 lesions, the p16INK4A/CDKN2A (henceforth referred to as p16) gene is inactivated in intermediate and late lesions (PanINs 2 and 3), and the TP53, MADH4, and BRCA2 genes are inactivated late, in PanIN-3 lesions. [4][5][6][7][8][9][10] …”

“…3 Telomere shortening and activating point mutations in the KRAS2 oncogene occur early in PanIN-1 lesions, the p16INK4A/CDKN2A (henceforth referred to as p16) gene is inactivated in intermediate and late lesions (PanINs 2 and 3), and the TP53, MADH4, and BRCA2 genes are inactivated late, in PanIN-3 lesions. [4][5][6][7][8][9][10] One of the most important of the genetic alterations in infiltrating adenocarcinoma of the pancreas and in PanIN, as judged by its high prevalence, is inactivation of the p16 gene. The p16 gene is inactivated in 40% of pancreatic cancers by homozygous deletion, in 40% by an intragenic mutation coupled with loss of the second allele, and in 15% by hypermethylation of the p16 gene promoter.…”