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

Abstract

Biliary tract carcinoma, including carcinoma of the gallbladder, intrahepatic bile ducts (cholangiocarcinoma), and extrahepatic bile ducts, affects 7500 people in the United States annually, and has an overall 32% 5-year survival rate for disease limited to the mucosa, and a dismal 10% 5-year survival for more advanced disease. The identification of factors involved in the pathogenesis and progression of biliary tract carcinoma is critical for devising effective methods of screening and treatment. Recent evidence suggests that reduction of the length of telomeres, which normally help maintain chromosomal stability, may promote the development and progression of a variety of carcinomas. Using a novel, recently validated telomere fluorescence in situ hybridization method, we examined telomere length in normal and inflamed gallbladder epithelium, metaplasia and dysplasia of the gallbladder, and biliary tract carcinoma to determine whether telomere shortening is associated with neoplastic progression in the biliary tract. Although normal and inflamed gallbladder epithelium demonstrated uniform normal telomere lengths, over half of all metaplastic lesions demonstrated shortened telomeres, supporting prior evidence that metaplastic lesions of the gallbladder are pre-neoplastic. Dysplastic epithelium and invasive carcinomas demonstrated almost universally abnormally short telomeres, indicating that telomere shortening occurs at an early, preinvasive stage of cancer development. In addition, invasive adenocarcinoma of the biliary tract frequently demonstrated intratumoral heterogeneity of telomere lengths. We conclude that telomere shortening is a consistent and early finding in the development of biliary tract carcinoma.

Updates on Precancerous Lesions of the Biliary Tract: Biliary Precancerous Lesion

“…For example, telomere shortening is one of the earliest molecular events occurring in response to inflammation, and varied length of the telomere correlates well with neoplastic progression. 24 Gradual increase in the expression of p53 and Ki-67 was observed along the disease progression from metaplasia to precursor, and to invasive carcinoma. 25 Moreover, the fact that metaplasia is often noted in the background of BilIN or carcinoma, and that BilIN has been reported in association with 10% to 45% of bile duct carcinomas, supports this sequential evolutionary pathway.…”

Current Management of Gallbladder Carcinoma

“…Telomere length, which is associated with cellular proliferation, genomic instability, and cancer precursors in a number of other tumor sites, exhibited progressive shortening through the stages of metaplasia, dysplasia, and carcinoma in the biliary tract [95]. Transcriptional analysis of GBCs has been accomplished using serial analysis of gene expression profiling.…”

Telomere dysfunction in peripheral blood lymphocytes from patients with primary sclerosing cholangitis and inflammatory bowel disease

“…As previously described [16,19], fresh slide spreads were incubated for 10 min in 2× standard saline citrate (2× SSC) at 37 • C, followed with fixation in formamide (diluted 1:40 in phosphate buffered saline (PBS) and 0.18 g MgCl 2 ) for 15 min. The slides were washed in PBS for 5 min and incubated in pepsin solution (75 g lyophilized pepsin dissolved in 50 ml HCl 0.01 N) followed by a wash in PBS for 5 min.…”

“…Telomere shortening was also demonstrated in metaplasia and dysplastia of biliary duct and in cholangiocarcinoma [19]. Since leucocyte telomere length has been demonstrated to be highly correlating with that in cells from other tissues [20], we hypothesized that patients with PSC display telomere dysfunction in peripheral blood lymphocytes as surrogate marker of genetic instability.…”