Chromosome 9p21 Loss and p16 Inactivation in Primary Sclerosing Cholangitis-Associated Cholangiocarcinoma

Ahrendt, Steven A.; Eisenberger, Claus Ferdinand; Yip, Lin; Rashid, Asif; Chow, John T.; Pitt, Henry A.; Sidransky, David

doi:10.1006/jsre.1999.5615

Cited by 82 publications

(45 citation statements)

References 26 publications

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“…In contrast to a previous report on 63% p16 point mutations in perihilar bile duct cancers, 21 we failed to detect any p14 or p16 mutations in BTCCL and BDC, a discrepancy that may be explained by geographic and environmental differences. Studies in intrahepatic cholangiocarcinomas 22 and bile tract cancers in primary sclerosing cholangitis (PSC) 23 also failed to detect any p16 point mutations. The study on intrahepatic cholangiocarcinomas 22 found p16 promoter hypermethylation in 88% and homozygous deletion in 5%, while the study on bile tract cancers in PSC 23 reported none with homozygous deletion, 9p21 LOH in 6 of 7 and p16 promoter hypermethylation in 2 of 6 bile duct cancers examined.…”

Section: Discussionmentioning

confidence: 99%

“…Studies in intrahepatic cholangiocarcinomas 22 and bile tract cancers in primary sclerosing cholangitis (PSC) 23 also failed to detect any p16 point mutations. The study on intrahepatic cholangiocarcinomas 22 found p16 promoter hypermethylation in 88% and homozygous deletion in 5%, while the study on bile tract cancers in PSC 23 reported none with homozygous deletion, 9p21 LOH in 6 of 7 and p16 promoter hypermethylation in 2 of 6 bile duct cancers examined. Intrahepatic and extrahepatic bile duct cancers seem to differ markedly in their molecular carcinogenesis, while PSC-associated BDC and sporadic BDC seem to share the same tumor pathogenesis.…”

Section: Discussionmentioning

confidence: 99%

“…17 p16 inactivation by point mutations and loss of heterozygosity has also been reported in bile tract cancers, 21 intrahepatic cholangiocarcinomas 22 and cholangiocarcinomas associated with primary sclerosing cholangitis. 23 In contrast to other tumor-suppressor genes, p16 is inactivated by at least 3 distinct mechanisms. 16,17 Beside point mutations and deletions, hypermethylation of 5Ј regulatory regions can lead to inactivation of p16.…”

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Inactivation of the INK4a/ARF locus and p53 in sporadic extrahepatic bile duct cancers and bile tract cancer cell lines

Caca

Feisthammel

Klee

et al. 2001

Intl Journal of Cancer

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The tumor-suppressor genes p14(ARF), p16(INK4a) and Tp53 are commonly inactivated in many tumors. We investigated their role in the pathogenesis of 9 bile tract cancer cell lines and 21 primary sporadic extrahepatic bile duct carcinomas. p53 and p16 protein expression was examined by Western blot analysis and immunohistochemistry. Mutation screening of p53 was done by SSCP and direct sequencing. Inactivating mechanisms of p14 and p16 were addressed by screening for mutations, homozygous deletions, chromosomal loss of 9p21 (loss of heterozygosity [LOH] analysis) and promoter hypermethylation of the p14/p16 genes. p53 overexpression could be detected in 7 of 9 cell lines and 7 of 21 primary tumors, but mutations were found in 3 cell lines only. p16 expression was absent in all cell lines, due to homozygous deletion of the gene in 8 of 9 cell lines and hypermethylation of the p16 promoter in one cell line (CC-LP-1). p14 exon 1␤ was homozygously deleted in 6 of 9 cell lines, while retained in CC-LP-1 and 2 additional lines. No p14 promoter hypermethylation could be detected. p16 expression was lost in 11 of 21 primary tumors. p16 promoter hypermethylation was present in 9 of 21 primary tumors, all with lost p16 expression. Allelic loss at 9p21 was detected in 13 of 21 primary tumors, 10 of 11 with lost p16 expression and 8 of 9 with methylated p16 promoter. No p14 promoter hypermethylation or p14/p16 mutations could be detected. Neither Tp53 nor p16 alterations showed obvious association with histopathologic or clinical characteristics. In conclusion, inactivation of the p16 gene is a frequent event in primary sporadic extrahepatic bile duct cancers, 9p21 LOH and promoter hypermethylation being the principal inactivating mechanisms. Therefore, p16, but not p14, seems to be the primary target of inactivation at the INK4a locus in bile duct cancers. Other mechanisms than Tp53 mutations seems to be predominantly responsible for stabilization of nuclear p53 protein in bile duct cancers. © 2002 Wiley-Liss, Inc. Key words: bile tract cancer; INK4a/ARF; p53; promoter hypermethylation; histopathologyCancer of the extrahepatic bile duct (BDC) is a rare malignancy comprising less than 2% of all cancer diagnoses. 1,2 Although progress has been made in establishing the diagnosis earlier, the prognosis is still poor. Since most patients present with advanced disease, potential curative surgical therapy is applicable only to a minority of patients (Ͻ30%). 3 Palliative treatment is restricted to biliary drainage by surgery, 4 stenting 5 or photodynamic therapy. 6,7 So far, the molecular events in BDC carcinogenesis are not well understood. According to the multistep model of tumorigenesis 8,9 accumulating mutations in proto-oncogenes, DNA repair genes and tumor-suppressor genes are responsible for the malignant transformation of biliary epithelial cells. Disruption of the p53 and Rb tumor-suppressor pathways are the most common molecular events in cancer cells. 9 The most commonly altered tumor-suppressor gene in human cancers Tp5...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Inactivation of the INK4a/ARF locus and p53 in sporadic extrahepatic bile duct cancers and bile tract cancer cell lines

Caca

Feisthammel

Klee

et al. 2001

Intl Journal of Cancer

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“…Taniai et al 19 reported that functional point mutations in the p16INK4a promoter region likely contribute to the initiation/progression of cholangiocarcinoma in primary sclerosing cholangitis. Ahrendt et al 20 described the loss of heterozygosity (9p21 loss) and promoter methylation of p16INK4a in primary sclerosing cholangitis-associated cholangiocarcinoma, which may result in gene inactivation. The mutations in these studies were not analyzed with UFISH, but they deal with the same chromosome region as that of the 9p21 UFISH probe.…”

Section: Commentmentioning

confidence: 99%

The Utility of UroVysion Fluorescence In Situ Hybridization in Pancreatic Fine-Needle Aspiration Samples Directed and Obtained by Endoscopic Ultrasonography

Henkes

Patel

Rosenkranz

et al. 2013

Archives of Pathology &Amp; Laboratory Medicine

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N Context.-The diagnosis of pancreatic adenocarcinoma can be challenging for the pathologist. Endoscopic ultrasound-guided, fine-needle aspiration (EUS-FNA) can be used to obtain samples of pancreatic masses. UroVysion fluorescence in situ hybridization (UFISH) has been reported to increase the sensitivity and to be very specific for the diagnosis of adenocarcinoma when combined with cytology in the diagnosis of biliary brushings and washings.Objectives.-To determine the sensitivity and specificity of UFISH on tissues obtained from pancreatic lesions suggestive of adenocarcinoma obtained by EUS-FNA, compared against fine-needle aspiration (FNA) results. Additionally, to use patient follow-up data to evaluate UFISH results in FNA samples that showed significant atypia but did not meet the criteria for malignancy.Design.-Sixty consecutive cases of pancreatic EUS-FNA from our institution submitted for UFISH testing.Results.-Polysomic UFISH has a sensitivity of 93% and a specificity of 100% when compared against FNA results. Follow-up studies showed that adding UFISH to FNA increased the sensitivity for patients with true-positive results from 83% to 94% and increased specificity from 85% to 100%. For 7 patients with suspicious FNA results who had sufficient follow-up, UFISH was 100% sensitive and 100% specific.Conclusions.-UFISH can be used to confirm the diagnosis of malignancy in pancreatic adenocarcinoma. Because of the high specificity, polysomic UFISH may help establish a diagnosis of malignancy when the FNA features are suggestive of, but not conclusive for, malignancy. The most common cause for a false-negative UFISH result was insufficient numbers of malignant cells. (Arch Pathol Lab Med. 2013;137:64-71; doi: 10.5858/ arpa.2011-0241-OA) P ancreatic cancer is the fourth leading cause of cancerrelated death in the United States. In 2010, it was estimated that 6% of cancer deaths in males and 7% of cancer deaths in females were due to pancreatic cancer. The 5-year survival rate for all stages of pancreatic cancer is the lowest of all the major cancer sites.

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“…INK4a inactivation despite variable methylation frequencies (25)(26)(27)(28)(29)(30)(31)(32). This promoter region hypermethylation has been shown to be associated with a poor clinical outcome.…”

Section: Epigenetic Alterations In Ccamentioning

confidence: 99%

Epigenetic alterations associated with cholangiocarcinoma (Review)

Isomoto¹

2009

Oncol Rep

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Abstract. Cholangiocarcinoma (CCA) is a highly lethal malignant tumor arising from the biliary tract epithelium. Chronic inflammatory conditions, including primary sclerosing cholangitis, liver fluke infestation, and hepatolithiasis, are considered risk factors, but the cause is still unknown in most cases. Recent advances in molecular pathogenesis have highlighted the importance of epigenetic alterations, including promoter hypermethylation and histone deacetylation, in the process of cholangiocarcinogenesis. More recently, research interest has been focusing on microRNA (mir), a major subtype of non-coding RNA. Mir is highly conserved among species and regulates the expression of specific target genes by binding to the 3'-untranslated regions of messenger RNA.

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Chromosome 9p21 Loss and p16 Inactivation in Primary Sclerosing Cholangitis-Associated Cholangiocarcinoma

Cited by 82 publications

References 26 publications

Inactivation of the INK4a/ARF locus and p53 in sporadic extrahepatic bile duct cancers and bile tract cancer cell lines

Inactivation of the INK4a/ARF locus and p53 in sporadic extrahepatic bile duct cancers and bile tract cancer cell lines

The Utility of UroVysion Fluorescence In Situ Hybridization in Pancreatic Fine-Needle Aspiration Samples Directed and Obtained by Endoscopic Ultrasonography

Epigenetic alterations associated with cholangiocarcinoma (Review)

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