Mutations of the BRAF gene in cholangiocarcinoma but not in hepatocellular carcinoma

Tannapfel, Andrea; Sommerer, Florian; Benicke, Markus; Katalinic, Alexander; Uhlmann, Dirk; Witzigmann, Helmut; Hauss, Johann; Wittekind, Christian

doi:10.1136/gut.52.5.706

Cited by 320 publications

(259 citation statements)

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“…Our findings are in line with recently published smaller series detecting BRAF mutations in 1% to 4% of evaluated cases. [26][27][28] We cannot confirm the exceedingly high mutation rates detected in early BRAF studies of European cohorts, 29,30 and conclude that the previously assumed regional difference in the genetics of biliary tract cancer in Europe versus the Americas is not existent. 2 Our data further demonstrate that BRAF mutations are restricted to intrahepatic cholangiocarcinomas and account for 3% in this subgroup.…”

Section: Discussionmentioning

confidence: 56%

BRAF V600E-specific immunohistochemistry reveals low mutation rates in biliary tract cancer and restriction to intrahepatic cholangiocarcinoma

et al. 2014

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BRAF mutations have emerged as an important predictive biomarker for metastasized melanoma. Other types of cancer may also benefit from BRAF mutation-targeted therapies. In biliary tract cancer, reported BRAF mutation rates are highly controversial, ranging from 0 to 33% in adenocarcinoma of the gallbladder and 0 to 22% in cholangiocarcinoma. We here analyzed tissue microarrays of a large cohort of biliary tract cancer (n ¼ 377) including 159 intrahepatic cholangiocarcinomas, 149 extrahepatic cholangiocarcinomas, and 69 adenocarcinomas of the gallbladder for BRAF V600E mutation using a highly sensitive immunohistochemical screening approach implementing the BRAF V600E protein-specific antibody VE1. All VE1-positive cases as well as 42 VE1-negative cases were additionally analyzed by Sanger sequencing. In total, only 5 VE1-positive cases were detected (5/377; 1%). BRAF V600E mutation was confirmed by direct sequencing in all cases. All 5 mutated cases were intrahepatic cholangiocarcinomas (5/159; 3%). None of the extrahepatic cholangiocarcinomas and adenocarcinomas of the gallbladder were VE1 positive. Apart from the subtype restriction of BRAF V600E mutation to intrahepatic cholangiocarcinoma and a female predominance (4 female, 1 male), no significant correlation with clinicopathological data and patient outcome was detected. In conclusion, we demonstrate that BRAF V600E mutation is a rare event in biliary tract cancer, accounting for only 1% of all subtypes, and is restricted to intrahepatic cholangiocarcinoma. In addition, we demonstrate that VE1 immunohistochemistry is a feasible approach to routinely screen for BRAF V600E mutation in biliary tract cancer patients, thereby facilitating the detection of rare patients who may benefit from BRAF mutation-targeted therapies.

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Section: Discussionmentioning

confidence: 56%

BRAF V600E-specific immunohistochemistry reveals low mutation rates in biliary tract cancer and restriction to intrahepatic cholangiocarcinoma

et al. 2014

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“…After microdissection, 22,23 methylation-specific PCR (MSP) was used to investigate the methylation status of the promoter region of the BLU, RASSF1A and SEMA3B genes. Microdissection was performed as described previously.…”

Section: Methylation Analysismentioning

confidence: 99%

“…Microdissection was performed as described previously. 22,23 After an initial bisulfite treatment to modify the DNA, PCR was performed to distinguish methylated from unmethylated DNA as described by Herman et al 24 Briefly, 2 mg of genomic DNA was denatured with 0.3 M NaOH; 10 mM hydroquinone and 3 M sodium bisulfite were added and incubated for 16 hr at 508C. Afterward, modified DNA was purified using the Wizard DNA purification resin (Promega, Madison, WI) followed by desulfonating in 0.3 M NaOH and subsequent ethanol precipitation and resuspension in 30-50 ml water.…”

Section: Methylation Analysismentioning

confidence: 99%

Allele loss and epigenetic inactivation of 3p21.3 in malignant liver tumors

Tischoff

Markwarth

Witzigmann

et al. 2005

Intl Journal of Cancer

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Previously, the RASSF1A, BLU and SEMAPHORIN 3B (SEMA3B) candidate tumor suppressor genes on chromosome 3p21.3 were found to be inactivated and downregulated by genetic and epigenetic changes in lung cancer. We analyzed the methylation status of RASSF1A, BLU and SEMA3B in 35 hepatocellular carcinomas (HCCs) and 15 cholangiocarcinomas (CCs) by methylationspecific PCR and loss of heterozygosity (LOH) at 3p21.3 after microdissection. The presence of mRNA transcripts was confirmed by semiquantitative PCR. SEMA3B hypermethylation was found in 29/35 HCCs (83%) and in all (15/15) patients with CC. BLU promoter hypermethylation was detected in 7/35 (20%) HCCs and 3/15 (20%) CCs. In 2 corresponding specimens of hepatitis B virus-related liver cirrhosis, BLU methylation was also observed, but not in uninvolved normal liver tissue. RASSF1A was methylated in 21/35 HCCs (60%) and in 10/15 CCs (67%). LOH at 3p21.3 occurred in 8/35 (23%) HCCs and 3/15 (20%) CCs. The presence of hypermethylation was statistically associated with LOH of SEMA3B and correlated with downregulation of mRNA transcripts. SEMA3B transcripts increased upon treatment of HCC cell lines with the demethylation compound 5-aza-2-deoxycytidine. In conclusion, our data indicate that 2-hit gene silencing of SEMA3B through epigenetic changes and allele loss is a common and important event in the carcinogenesis of malignant liver tumors. ' 2005 Wiley-Liss, Inc.Key words: hepatocellular carcinoma; cholangiocarcinoma; methylation; loss of heterozygosity; BLU; SEMA3B; RASSF1A Primary liver cancer is one of the most frequent carcinomas worldwide. Besides hepatocellular carcinoma (HCC), accounting for 80-90% of all primary liver cancers, cholangiocarcinoma (CC) is the second most common primary hepatic malignancy. The short arm of chromosome 3 has been shown to exhibit loss of heterozygosity (LOH) in several types of cancer, including ovarian, kidney, lung, nasopharyngeal and also liver cancer. 1,2 In particular, overlapping homozygous deletions in lung cancers have been identified in region 3p21.3. 3,4 In HCC, LOH of chromosome 3p occurred in about 30% of the patients. 5,6 Several genes located on chromosome 3p have been studied in HCC as well as CC and include RASSF1A on 3p21.31, FHIT at 3p14.2, RIZ1, VHL at 3p25. 7-10 These results directed an intensive search for possible tumor suppressor genes located in the 3p21 region for one or more genes that could function as gatekeepers in molecular pathogenesis of human cancers. A group of candidate tumor suppressor genes (designated BLU, SEMAPHORIN 3B, or RASSF1A) has recently been mapped to this critical gene-rich region. 2,[11][12][13] SEMAPHORIN 3B (SEMA3B) is a member of the semaphorin family, which is also located on 3p21.3. Semaphorins are a family of signaling molecules initially identified to play a role in axonal guidance and can be classified as either membrane-bound (classes 1, 4, 5 and 6) or secreted (classes 2 and 3). 14 The receptors for the class 3 semaphorins are also known as neuropilin receptors. The intr...

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“…The MAPK/ERK pathway is essential and critical for hepatic progenitor cell proliferation [41]. A report showed that disruption of the RAF/ MEK/MAPK pathway by a RAS or BRAF mutation was detected in more than 60 % of cholangiocarcinomas, indicating that these pathways are important in cholangiocarcinoma carcinogenesis [57]. Interestingly, it is a relatively specific event in cholangiocarcinoma rather than in hepatocellular carcinoma [57].…”

Section: Raf/mek/mapk Signaling Pathwaymentioning

confidence: 99%

Recent advances in cancer stem cell research for cholangiocarcinoma

Kokuryo

Yokoyama

Nagino

2012

J Hepato Biliary Pancreat

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Cancer stem cells have been identified as cells with the capacity to self‐renew and differentiate into multiple lineages of human malignancies. Cholangiocarcinoma is one of the most difficult intra‐abdominal malignancies that can be treated using a surgical approach. Chemotherapy in addition to surgery is necessary to improve patient survival. However, its clinical benefit is limited, and, to date, no other effective anticancer drug is available for this disease. Several reports have shown the existence of cholangiocarcinoma stem cells. Cell surface antigens such as CD133, CD24, EpCAM, CD44, and others have been used to isolate cholangiocarcinoma stem cells. In general, enhanced expression of these markers in resected specimens of cholangiocarcinoma was associated with malignant potential. Distinct and specific pathways are expected to be present in cancer stem cells compared to other cancer cells that have no stem cell properties. To date, reports showing possible signaling pathways in cholangiocarcinoma stem cells are limited. More research is anticipated. Targeting therapies for surface molecular markers or specific signaling pathways of cholangiocarcinoma stem cells may be important in order to change the clinical outcome of patients with this disease. However, no clinical trial has been performed so far. This review will focus on the markers and signaling pathways used to define cholangiocarcinoma stem cells. A novel therapeutic approach of targeting cholangiocarcinoma stem cells will also be discussed.

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Mutations of the BRAF gene in cholangiocarcinoma but not in hepatocellular carcinoma

Cited by 320 publications

References 20 publications

BRAF V600E-specific immunohistochemistry reveals low mutation rates in biliary tract cancer and restriction to intrahepatic cholangiocarcinoma

BRAF V600E-specific immunohistochemistry reveals low mutation rates in biliary tract cancer and restriction to intrahepatic cholangiocarcinoma

Allele loss and epigenetic inactivation of 3p21.3 in malignant liver tumors

Recent advances in cancer stem cell research for cholangiocarcinoma

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