title: BRAF V600E-specific immunohistochemistry reveals low mutation rates in biliary tract cancer and restriction to intrahepatic cholangiocarcinoma.
abstract: 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=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.
authors.affiliation: Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Goeppert
authors.affiliation: Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Lena
authors.initials: L
authors.lastname: Frauenschuh
authors.affiliation: Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Marcus
authors.initials: M
authors.lastname: Renner
authors.affiliation: Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Roessler
authors.affiliation: Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Albrecht
authors.initials: A
authors.lastname: Stenzinger
authors.affiliation: Institute of Pathology, Charité Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Frederick
authors.initials: F
authors.lastname: Klauschen
authors.affiliation: Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Arne
authors.initials: A
authors.lastname: Warth
authors.affiliation: Department of Neuroradiology, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Monika Nadja
authors.initials: MN
authors.lastname: Vogel
authors.affiliation: Department of General Visceral and Transplantation Surgery, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Arianeb
authors.initials: A
authors.lastname: Mehrabi
authors.affiliation: Department of General Visceral and Transplantation Surgery, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Mohammadreza
authors.initials: M
authors.lastname: Hafezi
authors.affiliation: Department of Neuropathology, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Katja
authors.initials: K
authors.lastname: Boehmer
authors.affiliation: 1] Department of Neuropathology, University Hospital Heidelberg, Heidelberg, Germany [2] Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: von Deimling
authors.affiliation: Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Schirmacher
authors.affiliation: Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Wilko
authors.initials: W
authors.lastname: Weichert
authors.affiliation: 1] Department of Neuropathology, University Hospital Heidelberg, Heidelberg, Germany [2] Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: David
authors.initials: D
authors.lastname: Capper
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001650:Bile Duct Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D001653:Bile Ducts, Intrahepatic / Q000378:metabolism* / Q000473:pathology; D018281:Cholangiocarcinoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D009154:Mutation; D059645:Mutation Rate; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics / Q000378:metabolism*; D046888:Tissue Array Analysis
chemical_list: C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf