title: Loss of BAP1 Expression Occurs Frequently in Intrahepatic Cholangiocarcinoma.
abstract: BRCA1-associated protein 1 (BAP1) is a deubiquitinating enzyme that functions as a tumor suppressor gene. Double hit BAP1 inactivation has been reported in a range of tumor types, including intrahepatic cholangiocarcinoma (ICC), sometimes in association with germline mutation.We performed immunohistochemistry for BAP1 on a well-characterized cohort of 211 ICC patients undergoing surgical resection with curative intent at 3 institutions based in 3 different countries. The median age at diagnosis was 65 years (range, 36.5-86) and 108 (51%) were men. Negative staining for BAP1 (defined as completely absent nuclear staining in the presence of positive internal controls in nonneoplastic cells) occurred in 55 ICCs (26%). BAP1 loss predicted a strong trend toward improved median survival of 40.80 months (95% CI, 28.14-53.46) versus 24.87 months (95% CI, 18.73-31.01), P = 0.059). In a multivariate model including age, sex, BAP1 status, tumor stage, tumor grade, lymphovascular invasion, and tumor size, female sex was associated with improved survival (hazard ratio [HR] 0.54; 95% CI, 0.34-0.85), while advanced tumor stage and lymphovascular invasion (HR 1.89; 95% CI, 1.09-3.28) correlated with decreased survival. In a multivariate analysis, high grade tumors were associated with BAP1 loss (odds ratio [OR] 3.32; 95% CI, 1.29-8.55), while lymphatic invasion was inversely associated with BAP1 loss (OR 0.36; 95% CI, 0.13-0.99).In conclusion, we observed a trend toward improved prognosis in ICC associated with absent expression of BAP1 and an association of BAP1 loss with higher histological grade and absent lymphatic invasion. Female sex was associated with improved survival while advanced tumor stage and lymphatic invasion were associated with decreased survival.
authors.affiliation: From the Cancer Diagnosis and Pathology Research Group, Kolling Institute of Medical Research, St Leonards, NSW, Australia (JA, LS, AC, MT, NW, MF, CWT, AJG); Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany (BG, MR, AS, WW, PS); Department of Anatomical Pathology, Royal North Shore Hospital, St Leonards (LS, AC, MF, AJG); Histopath Pathology, North Ryde (CWT); Sydney Medical School, University of Sydney, Sydney (JA,CWT, RCS, AM, JSS, TJH, AJG); Upper Gastrointestinal Surgical Unit, Royal North Shore Hospital, North Shore Private Hospital, St Leonards; Discipline of Surgery, University of Sydney (AM, JSS, TJH); Macquarie University Hospital, Macquarie University, Sydney (JSS); Department of Anatomical Pathology, SYDPATH, St Vincents Hospitals, Darlinghurst, NSW, Australia (AC); Department of Pathology and Diagnostics, ARC-NET Research Center (RTL, NS, AS); Department of Surgery, University and Hospital Trust of Verona, Verona, Italy (AR); and Sydney Vital Translational Research Centre, Royal North Shore Hospital, Pacific Highway, St Leonards, NSW, Australia (AJG).
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authors.lastname: Andrici
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authors.initials: B
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authors.forename: Loretta
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authors.lastname: Sioson
authors.forename: Adele
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authors.lastname: Clarkson
authors.forename: Marcus
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authors.lastname: Renner
authors.forename: Albrecht
authors.initials: A
authors.lastname: Stenzinger
authors.forename: Michael
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authors.forename: Nicole
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authors.lastname: Watson
authors.forename: Mahtab
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authors.lastname: Farzin
authors.forename: Christopher W
authors.initials: CW
authors.lastname: Toon
authors.forename: Ross C
authors.initials: RC
authors.lastname: Smith
authors.forename: Anubhav
authors.initials: A
authors.lastname: Mittal
authors.forename: Jaswinder S
authors.initials: JS
authors.lastname: Samra
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Hugh
authors.forename: Angela
authors.initials: A
authors.lastname: Chou
authors.forename: Rita T
authors.initials: RT
authors.lastname: Lawlor
authors.forename: Wilko
authors.initials: W
authors.lastname: Weichert
authors.forename: Peter
authors.initials: P
authors.lastname: Schirmacher
authors.forename: Nicola
authors.initials: N
authors.lastname: Sperandio
authors.forename: Andrea
authors.initials: A
authors.lastname: Ruzzenente
authors.forename: Aldo
authors.initials: A
authors.lastname: Scarpa
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Gill
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001650:Bile Duct Neoplasms / Q000378:metabolism* / Q000401:mortality* / Q000473:pathology; D001653:Bile Ducts, Intrahepatic / Q000473:pathology; D014408:Biomarkers, Tumor / Q000378:metabolism; D018281:Cholangiocarcinoma / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D005260:Female; D005858:Germany / Q000453:epidemiology; D006801:Humans; D007558:Italy / Q000453:epidemiology; D008297:Male; D008875:Middle Aged; D009517:New South Wales / Q000453:epidemiology; D010641:Phenotype; D012189:Retrospective Studies; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D043222:Ubiquitin Thiolesterase / Q000378:metabolism*
chemical_list: C400134:BAP1 protein, human; D014408:Biomarkers, Tumor; D025521:Tumor Suppressor Proteins; D043222:Ubiquitin Thiolesterase