Intrahepatic cholangiocarcinoma development in a patient with a novel BAP1 germline mutation and low exposure to asbestos

G Brandi, M Deserti, A Palloni, D Turchetti, R Zuntini, F Pedica, G Frega, S De Lorenzo, F Abbati, A Rizzo, M Di Marco, F Massari, S Tavolari

Research output: Contribution to journalArticlepeer-review


BRCA1 associated protein-1 (BAP1) germline mutations define a novel hereditary cancer syndrome, namely BAP1 tumor predisposition syndrome (BAP1-TPDS), characterized by an increased susceptibility to develop different cancer types, including mesothelioma, uveal and cutaneous melanoma, renal cell carcinoma, and basal cell and squamous cell carcinoma. Currently, the role of BAP1 germline mutations in intrahepatic cholangiocarcinoma (iCCA) pathogenesis is less known. Here we report the first clinical case of a female patient who developed an iCCA when she was 47-years-old and was found to carry a novel germline mutation at a splicing site of exon 4 in BAP1 gene (NM_004656.4: c.255_255+6del). An accurate anamnesis revealed the absence of risk factors linked to iCCA development, except for a low occupational exposure to asbestos. In tumor tissue, BAP1 sequencing, multiplex ligation-dependent probe amplification and immunoistochemistry showed the loss of heterozygosity and lack of nuclear expression, suggesting that BAP1 wild-type allele and functional protein were lost in cancer cells, in line with the classical two-hit model of tumor suppressor genes. Further studies are needed to confirm whether iCCA may be included into BAP1-TPDS cancer phenotypes and whether minimal asbestos exposure may facilitate the development of this malignancy in individuals carrying BAP1 germline mutations.

Original languageEnglish
Pages (from-to)57-62
Number of pages6
JournalCancer genetics
Publication statusPublished - Oct 2020


  • Asbestos/adverse effects
  • Bile Duct Neoplasms/etiology
  • Carcinogens
  • Cholangiocarcinoma/etiology
  • Female
  • Genetic Predisposition to Disease
  • Germ-Line Mutation
  • Humans
  • Middle Aged
  • Prognosis
  • Tumor Suppressor Proteins/genetics
  • Ubiquitin Thiolesterase/genetics


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