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

• Published in: Cancer genetics 2020-10, Vol.248-249, p.57-62
• Main Authors: Brandi, G, Deserti, M, Palloni, A, Turchetti, D, Zuntini, R, Pedica, F, Frega, G, De Lorenzo, S, Abbati, F, Rizzo, A, Di Marco, M, Massari, F, Tavolari, S
• Format: Article
• Language: English
• Subjects: Asbestos; Asbestos - adverse effects; BAP1 germline mutation; Bile Duct Neoplasms - etiology; Bile Duct Neoplasms - pathology; Carcinogens; Cholangiocarcinoma; Cholangiocarcinoma - etiology; Cholangiocarcinoma - pathology; Female; Genetic Predisposition to Disease; Germ-Line Mutation; Humans; Middle Aged; Prognosis; Tumor Suppressor Proteins - genetics; Ubiquitin Thiolesterase - genetics
• ISSN: 2210-7762; 2210-7770
• DOI: 10.1016/j.cancergen.2020.10.001

•Despite several pathological conditions have been clearly established as risk factors for intrahepatic cholangiocarcinoma (iCCA), the role of inherited genetic disorders in the pathogenesis of this disease is less known.•Here we report the first clinical case of a patient, occupationally exposed to low levels of asbestos, who developed an iCCA at a young age and was found to carry a novel heterozygous germline mutation at a splicing site of BAP1 gene (NM_004656.4: c.255_255+6del).•Although further epidemiological studies are needed to confirm whether iCCA may be included into the spectrum of BAP1 tumor predisposition syndrome (BAP1-TPDS) cancer phenotypes, these findings suggest that low asbestos exposure could facilitate the development of this malignancy among individuals carrying BAP1 germline mutations. 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.