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.

BRCA1相关蛋白1（BAP1 ）的种系突变定义了一种新型的遗传性癌症综合征，即BAP1肿瘤易感综合征（BAP1- TPDS），其特征是易患不同类型的癌症，包括间皮瘤，葡萄膜和皮肤黑色素瘤，肾细胞癌，以及基底细胞和鳞状细胞癌。目前，BAP1种系突变在肝内胆管癌（iCCA）发病机理中的作用尚不为人所知。在此，我们报道了第一例女性患者，该患者在47岁时发展出iCCA，并在BAP1的第4外显子的剪接位点携带了新的种系突变。基因（NM_004656.4：c.255_255 + 6del）。准确的回忆记录表明，除了低职业暴露于石棉外，没有与iCCA发育相关的危险因素。在肿瘤组织中，BAP1测序，多重连接依赖性探针扩增和免疫组织化学分析显示杂合性丧失和核表达不足，这表明BAP1野生型等位基因和功能蛋白在癌细胞中丢失，这与经典的两次打击一致抑制基因的模型。需要进一步的研究以确认iCCA是否可能包含在BAP1- TPDS癌症表型中，以及最低限度的石棉暴露是否可以促进携带BAP1的个体发生这种恶性肿瘤 种系突变。