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

Abstract

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. H ere 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.

Up-to-Date Pathologic Classification and Molecular Characteristics of Intrahepatic Cholangiocarcinoma

“…Approximately 8–12% of iCCAs have been reported to have known pathogenic or possibly deleterious germline mutations, and the most commonly found germline-mutated genes are BRCA1 and BRCA2 , which are associated with DNA repair mechanism and hereditary cancer syndromes ( 109 – 112 ) ( Table 1 ). Other germline variants linked with iCCA include APC , an antagonist of the Wnt signaling pathway, BAP1 , which mediates deubiquitination, and mismatch repair mechanism-related genes, namely MLH1 and MSH2 ( 109 , 111 , 113 ). However, evidence regarding the association between known hereditary cancer syndromes and iCCA is currently not fully established and requires further investigation.…”

Exposure to Asbestos and Increased Intrahepatic Cholangiocarcinoma Risk: Growing Evidences of a Putative Causal Link

“…Similarly, a recent WES analysis on iCCA patients, categorized according to recognized risk factors for this disease and to the Italian National Mesothelioma Register (ReNaM) questionnaire for asbestos exposure, revealed a higher rate of BAP1 somatic mutations in asbestos-exposed patients compared to non-exposed (27% vs 5%, p-value = 0.0289) [ 23 ]. Furthermore, the first clinical case of a 47 years-old patient developing an iCCA in absence of risk factors, except for occupational exposure to low levels of asbestos for about 15 years, has been reported [ 24 ]. This patient, along with BAP1 loss of heterozygosity in tumor cells (a frequent genetic event in iCCA [ 25 ]), also carried a BAP1 germline mutation (c.255_255 + 6del).…”

Impact of Alternative Splicing Variants on Liver Cancer Biology

“…The mutations found in BAP1-TPDS patients affect ubiquitin carboxyl hydrolase (UCH) and nuclear localization signal (NLS) domains and create a non-functional truncated protein, disrupting BAP1 deubiquitinating activity and nuclear localization, both required for BAP1 tumor suppressor function [ 143 ]. Evidence for the relationship between germline mutations in 3′SS or 5′SS of exon 4 of BAP1 pre-mRNA and the development of iCCA has been reported [ 144 ].…”