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

doi:10.1016/j.cancergen.2020.10.001

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. 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.

Highlights

Cholangiocarcinoma (CCA) is the second most common primary liver cancer after hepatocellular carcinoma and arises from the epithelial cells of the intrahepatic and extrahepatic biliary tree [1]
To date the whole spectrum of the cancer types associated with BRCA1 associated protein-1 (BAP1)-TPDS still remains to be fully characterized; notwithstanding, it is becoming clear that besides mesothelioma, uveal and cutaneous melanomas, renal cell carcinomas, basal cell and squamous cell carcinomas, other tumors may be linked to this syndrome [4]
In the present study we report the clinical case of a female patient who developed an intrahepatic cholangiocarcinoma (iCCA) when she was 47-years-old and who was found to carry a novel heterozygous germline mutation in the ubiquitin carboxyl hydrolase (UCH) domain of BAP1 gene (NM_004656.4: c.255_255+6del)

Summary

Introduction

Cholangiocarcinoma (CCA) is the second most common primary liver cancer after hepatocellular carcinoma and arises from the epithelial cells of the intrahepatic (iCCA) and extrahepatic (eCCA) biliary tree [1]. The tumor suppressor function of BAP1 has been ascribed to its ability to maintain genome integrity, and to regulate mitochondrial apoptosis and ferroptosis upon exposure to cellular stress conditions ([3,9,10]). Impairment of these cellular mechanisms makes BAP1 mutant cells more prone to accumulate DNA mutations and may account for the high cancer rate observed in individuals carrying BAP1 germline mutations. To date the whole spectrum of the cancer types associated with BAP1-TPDS still remains to be fully characterized; notwithstanding, it is becoming clear that besides mesothelioma, uveal and cutaneous melanomas, renal cell carcinomas, basal cell and squamous cell carcinomas, other tumors may be linked to this syndrome [4]

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Results

Conclusion