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

Our plain-English summary of Intrahepatic cholangiocarcinoma development in a patient with a novel BAP1 germline mutation and low exposure to asbestos, by G. Brandi, M. Deserti, A. Palloni, et al (Cancer Genetics, 2020).

The study

• Authors: 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
• Journal: Cancer Genetics
• Published: 2020;248-249:57-62
• Type of article: Case report
• Cited by: 15 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

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.

Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.

In plain English

This case report described one woman, treated at a university hospital in Bologna, Italy, who was diagnosed at age 47 with intrahepatic cholangiocarcinoma, a cancer of the bile ducts inside the liver. Using a standardized questionnaire, the authors found no known risk factors for this cancer except low occupational asbestos exposure during about 15 years working in industrial kitchens. The article did not name a fiber type. Despite surgery and chemotherapy, the cancer spread, and she died in October 2018. Several relatives had cancer, including a brother with kidney cancer and pleural mesothelioma and an uncle with uveal melanoma, prompting genetic testing. Blood tests showed a previously undescribed germline change in her BAP1 gene, meaning one present in her normal cells. Tests on her tumor showed that the remaining normal copy of the gene was lost and that BAP1 protein was missing from tumor cell nuclei. The authors concluded that this was the first clinical evidence of a possible link between BAP1 mutations and this cancer in a person with low asbestos exposure, and called for further studies. No relatives were available for testing.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: case report (one patient)
• Who was studied: One woman aged 47 at presentation in April 2017, from a university hospital in Bologna, Italy, diagnosed with intrahepatic cholangiocarcinoma
• Exposure: Low occupational exposure to asbestos, assessed with a standardized questionnaire, during about 15 years of work in industrial kitchens. No fiber type was specified. No other risk factors for intrahepatic cholangiocarcinoma were found.
• Main results:
  • The patient was diagnosed with intrahepatic cholangiocarcinoma, stage pT3N0M0 (stage IIIA), after liver surgery in June 2017.
  • Despite three lines of chemotherapy and palliative radiotherapy, the disease progressed, and the patient died in October 2018.
  • The family history, based on the patient's report, included a brother with kidney cancer and pleural mesothelioma and an uncle with uveal melanoma.
  • Blood testing found a novel heterozygous (one-copy) germline BAP1 mutation at a splice site of exon 4 (NM_004656.4: c.255_255+6del). Its transmission within the family could not be assessed.
  • Tumor tissue showed loss of heterozygosity of BAP1. The authors reported that MLPA analysis showed whole gene deletion.
  • In the patient's tumor, BAP1 protein staining was negative in cell nuclei, with faint staining in the cytoplasm.
• The authors' conclusion: The authors concluded that they reported the first clinical evidence of a possible link between BAP1 germline mutations and intrahepatic cholangiocarcinoma in a patient exposed to low levels of asbestos. They said further studies are needed to confirm whether this cancer belongs to the BAP1 tumor predisposition syndrome and whether minimal asbestos exposure may facilitate its development in mutation carriers.
• Limitations the authors state:
  • No other relatives were available for genetic testing, so the authors could not check whether the mutation segregated with cancer in the family.
  • The functional role of the novel mutation is unknown.

Topics

Medical terms in this study, explained in our Lexicon: BAP1, Germline Mutation, BAP1 Tumor Predisposition Syndrome, Mesothelioma, Carcinoma, Squamous Cell Carcinoma, Occupational Exposure, Tumor Suppressor Gene.

Related studies

• Asbestos exposure as an additional risk factor for small duct intrahepatic cholangiocarcinoma: a pilot study — F. Vasuri, M. Deserti, et al. (2023)
• Germline BAP1 mutations predispose also to multiple basal cell carcinomas — A. de la Fouchardière, O. Cabaret, et al. (2015)
• A recurrent germline BAP1 mutation and extension of the BAP1 tumor predisposition spectrum to include basal cell carcinoma — K.A. Wadt, L.G. Aoude, et al. (2015)
• Germline mutation of Bap1 accelerates development of asbestos-induced malignant mesothelioma — J. Xu, Y. Kadariya, et al. (2014)
• CDKN2A and BAP1 germline mutations predispose to melanoma and mesothelioma — M. Betti, A. Aspesi, et al. (2016)
• Prevalence and Preliminary Validation of Screening Criteria to Identify Carriers of Germline BAP1 Mutations — M.G. Zauderer, G. Jayakumaran, et al. (2019)

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