Expanding the clinical phenotype of hereditary BAP1 cancer predisposition syndrome, reporting three new cases

Our plain-English summary of Expanding the clinical phenotype of hereditary BAP1 cancer predisposition syndrome, reporting three new cases, by R. Pilarski, C.M. Cebulla, J.B. Massengill, et al (Genes, Chromosomes & Cancer, 2014).

The study

• Authors: R. Pilarski, C.M. Cebulla, J.B. Massengill, K. Rai, T. Rich, L. Strong, B. McGillivray, M.J. Asrat, F.H. Davidorf, M.H. Abdel-Rahman
• Journal: Genes, Chromosomes & Cancer
• Published: 2014;53(2):177-82
• Type of article: Case report
• Cited by: 91 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

The clinical phenotype of BAP1 hereditary cancer predisposition syndrome (MIM 614327) includes uveal melanoma (UM), cutaneous melanoma (CM), renal cell carcinoma (RCC), and mesothelioma. However, the frequency of the syndrome in patients with UM and the association with other cancers are still not clear. In this study, we screened 46 previously untested, unrelated UM patients with high risk for hereditary cancer for germline mutation in BAP1. We also studied four additional patients with a personal or family history suggestive of BAP1 hereditary cancer syndrome. We identified three patients with germline pathogenic mutations (c.2050 C>T, pGln684*; c.1182C>G, p.Tyr394*, and c.1882_1885delTCAC, p. Ser628Profs*8) in BAP1. Two of these three patients presented with UM and the third with a metastatic adenocarcinoma likely from a hepatic cholangiocarcinoma. Reported family histories included UM, mesothelioma, RCC, CM, and several other internal malignancies. The results of this study confirm the association between germline BAP1 mutation and predisposition to UM, mesothelioma, CM and RCC. However, other cancers, such as cholangiocarcinoma and breast carcinoma may be part of the phenotype of this hereditary cancer predisposition syndrome. In addition, the results support the existence of other candidate genes in addition to BAP1 contributing to hereditary predisposition to UM.

Copyright © 2013 Wiley Periodicals, Inc.

In plain English

Researchers at The Ohio State University tested 50 patients for inherited (germline) mutations in the BAP1 gene. Forty-six had uveal melanoma, a melanoma of the eye, along with features suggesting hereditary cancer. Four others had personal or family histories suggesting BAP1 cancer syndrome. Three patients carried disease-causing BAP1 mutations. Four had variants of uncertain significance that the authors judged likely not disease-causing. Two of the three carriers had uveal melanoma. The third, a man, had a cancer that had spread, likely from a bile duct cancer in the liver (cholangiocarcinoma). Their families included uveal melanoma, mesothelioma, kidney cancer, skin melanoma and other cancers. In one family, a relative carrying the mutation had a peritoneal tumor first diagnosed as a serous carcinoma. Slide review and staining confirmed it was mesothelial, and the authors described it as a well-differentiated papillary mesothelioma. The article did not report asbestos exposure histories. The authors concluded that BAP1 mutations appear to predispose to uveal melanoma, skin melanoma, mesothelioma and kidney cancer, and that cholangiocarcinoma and breast cancer may be part of the syndrome. They noted that DNA and tissue from other relatives were unavailable.

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: Genetic screening study with case descriptions of three families carrying BAP1 mutations
• Who was studied: 50 patients not included in the group's earlier study: 34 women and 16 men, average age 46 years (range 15 to 85). Forty-six had uveal melanoma with high-risk features. Four had personal or family histories highly suggestive of BAP1 cancer syndrome. Testing was done under an Ohio State University research protocol.
• Exposure: Inherited (germline) BAP1 gene mutations, found by DNA sequencing of blood samples. Asbestos exposure was not studied or reported. In the discussion, the authors stated that well-differentiated papillary mesothelioma is not related to asbestos exposure.
• Main results:
  • Of the 50 patients tested, 3 had disease-causing BAP1 mutations and 4 had variants of uncertain significance.
  • Computer prediction suggested the four uncertain variants were likely not disease-causing.
  • Family FUM064: the woman tested first had uveal melanoma at age 41. Mesothelioma had been diagnosed in three of her father's relatives.
  • Family FUM064: a cousin carrying the same mutation had a peritoneal tumor first diagnosed as a serous carcinoma. Slide review and staining confirmed it was mesothelial (well-differentiated papillary mesothelioma). The tumor cells showed loss of BAP1 in the cell nucleus.
  • Family FUM103: a man had a cancer that had spread to his rib, and a liver lesion. Staining suggested it most likely began as a cholangiocarcinoma. His family history included mesothelioma.
  • Family FUM104: a deceased woman with skin melanoma, uveal melanoma and colorectal cancer carried a mutation. So did her son, who had kidney cancer, and a great maternal aunt, who had invasive breast cancer. Mesothelioma occurred in multiple family members.
  • The authors stated that this study confirms their earlier finding that BAP1 mutations are uncommon in uveal melanoma patients.
• The authors' conclusion: The authors concluded that germline BAP1 mutations appear to predispose to uveal melanoma, cutaneous melanoma, mesothelioma and renal cell carcinoma. They added that cholangiocarcinoma and breast carcinoma may be part of the syndrome, and that other genes likely contribute to hereditary uveal melanoma.
• Limitations the authors state:
  • No tissue was available from the liver lesion to confirm the suspected cholangiocarcinoma.
  • DNA and tumor tissue were not available for other relatives, so their mutation status was unknown.
  • The data were too limited to estimate lifetime risks or average age at diagnosis for the associated cancers.
  • It is not established whether other cancers in carriers' families were coincidental or caused by the mutation.

Topics

Medical terms in this study, explained in our Lexicon: BAP1, Carcinoma, Mesothelioma, Germline Mutation, Adenocarcinoma, BAP1 Tumor Predisposition Syndrome.

Related studies

• Histomorphologic spectrum of BAP1 negative melanocytic neoplasms in a family with BAP1-associated cancer susceptibility syndrome — Z. Marušić, M. Buljan, et al. (2015)
• Comprehensive review of BAP1 tumor predisposition syndrome with report of two new cases — K. Rai, R. Pilarski, et al. (2016)
• Histologically Diverse BAP1-Deficient Melanocytic Tumors in a Patient With BAP1 Tumor Predisposition Syndrome — A. Louw, J. Creaney, et al. (2020)
• Connecting molecular pathways to hereditary cancer risk syndromes — J.R. Testa, D. Malkin, et al. (2013)
• Analysis of BAP1 Germline Gene Mutation in Young Uveal Melanoma Patients — C.M. Cebulla, E.M. Binkley, et al. (2015)
• Post-thoracotomy neuralgic amyotrophy in a patient with BAP1 tumor predisposition syndrome: Multimodality longitudinal follow-up — N. Jazebi, N. Dargah-Zada, et al. (2021)

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