Comprehensive review of BAP1 tumor predisposition syndrome with report of two new cases

Our plain-English summary of Comprehensive review of BAP1 tumor predisposition syndrome with report of two new cases, by K. Rai, R. Pilarski, C.M. Cebulla, et al (Clinical Genetics, 2016).

The study

• Authors: K. Rai, R. Pilarski, C.M. Cebulla, M.H. Abdel-Rahman
• Journal: Clinical Genetics
• Published: 2016;89(3):285-94
• Type of article: Case report, Review
• Cited by: 186 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

The BRCA1-associated protein-1 (BAP1) tumor predisposition syndrome (BAP1-TPDS) is a recently identified hereditary cancer syndrome. Germline mutations in this tumor suppressor gene predispose families to the development of various malignancies. The molecular functions of the gene as well as the clinical phenotype of the syndrome are still being clarified. We sought to conduct a comprehensive review of published research into BAP1-TPDS to more thoroughly delineate the clinical implications of germline BAP1 mutations. We also report two additional families with germline BAP1 mutations. Current evidence demonstrates that germline BAP1 mutations predispose families to uveal melanoma, renal cell carcinoma, malignant mesothelioma, cutaneous melanoma, and possibly to a range of other cancers as well. Some of these cancers tend to be more aggressive, have a propensity to metastasize, and onset earlier in life in patients with BAP1 mutations as compared to non-predisposed patients with equivalent cancers. Although further research is necessary, this information can aid in the management, diagnosis, and therapy of these patients and their families, and highlights the importance of genetic counseling.

© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

In plain English

This article reviewed published reports on BAP1 tumor predisposition syndrome, an inherited cancer condition caused by germline BAP1 gene mutations, and described two new families. The authors searched PubMed for English-language articles published through 18 May 2015, and 27 of them described patients with germline BAP1 mutations. Counting the new families, 57 families with 174 mutation carriers had been reported. Of the 174 carriers, 54 (31%) had uveal melanoma, 39 (22%) malignant mesothelioma, 23 (13%) cutaneous melanoma and 18 (10%) renal cell carcinoma. Of the 39 with mesothelioma, 26 had pleural, 12 peritoneal and 1 both, and all 13 with peritoneal disease were female. Median age at mesothelioma onset was 56 years, compared with a general-population figure of 74 that the authors cited. In the new families, the two index patients developed mesothelioma at ages 71 and 60. The authors wrote that the role of asbestos in this syndrome is unclear. They concluded that these four cancers and atypical Spitz tumors are clearly part of the syndrome. They found no clear link between mutation type and cancer type. They cautioned that the reported penetrance (148 of 174 carriers with cancer) is likely inflated by testing bias.

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: Literature review of published reports of germline BAP1 mutation carriers, plus a report of two new families tested by the authors
• Who was studied: 57 families with 174 reported carriers of germline BAP1 mutations (67 male, 95 female, 12 with no sex reported), drawn from 27 published articles plus two new families (FUM124 and FUM128) studied at The Ohio State University
• Exposure: Inherited (germline) mutations in the BAP1 gene. Asbestos exposure was not studied; the authors stated that its role in this syndrome is unclear.
• Main results:
  • 39 of 174 reported germline BAP1 mutation carriers (22%) had been diagnosed with malignant mesothelioma, with a median age of onset earlier than in the general population
  • Median age of mesothelioma onset among BAP1 carriers was 56 years (range 34 to 85), compared with 74 years in the general-population figure the authors cited (Table 1)
  • Among the 39 carriers with mesothelioma, 26 (67%) had pleural mesothelioma, 12 (31%) had peritoneal mesothelioma, and 1 had both
  • All 13 carriers with peritoneal mesothelioma were female
  • 14 of the carriers with mesothelioma (36%) had been diagnosed with another primary cancer, excluding cases of multiple mesothelioma
  • 54 of 174 carriers (31%) had uveal melanoma, the most common cancer in the group
  • 23 of 174 carriers (13%) had cutaneous melanoma
  • 18 of 174 carriers (10%) had renal cell carcinoma
  • New family FUM124: the proband had mesothelioma between the rib cage and chest wall at age 71 and carried a missense mutation (c.539T>C, p.L180P)
  • New family FUM128: the proband had epithelioid peritoneal mesothelioma at age 60 and carried an intronic variant (c.256-4_256-2del) that was confirmed to cause abnormal splicing
  • 148 of 174 reported carriers (85%) had cancer, which the authors read as high penetrance
  • The authors found no clear link between the type or location of the mutation and the type of cancer
• The authors' conclusion: The authors concluded that uveal melanoma, mesothelioma, cutaneous melanoma, renal cell carcinoma and atypical Spitz tumors are clearly established as part of the syndrome. They wrote that breast cancer and basal cell carcinoma might be associated but need further study. In their view, mesothelioma patients with germline mutations appear to survive longer, and increased screening is indicated.
• Limitations the authors state:
  • Many of the reported cancers were not confirmed by review of medical records
  • Comparison with general-population cancer rates is imperfect, because the carriers were reported from many countries while SEER data come from the United States
  • Penetrance is likely overestimated because the people who get tested are mostly those already affected by cancer
  • How common atypical Spitz tumors are among carriers is unclear, because most reported patients were not checked for them

Topics

Medical terms in this study, explained in our Lexicon: BAP1 Tumor Predisposition Syndrome, BAP1, Germline Mutation, Tumor Suppressor Gene, Carcinoma, Malignant Mesothelioma, Metastasis, Genetic Counseling.

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