The spectrum of tumors harboring BAP1 gene alterations

Our plain-English summary of The spectrum of tumors harboring BAP1 gene alterations, by Y. Laitman, J. Newberg, R.B. Molho, et al (Cancer Genetics, 2021).

The study

• Authors: Y. Laitman, J. Newberg, R.B. Molho, D.X. Jin, E. Friedman
• Journal: Cancer Genetics
• Published: 2021;256-257:31-35
• Cited by: 14 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Germline mutations in the BRCA1-associated protein (BAP1) gene (MIM # 603089) are associated with a substantially increased risk for developing melanoma, mesothelioma, and renal cell carcinoma. Somatic inactivation of the BAP1 gene was noted in these and other tumors types, including esophageal cancer and cholangiocarcinoma. The favorable response of BRCA1/2-associated tumors to poly (ADP-ribose) polymerase (PARP) inhibitor therapy, raises the possibility that tumors harboring BAP1 mutations may exhibit similar sensitivity to PARP inhibitor therapy. Given the possibility that BAP1 alterations may have therapeutic implications, this study was aimed to describe the spectrum of tumors that harbor BAP1 alterations. The Foundation Medicine database was queried for known or likely pathogenic BAP1 genomic variants through July 2019. Overall, 4982/374,694 (1.81%) tumors harbored pathogenic BAP1 genomic alterations. Highest rates were noted in mesothelioma (45.24%), cholangiocarcinoma (13.37%), renal cell carcinoma (10.52%), thymic cancer (8.16%), salivary gland cancer (6.18%), and melanoma (5.1%). There were 59 unique BAP1 short variants detected in at least 10 samples. More same tissue tumors of squamous cell histology harbored BAP1 alterations than adenocarcinomas. The current study highlights tumor types that display higher than previously appreciated rates of somatic BAP1 genomic alterations.

Copyright © 2021. Published by Elsevier Inc.

In plain English

This study searched the Foundation Medicine database for known or likely harmful changes (alterations) in the BAP1 gene in tumor tissue. The database held tumor samples genetically profiled during routine clinical care through July 2019. Of 274,694 tumors, 4982 (1.81%) carried at least one such alteration. The highest rates were in mesothelioma (45.24%), then cholangiocarcinoma, a bile duct cancer (13.37%), renal cell carcinoma (10.52%), thymic cancer (8.16%), squamous cell cancer of the cervix (7.52%), salivary gland cancer (6.18%) and melanoma (5.1%). The rates in pleural mesothelioma (44.27%) and peritoneal mesothelioma (48.32%) were not statistically significantly different. In 180 of 1271 mesotheliomas (14.1%), copies of the BAP1 gene were deleted. Ocular melanoma had a higher rate than skin melanoma (48.3% vs 1.67%). The authors described a possible pattern: squamous cell tumors seemed to carry alterations more often than adenocarcinomas of the same organ. For example, the rates in the cervix were 7.52% vs 0.6%. The authors concluded that BAP1 alterations occur in more tumor types than previously appreciated. They noted that the database held limited clinical information.

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: Retrospective analysis of a commercial tumor genomic profiling database (Foundation Medicine); tumors were profiled during routine clinical care
• Who was studied: 274,694 tumors from 21 organ systems, profiled at a laboratory in Cambridge, MA, USA, with samples through July 2019; frequencies were reported only for tumor types with at least 300 samples
• Exposure: No asbestos or other environmental exposure was studied. The study looked at known or likely pathogenic alterations in the BAP1 gene in tumor tissue: point mutations, insertions and deletions, copy number deletions and rearrangements.
• Main results:
  • Across all tumors, 4982 of 274,694 (1.81%) carried at least one pathogenic BAP1 alteration; 148 of these carried 2 or more BAP1 variants
  • Highest rates by tumor type: mesothelioma 45.24%, cholangiocarcinoma 13.37%, renal cell carcinoma 10.52%, thymic cancer 8.16%, cervical squamous cell cancer 7.52%, salivary gland 6.18%, melanoma 5.1%
  • Pleural mesothelioma (44.27%) and peritoneal mesothelioma (48.32%) did not differ statistically significantly in their rate of BAP1 pathogenic variants
  • BAP1 copy number deletions were found in 686 of all tumors (0.25%). Among mesotheliomas, 180 of 1271 (14.1%) had them, the highest rate of any tumor type.
  • Ocular melanoma had a statistically significantly higher rate of BAP1 inactivating mutations than skin melanoma: over 48.3% vs 1.67%
  • The authors said higher frequencies of BAP1 alterations 'seem to be associated' with squamous cell histology compared with adenocarcinoma within the same organ. They gave two comparisons: cervical squamous cell carcinoma 7.52% vs cervical adenocarcinoma 0.6% (OR = 13.5), and anal squamous cell cancer 2.88% vs rectal adenocarcinoma 0.23% (OR = 13.1).
  • In kidney cancer, 202 of 1422 clear cell carcinomas (14.2%) carried BAP1 alterations, compared with 20 of 340 papillary carcinomas (5.88%) (OR = 2.6)
  • 1974 unique BAP1 variants were detected, 1857 of them unique short variants; 59 unique short variants were detected more than 10 times
• The authors' conclusion: The authors concluded that BAP1 somatic inactivation occurs in a wider range of tumors than previously appreciated, and that this information may help design future trials of targeted therapies. They added that there are insufficient data to support routine use of PARP inhibitors in BAP1-mutated tumors.
• Limitations the authors state:
  • The database held limited clinical data, so the authors could not assess the reported high rate of BAP1 mutations in metastatic uveal melanoma

Topics

Medical terms in this study, explained in our Lexicon: BAP1, Germline Mutation, Mesothelioma, Carcinoma, Esophageal Cancer, Squamous Cell, Histology, Adenocarcinoma.

Related studies

• Different prognostic roles of tumor suppressor gene BAP1 in cancer: A systematic review with meta-analysis — C. Luchini, N. Veronese, et al. (2016)
• High Incidence of Somatic BAP1 alterations in sporadic malignant mesothelioma — M. Nasu, M. Emi, et al. (2015)
• Tumours associated with BAP1 mutations — R. Murali, T. Wiesner, et al. (2013)
• BAP1 gene mutations in Egyptian patients with advanced sporadic malignant pleural mesothelioma (MPM): relation with clinical outcomes and survival — A.A. Bahnasy, R.S. El-Din, et al. (2018)
• 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)
• Comprehensive review of BAP1 tumor predisposition syndrome with report of two new cases — K. Rai, R. Pilarski, et al. (2016)

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