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      Concurrent germline and somatic pathogenic BAP1 variants in a patient with metastatic bladder cancer

      case-report

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          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Germline pathogenic variants in the BRCA1-associated protein-1 ( BAP1) gene cause the BAP1 tumor predisposition syndrome (TPDS). BAP1 TPDS is associated with an increased risk of uveal and cutaneous melanoma, mesothelioma, renal cell carcinoma, and several other cancer subtypes. Here, we report a germline nonsense BAP1 variant (c.850G>T, p.Glu284Ter) in a patient with bladder cancer and a strong family history of malignancy. Concurrently, we identified a somatic frameshift BAP1 variant, and as expected, immunostaining validated the loss of BAP1 protein in patient-derived tumor specimens. Together, these data provide strong evidence of pathogenicity in this case. With the addition of bladder cancer to the tumor types reported with germline BAP1 mutations, our understanding of the BAP1 TPDS continues to evolve, and may affect future screening and surveillance guidelines.

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          Pathogenic Germline Variants in 10,389 Adult Cancers

          Francis Carey, Antonio Jimeno, Ruth Steele … (2018)
          We conducted the largest investigation of predisposition variants in cancer to date, discovering 853 pathogenic or likely pathogenic variants in 8% of 10,389 cases from 33 cancer types. Twenty-one genes showed single or cross-cancer associations, including novel associations of SDHA in melanoma and PALB2 in stomach adenocarcinoma. The 659 predisposition variants and 18 additional large deletions in tumor suppressors, including ATM, BRCA1, and NF1, showed low gene expression and frequent (43%) loss of heterozygosity or biallelic two-hit events. We also discovered 33 such variants in oncogenes, including missenses in MET, RET, and PTPN11 associated with high gene expression. We nominated 47 additional predisposition variants from prioritized VUSs supported by multiple evidences involving case-control frequency, loss of heterozygosity, expression effect, and co-localization with mutations and modified residues. Our integrative approach links rare predisposition variants to functional consequences, informing future guidelines of variant classification and germline genetic testing in cancer.
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            BAP1 loss defines a new class of renal cell carcinoma

            Samuel Peña-Llopis, Silvia Vega-Rubín-de-Celis, Arnold Liao … (2012)
            The molecular pathogenesis of renal cell carcinoma (RCC) is poorly understood. Whole-genome and exome sequencing followed by innovative tumorgraft analyses (to accurately determine mutant allele ratios) identified several putative two-hit tumor suppressor genes including BAP1. BAP1, a nuclear deubiquitinase, is inactivated in 15% of clear-cell RCCs. BAP1 cofractionates with and binds to HCF-1 in tumorgrafts. Mutations disrupting the HCF-1 binding motif impair BAP1-mediated suppression of cell proliferation, but not H2AK119ub1 deubiquitination. BAP1 loss sensitizes RCC cells in vitro to genotoxic stress. Interestingly, BAP1 and PBRM1 mutations anticorrelate in tumors (P=3×10−5), and combined loss of BAP1 and PBRM1 in a few RCCs was associated with rhabdoid features (q=0.0007). BAP1 and PBRM1 regulate seemingly different gene expression programs, and BAP1 loss was associated with high tumor grade (q=0.0005). Our results establish the foundation for an integrated pathological and molecular genetic classification of RCC, paving the way for subtype-specific treatments exploiting genetic vulnerabilities.
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              The rules and impact of nonsense-mediated mRNA decay in human cancers

              Rik G.H. Lindeboom, Fran Supek, Ben Lehner (2016)
              Premature termination codons (PTCs) cause a large proportion of inherited human genetic diseases. PTC-containing transcripts can be degraded by an mRNA surveillance pathway termed nonsense-mediated mRNA decay (NMD). However, the efficiency of NMD varies; it is inefficient when a PTC is located downstream of the last exon junction complex (EJC). We used matched exome and transcriptome data from 9,769 human tumors to systematically elucidate the rules of NMD targeting in human cells. An integrated model incorporating multiple rules beyond the canonical EJC model explains approximately three-quarters of the non-random variance in NMD efficiency across thousands of PTCs. We also show that dosage compensation may mask the effects of NMD. Applying the NMD model identifies signatures of both positive and negative selection on NMD-triggering mutations in human tumors and provides a classification of tumor suppressor genes.
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                Author and article information

                Contributors
                Bernhard J. Eigl:
                ORCID: http://orcid.org/0000-0003-1653-6929
                bernie.Eigl@bccancer.bc.ca
                Journal
                Journal ID (nlm-ta): NPJ Genom Med
                Journal ID (iso-abbrev): NPJ Genom Med
                Title: NPJ Genomic Medicine
                Publisher: Nature Publishing Group UK (London )
                ISSN (Electronic): 2056-7944
                Publication date (Electronic): 23 March 2020
                Publication date PMC-release: 23 March 2020
                Publication date Collection: 2020
                Volume: 5
                Electronic Location Identifier: 12
                Affiliations
                [1 ]ISNI 0000 0001 0702 3000, GRID grid.248762.d, Department of Medical Oncology, , British Columbia Cancer Agency, ; Vancouver, BC Canada
                [2 ]ISNI 000000041936754X, GRID grid.38142.3c, Department of Pediatric Oncology, Dana-Farber Cancer Institute, , Harvard Medical School, ; Boston, MA USA
                [3 ]ISNI 0000 0001 2288 9830, GRID grid.17091.3e, Vancouver Prostate Centre, Department of Urologic Sciences, , University of British Columbia, ; Vancouver, BC Canada
                [4 ]ISNI 0000 0001 0702 3000, GRID grid.248762.d, Department of Pathology, , British Columbia Cancer Agency, ; Vancouver, BC Canada
                [5 ]ISNI 0000 0001 0702 3000, GRID grid.248762.d, Hereditary Cancer Program, , British Columbia Cancer Agency, ; Vancouver, BC Canada
                Author information
                http://orcid.org/0000-0001-5606-0908
                http://orcid.org/0000-0003-1653-6929
                Article
                Publisher ID: 121
                DOI: 10.1038/s41525-020-0121-8
                PMC ID: 7089973
                SO-VID: 7fb876fa-1209-4208-aca3-069b27f8a163
                Copyright © © The Author(s) 2020
                License:

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                Date received : 9 October 2019
                Date accepted : 28 January 2020
                Categories
                Subject: Case Report
                Custom metadata
                issue-copyright-statement © The Author(s) 2020

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