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      Integrative genomic analysis of peritoneal malignant mesothelioma: understanding a case with extraordinary chemotherapy response

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          Abstract

          Peritoneal malignant mesothelioma is a rare disease with a generally poor prognosis and poor response to chemotherapy. To improve survival there is a need for increased molecular understanding of the disease, including chemotherapy sensitivity and resistance. We here present an unusual case concerning a young woman with extensive peritoneal mesothelioma who had a remarkable response to palliative chemotherapy (platinum/pemetrexed). Tumor samples collected at surgery before and after treatment were analyzed on the genomic and transcriptional levels (exome sequencing, RNA-seq, and smallRNA-seq). Integrative analysis of single nucleotide and copy-number variants, mutational signatures, and gene expression was performed to provide a comprehensive picture of the disease. LATS1/2 were identified as the main mutational drivers together with homozygous loss of BAP1 and PBRM1, which also may have contributed to the extraordinary chemotherapy response. The presence of the S3 mutational signature is consistent with homologous recombination DNA repair defects due to BAP1 loss. Up-regulation of the PI3K/AKT/mTOR pathway after treatment, supported by deactivated PTEN through miRNA regulation, is associated with cancer progression and could explain chemotherapy resistance. The molecular profile suggests potential benefit from experimental targeting of PARP, EZH2, the PI3K/AKT/mTOR pathway and possibly also from immune checkpoint inhibition. In addition to providing the molecular background for this unusual case of peritoneal mesothelioma, the results show the potential value of integrative genomic analysis in precision medicine.

          Most cited references37

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          Targeting EZH2 in cancer.

          Recent genomic studies have resulted in an emerging understanding of the role of chromatin regulators in the development of cancer. EZH2, a histone methyl transferase subunit of a Polycomb repressor complex, is recurrently mutated in several forms of cancer and is highly expressed in numerous others. Notably, both gain-of-function and loss-of-function mutations occur in cancers but are associated with distinct cancer types. Here we review the spectrum of EZH2-associated mutations, discuss the mechanisms underlying EZH2 function, and synthesize a unifying perspective that the promotion of cancer arises from disruption of the role of EZH2 as a master regulator of transcription. We further discuss EZH2 inhibitors that are now showing early signs of promise in clinical trials and also additional strategies to combat roles of EZH2 in cancer.
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            Deficiency in the repair of DNA damage by homologous recombination and sensitivity to poly(ADP-ribose) polymerase inhibition.

            Deficiency in either of the breast cancer susceptibility proteins BRCA1 or BRCA2 induces profound cellular sensitivity to the inhibition of poly(ADP-ribose) polymerase (PARP) activity. We hypothesized that the critical role of BRCA1 and BRCA2 in the repair of double-strand breaks by homologous recombination (HR) was the underlying reason for this sensitivity. Here, we examine the effects of deficiency of several proteins involved in HR on sensitivity to PARP inhibition. We show that deficiency of RAD51, RAD54, DSS1, RPA1, NBS1, ATR, ATM, CHK1, CHK2, FANCD2, FANCA, or FANCC induces such sensitivity. This suggests that BRCA-deficient cells are, at least in part, sensitive to PARP inhibition because of HR deficiency. These results indicate that PARP inhibition might be a useful therapeutic strategy not only for the treatment of BRCA mutation-associated tumors but also for the treatment of a wider range of tumors bearing a variety of deficiencies in the HR pathway or displaying properties of 'BRCAness.'
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              BAP1 loss defines a new class of renal cell carcinoma

              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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                Author and article information

                Journal
                Cold Spring Harb Mol Case Stud
                Cold Spring Harb Mol Case Stud
                cshmcs
                cshmcs
                cshmcs
                Cold Spring Harbor Molecular Case Studies
                Cold Spring Harbor Laboratory Press
                2373-2873
                April 2019
                : 5
                : 2
                : a003566
                Affiliations
                [1 ]Department of Tumor Biology, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital, 0310 Oslo, Norway;
                [2 ]Department of Informatics, University of Oslo, 0373 Oslo, Norway;
                [3 ]Bioinformatics Core Facility, Institute for Medical Informatics, Oslo University Hospital, 0310 Oslo, Norway;
                [4 ]Department of Pathology, The Norwegian Radium Hospital, Oslo University Hospital, 0310 Oslo, Norway;
                [5 ]Department of Radiology, The Norwegian Radium Hospital, Oslo University Hospital, 0310 Oslo, Norway;
                [6 ]Department of Oncology, Oslo University Hospital, 0310 Oslo, Norway;
                [7 ]Department of Gastroenterological Surgery, The Norwegian Radium Hospital, Oslo University Hospital, 0310 Oslo, Norway;
                [8 ]Institute of Clinical Medicine, University of Oslo, 1171 Oslo, Norway
                Author notes
                Article
                MCS003566Lun
                10.1101/mcs.a003566
                6549577
                30862609
                60ccb0c2-eec2-4b5f-9295-ab3c91b296c2
                © 2019 Lund-Andersen et al.; Published by Cold Spring Harbor Laboratory Press

                This article is distributed under the terms of the Creative Commons Attribution-NonCommercial License, which permits reuse and redistribution, except for commercial purposes, provided that the original author and source are credited.

                History
                : 10 October 2018
                : 17 February 2019
                Page count
                Pages: 14
                Funding
                Funded by: Norwegian Cancer Society
                Award ID: 4499184
                Funded by: South-Eastern Norway Regional Health Authority
                Award ID: 2014041
                Categories
                Research Report

                peritoneal mesothelioma
                peritoneal mesothelioma

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