2. Academic Validation
  3. Integrated genomics point to immune vulnerabilities in pleural mesothelioma

Integrated genomics point to immune vulnerabilities in pleural mesothelioma

  • Sci Rep. 2021 Sep 27;11(1):19138. doi: 10.1038/s41598-021-98414-w.
Anca Nastase  # 1,  Amit Mandal  # 1,  Shir Kiong Lu 1,  Hima Anbunathan 1,  Deborah Morris-Rosendahl 1 2,  Yu Zhi Zhang 1 3,  Xiao-Ming Sun 4,  Spyridon Gennatas 1,  Robert C Rintoul 5 6,  Matthew Edwards 2,  Alex Bowman 3,  Tatyana Chernova 4,  Tim Benepal 7,  Eric Lim 8,  Anthony Newman Taylor 1,  Andrew G Nicholson 1 3,  Sanjay Popat 9 10,  Anne E Willis 4,  Marion MacFarlane 4,  Mark Lathrop 11,  Anne M Bowcock 1,  Miriam F Moffatt 12,  William O C M Cookson 13
Affiliations

Affiliations

  • 1 National Heart and Lung Institute, Imperial College London, Dovehouse Street, London, SW36LY, UK.
  • 2 Clinical Genetics and Genomics, Royal Brompton and Harefield NHS Foundation Trust, London, UK.
  • 3 Department of Histopathology, Royal Brompton and Harefield NHS Foundation Trust, London, UK.
  • 4 Medical Research Council Toxicology Unit, University of Cambridge, Cambridge, UK.
  • 5 Department of Thoracic Oncology, Papworth Hospital, Cambridge, UK.
  • 6 Department of Oncology, University of Cambridge, Cambridge, UK.
  • 7 Department of Oncology, St George's Healthcare NHS Foundation Trust, London, UK.
  • 8 Department of Thoracic Surgery, Royal Brompton and Harefield NHS Foundation Trust, London, UK.
  • 9 Department of Medicine, Royal Marsden Hospital, London, UK.
  • 10 The Institute of Cancer Research, London, UK.
  • 11 Department of Human Genetics, McGill Genome Centre, Montreal, QC, Canada.
  • 12 National Heart and Lung Institute, Imperial College London, Dovehouse Street, London, SW36LY, UK. m.moffatt@imperial.ac.uk.
  • 13 National Heart and Lung Institute, Imperial College London, Dovehouse Street, London, SW36LY, UK. w.cookson@imperial.ac.uk.
  • # Contributed equally.
PMID: 34580349 DOI: 10.1038/s41598-021-98414-w
Abstract

Pleural mesothelioma is an aggressive malignancy with limited effective therapies. In order to identify therapeutic targets, we integrated SNP genotyping, Sequencing and transcriptomics from tumours and low-passage patient-derived cells. Previously unrecognised deletions of SUFU locus (10q24.32), observed in 21% of 118 tumours, resulted in disordered expression of transcripts from Hedgehog pathways and the T-cell synapse including VISTA. Co-deletion of Interferon Type I genes and CDKN2A was present in half of tumours and was a predictor of poor survival. We also found previously unrecognised deletions in RB1 in 26% of cases and show sub-micromolar responses to downstream PLK1, CHEK1 and Aurora Kinase inhibitors in primary mesothelioma cells. Defects in Hippo pathways that included RASSF7 amplification and NF2 or LATS1/2 mutations were present in 50% of tumours and were accompanied by micromolar responses to the YAP1 inhibitor Verteporfin. Our results suggest new therapeutic avenues in mesothelioma and indicate targets and biomarkers for immunotherapy.

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