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
  • 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. [email protected].
  • 13. National Heart and Lung Institute, Imperial College London, Dovehouse Street, London, SW36LY, UK. [email protected].
  • # 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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