Integrated genomics point to immune vulnerabilities in pleural mesothelioma

Our plain-English summary of Integrated genomics point to immune vulnerabilities in pleural mesothelioma, by A. Nastase, A. Mandal, S.K. Lu, et al (Scientific Reports, 2021).

The study

• Authors: A. Nastase, A. Mandal, S.K. Lu, H. Anbunathan, D. Morris-Rosendahl, Y.Z. Zhang, X.M. Sun, S. Gennatas, R.C. Rintoul, M. Edwards, A. Bowman, T. Chernova, T. Benepal, E. Lim, A.N. Taylor, A.G. Nicholson, S. Popat, A.E. Willis, M. MacFarlane, M. Lathrop, A.M. Bowcock, M.F. Moffatt, W.O.C.M. Cookson
• Journal: Scientific Reports
• Published: 2021;11(1):19138
• Cited by: 19 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

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.

© 2021. The Author(s).

In plain English

This laboratory genomics study examined pleural mesothelioma tumours from 121 patients (87% male), collected through UK tissue banks and the EQUALITY study. The authors mapped gene copy-number changes in 118 tumours, sequenced genes, measured gene activity in 35 tumours and stained 28. They tested eight drugs on three patient-derived cell cultures and three comparison cell lines. Asbestos exposure was documented clinically in 69% of cases, but accurate exposure estimates were unavailable for analysis. Median survival was 9.9 months; survival data were available for 110 patients. CDKN2A deletion was found in 71 of 118 tumours (60%) and was associated with shorter survival (8.8 vs 13.0 months, P = 0.02). Previously unrecognised deletions included RB1 (26%) and the SUFU region (21%). SUFU deletion was associated with lower activity of immune-cell genes. Survival with co-deletion of CDKN2A and Type I interferon genes did not differ statistically from CDKN2A deletion alone (8.3 vs 10.7 months, P = 0.6). In cell cultures, Aurora kinase, PLK1 and CHEK1 inhibitors gave sub-micromolar to micromolar responses, and verteporfin micromolar responses. The authors concluded these drug types may have roles in treating mesothelioma growth.

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: Laboratory genomic study of tumour samples (gene copy-number mapping with SNP arrays, whole exome and targeted sequencing, RNA sequencing, tissue staining) combined with drug testing in cell cultures
• Who was studied: 121 patients with pleural mesothelioma whose tumour samples came from UK sources: the Royal Brompton and Harefield biobanks (surgical biopsies 2006 to 2011), MesobanK UK and the EQUALITY study. 105 of the 121 were male. 90 tumours were epithelioid, 25 biphasic and 6 sarcomatoid. Survival data were available for 110 patients. Numbers analysed differed by test: 118 by copy-number analysis, 50 by whole exome sequencing, 119 by targeted sequencing, 35 by RNA sequencing and 28 by staining. In addition, 19 patient-derived cell cultures were whole-genome sequenced.
• Exposure: Asbestos exposure was documented clinically in 69% of cases. No fiber types, doses or jobs were reported, and exposure was not analysed. The laboratory drug tests used eight drugs: niraparib, olaparib, vismodegib, verteporfin, palbociclib, alisertib, volasertib and AZD7762.
• Main results:
  • The median overall survival for all subjects was 9.9 months. Survival time from diagnosis to death or last follow-up was available for 110 patients.
  • CDKN2A deletion was found in 71 of 118 tumours (60%). It was associated with worse overall survival than CDKN2A wild type: 8.8 vs 13.0 months, P = 0.02.
  • Type I interferon genes showed a predicted homozygous deletion in 38 of 118 patients (32%) and a heterozygous deletion in 24 of 118 (20%). Median survival with co-deletion of CDKN2A and Type I interferon genes was not statistically different from survival with CDKN2A deletion alone: 8.3 vs 10.7 months, P = 0.6.
  • A previously unrecognised deletion of the RB1 locus was found in 31 of 118 patients (26%).
  • Deletion of the SUFU locus in 25 of 118 tumours (21%) was associated with upregulation of PTCH2, a sign of disordered Hedgehog signalling. It was also associated with downregulation of T-cell and other immune-cell genes.
  • RASSF7 amplification was found in 39 of 118 tumours (33%). Counting this together with NF2, LATS1 and LATS2 mutations, lesions in Hippo pathways were present in 50% of tumours.
  • In targeted sequencing, BAP1 was mutated in 39 subjects (33%), NF2 in 24 (20%), TP53 in 9 (8%) and SETD2 in 7 (6%).
  • Patients with TP53 mutations had worse survival than those without: mean overall survival 5.7 vs 13.6 months, P = 0.0005.
  • PD-L1 staining was low: only 4 of 28 stained tumours (14%) showed 10% or more expression.
  • In cell cultures, the Aurora kinase inhibitor alisertib, the PLK1/2/3 inhibitor volasertib and the CHEK1/2 inhibitor AZD7762 gave micromolar to sub-micromolar responses.
  • Mesothelioma cells responded to the YAP inhibitor verteporfin at micromolar levels. The immortalised Met-5A mesothelial cells, which are not NF2-deficient, also responded.
  • The PARP inhibitors (niraparib and olaparib) did not consistently inhibit primary cell growth. Palbociclib showed only minor effects. Vismodegib inhibited only one primary cell culture.
• The authors' conclusion: The authors concluded that their analyses suggest roles for Aurora kinase, PLK, CHEK and YAP inhibitors in treating mesothelioma growth. They also suggested that interferon Type I and SUFU deletions may serve as biomarkers to guide immunotherapy.
• Limitations the authors state:
  • The study was not powered to investigate what determines fibrosis.
  • There were no accurate estimates of asbestos exposure from occupational histories or lung fibre counts, so exposure could not be included as a covariate.
  • Detecting small or uncommon amplifications and deletions in mixed tumour samples may be problematic.
  • The study was not powered to test systematically what determines histological subtypes or features.
  • Drugs were tested only one at a time, in patient-derived cells. The authors noted that 3D models including fibroblasts and immune cells may give better understanding of drug effects.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, CDKN2A, Mesothelioma, Biomarker, Immunotherapy.

Related studies

• Diffuse Pleural Mesotheliomas with Genomic Near-Haploidization: A Newly Recognized Subset with Distinct Clinical, Histologic, and Molecular Features — S.R. Yang, G. Jayakumaran, et al. (2024)
• Systemic characterization of alternative splicing related to prognosis and immune infiltration in malignant mesothelioma — J. Lai, H. Yang, et al. (2021)
• Insights Into Genomic Drivers, Transcriptomic Heterogeneity, and Therapeutic Vulnerabilities From Novel Mesothelioma Cell Lines — Y. Wu, F. Cao, et al. (2026)
• Can CpG methylation serve as surrogate markers for immune infiltration in cancer? — M.D. Bacolod, F. Barany, et al. (2019)
• Genomic Landscape of Malignant Mesotheliomas — S. Kato, B.N. Tomson, et al. (2016)
• Translating mesothelioma molecular genomics and dependencies into precision oncology-based therapies — T.K. Hinz, L.E. Heasley (2020)

Browse more research in Scientific Reports, or return to medical research.