Clonal architecture in mesothelioma is prognostic and shapes the tumour microenvironment

Our plain-English summary of Clonal architecture in mesothelioma is prognostic and shapes the tumour microenvironment, by M. Zhang, J.L. Luo, Q. Sun, et al (Nature Communications, 2021).

The study

• Authors: M. Zhang, J.L. Luo, Q. Sun, J. Harber, A.G. Dawson, A. Nakas, S. Busacca, A.J. Sharkey, D. Waller, M.T. Sheaff, C. Richards, P. Wells-Jordan, A. Gaba, C. Poile, E.Y. Baitei, A. Bzura, J. Dzialo, M. Jama, J. Le Quesne, A. Bajaj, L. Martinson, J.A. Shaw, C. Pritchard, T. Kamata, N. Kuse, L. Brannan, P. De Philip Zhang, H. Yang, G. Griffiths, G. Wilson, C. Swanton, F. Dudbridge, E.J. Hollox, D.A. Fennell
• Journal: Nature Communications
• Published: 2021;12(1):1751
• Cited by: 99 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant Pleural Mesothelioma (MPM) is typically diagnosed 20-50 years after exposure to asbestos and evolves along an unknown evolutionary trajectory. To elucidate this path, we conducted multi-regional exome sequencing of 90 tumour samples from 22 MPMs acquired at surgery. Here we show that exomic intratumour heterogeneity varies widely across the cohort. Phylogenetic tree topology ranges from linear to highly branched, reflecting a steep gradient of genomic instability. Using transfer learning, we detect repeated evolution, resolving 5 clusters that are prognostic, with temporally ordered clonal drivers. BAP1/-3p21 and FBXW7/-chr4 events are always early clonal. In contrast, NF2/-22q events, leading to Hippo pathway inactivation are predominantly late clonal, positively selected, and when subclonal, exhibit parallel evolution indicating an evolutionary constraint. Very late somatic alteration of NF2/22q occurred in one patient 12 years after surgery. Clonal architecture and evolutionary clusters dictate MPM inflammation and immune evasion. These results reveal potentially drugable evolutionary bottlenecking in MPM, and an impact of clonal architecture on shaping the immune landscape, with potential to dictate the clinical response to immune checkpoint inhibition.

In plain English

This genetic study examined tumours from 22 patients with malignant pleural mesothelioma operated on at Glenfield Hospital, Leicester, UK. The authors sequenced the protein-coding DNA of 90 tumour samples, four or five from set locations in each tumour, comparing them with each patient's blood DNA. Seventeen patients had epithelioid and five had biphasic mesothelioma. The article reports no results on asbestos exposure. The tumours carried few mutations (about 1 per megabase of DNA) but frequent chromosome losses; loss of 22q, containing the NF2 gene, was found in 82%. From their reconstruction of tumour development, the authors inferred that BAP1/3p21 and chromosome 4 changes arose early, although some tumours gained later second BAP1 hits; NF2/22q changes mostly arose later. A computer method sorted the tumours into five groups. Group 5 patients (7) had shorter progression-free survival (hazard ratio 3.52, 95% confidence interval 1.22 to 10.13) and lower overall survival (hazard ratio 4.43, 1.42 to 13.77) than the other groups. The authors concluded that the tumours' clonal architecture (how their cell populations are genetically organised) affects patient survival and the tumour microenvironment.

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: Genetic (tumour DNA sequencing) study of tumour samples taken at surgery. Multiple regions were sampled per tumour, compared with blood DNA, and patients were followed for progression and survival.
• Who was studied: 22 patients with malignant pleural mesothelioma (the MEDUSA22 cohort) who had extended pleurectomy decortication at Glenfield Hospital, University of Leicester, UK. 90 tumour regions were sequenced, 4 to 5 per patient. 17 patients had epithelioid and 5 had biphasic histology. One patient had received chemotherapy before surgery. Study dates are not given.
• Exposure: Asbestos exposure was not the subject of analysis. It was listed among the clinical data collected, but no exposure results, fiber types or doses are reported. The study examined genetic changes in the tumours.
• Main results:
  • Across the cohort, total mutation burden was low: 1 mutation per megabase (range 0.4 to 1.6).
  • 64% of the tumours had a 'linear' evolutionary tree, meaning no subclonal branching.
  • BAP1 was the most frequent clonal driver mutation, found in eight patients (36%).
  • Among clonal copy number changes, the most frequent was loss of 22q (containing NF2), seen in 82% of the tumours.
  • Clonal homozygous deletion of the 9p21.3 region (CDKN2A/B and MTAP) was found in seven patients (32%).
  • In the inferred evolutionary trajectories, events involving BAP1 or its locus 3p21 were a repeated, universally early event.
  • BAP1 alterations were mostly heterozygous. Second hits leading to complete BAP1 inactivation were found both as clonal (early) and subclonal (later) events.
  • Loss of chromosome 4, 3p21 and 9p21.3 were consistently found to be early clonal events.
  • NF2/22q loss was predominantly a late clonal event.
  • Tumour DNA was detected in blood plasma in 4 of 11 patients tested. Overall survival was significantly lower in these patients (log-rank p = 0.020; hazard ratio 5.20; 95% confidence interval 1.12 to 24.09).
  • Patients in evolutionary cluster C5 (7 patients) had shorter progression-free survival than patients in clusters C1 to C4 (p = 0.013; hazard ratio 3.52; 95% confidence interval 1.22 to 10.13; n = 22 patients).
  • Patients in cluster C5 also had lower overall survival than patients in clusters C1 to C4 (p = 0.005; hazard ratio 4.43; 95% confidence interval 1.42 to 13.77).
  • When the clusters were applied to The Cancer Genome Atlas mesothelioma data, C5 again had a poorer prognosis. In both datasets, C5 consisted only of epithelioid tumours.
  • Cluster C5 was associated with higher infiltration by CD8 T lymphocytes (cell count p = 0.032; n = 15 patients).
  • Loss of heterozygosity in the HLA immune genes was found in five patients and was always subclonal (a later event).
  • One additional patient, who was not enrolled in the study cohort, showed subclonal NF2 copy number loss when the disease progressed, about 12 years after surgery.
• The authors' conclusion: The authors concluded that the clonal architecture of mesothelioma affects patient survival and the make-up of the tumour microenvironment. They also suggested that it shapes immune surveillance of the tumour before immune escape involving HLA loss.
• Limitations the authors state:
  • The authors described the patient cohort as relatively small and gave this as the reason for their choice of statistical tests.
  • The rate of detecting tumour DNA in blood plasma was low: 4 of 11 patients.
  • The authors noted that methods able to detect minute deletions suggest a generally higher rate of BAP1 alterations in mesothelioma than the 36% they reported.

Topics

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

Medical terms in this study, explained in our Lexicon: Mesothelioma, Pleural Mesothelioma, BAP1, Inflammation.

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• High Incidence of Somatic BAP1 alterations in sporadic malignant mesothelioma — M. Nasu, M. Emi, et al. (2015)
• Potential Diagnostic and Prognostic Role of Microenvironment in Malignant Pleural Mesothelioma — I.C. Salaroglio, J. Kopecka, et al. (2019)
• Characterization of the immune microenvironment in malignant pleural mesothelioma reveals prognostic subgroups of patients — N. Fusco, V. Vaira, et al. (2020)
• Prognostic Role of PD-L1 in Malignant Pleural Mesothelioma: Unraveling the Complexity of the Tumor Microenvironment in Mesothelioma — M. de Perrot (2021)

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