Clonal architecture in mesothelioma is prognostic and shapes the tumour microenvironment.

Chromosome Deletion Clone Cells / metabolism Cluster Analysis Cohort Studies Humans Kaplan-Meier Estimate Lung Neoplasms / genetics Mesothelioma / genetics Mutation Pleural Neoplasms / genetics Prognosis Tumor Microenvironment / genetics Tumor Suppressor Proteins / classification Exome Sequencing / methods

Journal

Nature communications

ISSN: 2041-1723

Titre abrégé: Nat Commun

Pays: England

ID NLM: 101528555

Informations de publication

Date de publication:
19 03 2021

Historique:

received: 18 09 2020

accepted: 04 02 2021

entrez: 20 3 2021

pubmed: 21 3 2021

medline: 7 4 2021

Statut: epublish

Résumé

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.

Identifiants

DOI: 10.1038/s41467-021-21798-w PMID: 33741915 PMC: PMC7979861

pubmed: 33741915

doi: 10.1038/s41467-021-21798-w

pii: 10.1038/s41467-021-21798-w

pmc: PMC7979861

doi:

Substances chimiques

Tumor Suppressor Proteins 0

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

Pagination

1751

Subventions

Organisme : Cancer Research UK

ID : C61811/A24218

Pays : United Kingdom

Organisme : Department of Health

Pays : United Kingdom

Commentaires et corrections

Type : ErratumIn

Références

Wagner, J. C., Sleggs, C. A. & Marchand, P. Diffuse pleural mesothelioma and asbestos exposure in the North Western Cape Province. Br. J. Ind. Med. 17, 260–271 (1960).

pubmed: 13782506 pmcid: 1038078

Odgerel, C. O. et al. Estimation of the global burden of mesothelioma deaths from incomplete national mortality data. Occup. Environ. Med. 74, 851–858 (2017).

pubmed: 28866609 doi: 10.1136/oemed-2017-104298

Kircheva, D. Y. et al. Specimen weight and volume: important predictors of survival in malignant pleural mesothelioma. Eur. J. Cardiothorac. Surg. 49, 1642–1647 (2016).

pubmed: 26802143 doi: 10.1093/ejcts/ezv422

Baas, P. et al. First-line nivolumab plus ipilimumab in unresectable malignant pleural mesothelioma (CheckMate 743): a multicentre, randomised, open-label, phase 3 trial. The Lancet. 397, 375–386 (2021).

doi: 10.1016/S0140-6736(20)32714-8

Yap, T. A., Aerts, J. G., Popat, S. & Fennell, D. A. Novel insights into mesothelioma biology and implications for therapy. Nat. Rev. Cancer 17, 475–488 (2017).

pubmed: 28740119 doi: 10.1038/nrc.2017.42

Bott, M. et al. The nuclear deubiquitinase BAP1 is commonly inactivated by somatic mutations and 3p21.1 losses in malignant pleural mesothelioma. Nat. Genet. 43, 668–672 (2011).

pubmed: 21642991 pmcid: 4643098 doi: 10.1038/ng.855

Hmeljak, J. et al. Integrative molecular characterization of malignant pleural mesothelioma. Cancer Discov. 8, 1548–1565 (2018).

pubmed: 30322867 pmcid: 6310008 doi: 10.1158/2159-8290.CD-18-0804

Jongsma, J. et al. A conditional mouse model for malignant mesothelioma. Cancer Cell 13, 261–271 (2008).

pubmed: 18328429 doi: 10.1016/j.ccr.2008.01.030

Kadariya, Y. et al. Bap1 Is a bona fide tumor suppressor: genetic evidence from mouse models carrying heterozygous germline Bap1 mutations. Cancer Res. 76, 2836–2844 (2016).

pubmed: 26896281 pmcid: 4873414 doi: 10.1158/0008-5472.CAN-15-3371

Badhai, J. et al. Combined deletion of Bap1, Nf2, and Cdkn2ab causes rapid onset of malignant mesothelioma in mice. J. Exp. Med. https://doi.org/10.1084/jem.20191257 (2020).

Wu, J. et al. Intercellular interaction dictates cancer cell ferroptosis via NF2-YAP signalling. Nature 572, 402–406 (2019).

pubmed: 31341276 pmcid: 6697195 doi: 10.1038/s41586-019-1426-6

Jamal-Hanjani, M. et al. Tracking the evolution of non-small-cell lung cancer. N. Engl. J. Med. 376, 2109–2121 (2017).

pubmed: 28445112 doi: 10.1056/NEJMoa1616288

McGranahan, N. et al. Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade. Science 351, 1463–1469 (2016).

pubmed: 26940869 pmcid: 4984254 doi: 10.1126/science.aaf1490

Rosenthal, R. et al. Neoantigen-directed immune escape in lung cancer evolution. Nature 567, 479–485 (2019).

pubmed: 30894752 pmcid: 6954100 doi: 10.1038/s41586-019-1032-7

McGranahan, N. et al. Allele-specific HLA loss and immune escape in lung cancer evolution. Cell 171, 1259–1271.e1211 (2017).

pubmed: 29107330 pmcid: 5720478 doi: 10.1016/j.cell.2017.10.001

Gundem, G. et al. The evolutionary history of lethal metastatic prostate cancer. Nature 520, 353–357 (2015).

pubmed: 25830880 pmcid: 4413032 doi: 10.1038/nature14347

McPherson, A. et al. Divergent modes of clonal spread and intraperitoneal mixing in high-grade serous ovarian cancer. Nat. Genet. 48, 758–767 (2016).

pubmed: 27182968 doi: 10.1038/ng.3573

de Bruin, E. C. et al. Spatial and temporal diversity in genomic instability processes defines lung cancer evolution. Science 346, 251–256 (2014).

pubmed: 25301630 pmcid: 4636050 doi: 10.1126/science.1253462

Rosenthal, R., McGranahan, N., Herrero, J., Taylor, B. S. & Swanton, C. DeconstructSigs: delineating mutational processes in single tumors distinguishes DNA repair deficiencies and patterns of carcinoma evolution. Genome Biol. 17, 31 (2016).

pubmed: 26899170 pmcid: 4762164 doi: 10.1186/s13059-016-0893-4

Alexandrov, L. B. et al. The repertoire of mutational signatures in human cancer. Nature 578, 94–101 (2020).

pubmed: 32025018 pmcid: 7054213 doi: 10.1038/s41586-020-1943-3

Martincorena, I. et al. Universal patterns of selection in cancer and somatic tissues. Cell 173, 1823 (2018).

pubmed: 29906452 pmcid: 6857632 doi: 10.1016/j.cell.2018.06.001

Testa, J. R. et al. Germline BAP1 mutations predispose to malignant mesothelioma. Nat. Genet. 43, 1022–1025 (2011).

pubmed: 21874000 pmcid: 3184199 doi: 10.1038/ng.912

Rabbitts, T. H., Forster, A., Larson, R. & Nathan, P. Fusion of the dominant negative transcription regulator CHOP with a novel gene FUS by translocation t(12;16) in malignant liposarcoma. Nat. Genet. 4, 175–180 (1993).

pubmed: 7503811 doi: 10.1038/ng0693-175

Barbieri, C. E. et al. Exome sequencing identifies recurrent SPOP, FOXA1 and MED12 mutations in prostate cancer. Nat. Genet. 44, 685–689 (2012).

pubmed: 22610119 pmcid: 3673022 doi: 10.1038/ng.2279

Guo, Z. Q. et al. Small-molecule targeting of E3 ligase adaptor SPOP in kidney cancer. Cancer Cell 30, 474–484 (2016).

pubmed: 27622336 doi: 10.1016/j.ccell.2016.08.003

Lopez, S. et al. Interplay between whole-genome doubling and the accumulation of deleterious alterations in cancer evolution. Nat. Genet. 52, 283–293 (2020).

pubmed: 32139907 pmcid: 7116784 doi: 10.1038/s41588-020-0584-7

Caravagna, G. et al. Detecting repeated cancer evolution from multi-region tumor sequencing data. Nat. Methods 15, 707–714 (2018).

pubmed: 30171232 pmcid: 6380470 doi: 10.1038/s41592-018-0108-x

Venkatesan, S., Birkbak, N. J. & Swanton, C. Constraints in cancer evolution. Biochem. Soc. Trans. 45, 1–13 (2017).

pubmed: 28202655 doi: 10.1042/BST20160229

Courtiol, P. et al. Deep learning-based classification of mesothelioma improves prediction of patient outcome. Nat. Med. 25, 1519–1525 (2019).

pubmed: 31591589 doi: 10.1038/s41591-019-0583-3

LaFave, L. M. et al. Loss of BAP1 function leads to EZH2-dependent transformation. Nat. Med. 21, 1344–1349 (2015).

pubmed: 26437366 pmcid: 4636469 doi: 10.1038/nm.3947

Yoshikawa, Y. et al. High-density array-CGH with targeted NGS unmask multiple noncontiguous minute deletions on chromosome 3p21 in mesothelioma. Proc. Natl Acad. Sci. USA 113, 13432–13437 (2016).

pubmed: 27834213 pmcid: 5127333 doi: 10.1073/pnas.1612074113

Wertz, I. E. et al. Sensitivity to antitubulin chemotherapeutics is regulated by MCL1 and FBW7. Nature 471, 110–114 (2011).

pubmed: 21368834 doi: 10.1038/nature09779

Inuzuka, H. et al. SCF(FBW7) regulates cellular apoptosis by targeting MCL1 for ubiquitylation and destruction. Nature 471, 104–109 (2011).

pubmed: 21368833 pmcid: 3076007 doi: 10.1038/nature09732

Stebbing, J. et al. The efficacy and safety of weekly vinorelbine in relapsed malignant pleural mesothelioma. Lung Cancer 63, 94–97 (2009).

pubmed: 18486273 doi: 10.1016/j.lungcan.2008.04.001

Fennell, D. A. et al. Maintenance defactinib versus placebo after first-line chemotherapy in patients with merlin-stratified pleural mesothelioma: COMMAND-A double-blind, randomized, phase II study. J. Clin. Oncol. 37, 790–798 (2019).

pubmed: 30785827 doi: 10.1200/JCO.2018.79.0543

Shapiro, I. M. et al. Merlin deficiency predicts FAK inhibitor sensitivity: a synthetic lethal relationship. Sci. Transl. Med. 6, 237ra268 (2014).

doi: 10.1126/scitranslmed.3008639

Tang, Y. et al. Selective inhibition of STRN3-containing PP2A phosphatase restores hippo tumor-suppressor activity in gastric cancer. Cancer Cell https://doi.org/10.1016/j.ccell.2020.05.019 (2020).

Fennell, D. Cancer-cell death ironed out. Nature 572, 314–315 (2019).

pubmed: 31406306 doi: 10.1038/d41586-019-02218-y

Kurppa, K. J. et al. Treatment-induced tumor dormancy through yap-mediated transcriptional reprogramming of the apoptotic pathway. Cancer Cell 37, 104–122.e112 (2020).

pubmed: 31935369 pmcid: 7146079 doi: 10.1016/j.ccell.2019.12.006

Su, D. et al. Identification of predictors of drug sensitivity using patient-derived models of esophageal squamous cell carcinoma. Nat. Commun. 10, 5076 (2019).

pubmed: 31700061 pmcid: 6838071 doi: 10.1038/s41467-019-12846-7

Mavrakis, K. J. et al. Disordered methionine metabolism in MTAP/CDKN2A-deleted cancers leads to dependence on PRMT5. Science 351, 1208–1213 (2016).

pubmed: 26912361 doi: 10.1126/science.aad5944

Kryukov, G. V. et al. MTAP deletion confers enhanced dependency on the PRMT5 arginine methyltransferase in cancer cells. Science 351, 1214–1218 (2016).

pubmed: 26912360 pmcid: 4997612 doi: 10.1126/science.aad5214

Marjon, K. et al. MTAP deletions in cancer create vulnerability to targeting of the MAT2A/PRMT5/RIOK1 axis. Cell Rep. 15, 574–587 (2016).

pubmed: 27068473 doi: 10.1016/j.celrep.2016.03.043

Alley, E. W. et al. Clinical safety and activity of pembrolizumab in patients with malignant pleural mesothelioma (KEYNOTE-028): preliminary results from a non-randomised, open-label, phase 1b trial. Lancet Oncol. 18, 623–630 (2017).

pubmed: 28291584 doi: 10.1016/S1470-2045(17)30169-9

Scherpereel, A. et al. Nivolumab or nivolumab plus ipilimumab in patients with relapsed malignant pleural mesothelioma (IFCT-1501 MAPS2): a multicentre, open-label, randomised, non-comparative, phase 2 trial. Lancet Oncol. 20, 239–253 (2019).

pubmed: 30660609 doi: 10.1016/S1470-2045(18)30765-4

Disselhorst, M. J. et al. Ipilimumab and nivolumab in the treatment of recurrent malignant pleural mesothelioma (INITIATE): results of a prospective, single-arm, phase 2 trial. Lancet Respir. Med. 7, 260–270 (2019).

pubmed: 30660511 doi: 10.1016/S2213-2600(18)30420-X

Fennell, D. A. et al. CONFIRM: a double-blind, placebo-controlled phase III clinical trial investigating the effect of nivolumab in patients with relapsed mesothelioma: study protocol for a randomised controlled trial. Trials 19, 233 (2018).

pubmed: 29669604 pmcid: 5907297 doi: 10.1186/s13063-018-2602-y

Li, H. et al. The Sequence Alignment/Map format and SAMtools. Bioinformatics 25, 2078–2079 (2009).

pubmed: 19505943 pmcid: 2723002 doi: 10.1093/bioinformatics/btp352

Yang, H. & Wang, K. Genomic variant annotation and prioritization with ANNOVAR and wANNOVAR. Nat. Protoc. 10, 1556–1566 (2015).

pubmed: 26379229 pmcid: 4718734 doi: 10.1038/nprot.2015.105

Malikic, S., McPherson, A. W., Donmez, N. & Sahinalp, C. S. Clonality inference in multiple tumor samples using phylogeny. Bioinformatics 31, 1349–1356 (2015).

pubmed: 25568283 doi: 10.1093/bioinformatics/btv003

Dang, H. X. et al. ClonEvol: clonal ordering and visualization in cancer sequencing. Ann. Oncol. 28, 3076–3082 (2017).

pubmed: 28950321 pmcid: 5834020 doi: 10.1093/annonc/mdx517

Bueno, R. et al. Comprehensive genomic analysis of malignant pleural mesothelioma identifies recurrent mutations, gene fusions and splicing alterations. Nat. Genet. 48, 407–416 (2016).

pubmed: 26928227 doi: 10.1038/ng.3520

Hundal, J. et al. pVACtools: a computational toolkit to identify and visualize cancer neoantigens. Cancer Immunol. Res. 8, 409–420 (2020).

pubmed: 31907209 pmcid: 7056579 doi: 10.1158/2326-6066.CIR-19-0401