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Comprehensive genomic analysis of malignant pleural mesothelioma identifies recurrent mutations, gene fusions and splicing alterations

Abstract

We analyzed transcriptomes (n = 211), whole exomes (n = 99) and targeted exomes (n = 103) from 216 malignant pleural mesothelioma (MPM) tumors. Using RNA-seq data, we identified four distinct molecular subtypes: sarcomatoid, epithelioid, biphasic-epithelioid (biphasic-E) and biphasic-sarcomatoid (biphasic-S). Through exome analysis, we found BAP1, NF2, TP53, SETD2, DDX3X, ULK2, RYR2, CFAP45, SETDB1 and DDX51 to be significantly mutated (q-score ≥ 0.8) in MPMs. We identified recurrent mutations in several genes, including SF3B1 (2%; 4/216) and TRAF7 (2%; 5/216). SF3B1-mutant samples showed a splicing profile distinct from that of wild-type tumors. TRAF7 alterations occurred primarily in the WD40 domain and were, except in one case, mutually exclusive with NF2 alterations. We found recurrent gene fusions and splice alterations to be frequent mechanisms for inactivation of NF2, BAP1 and SETD2. Through integrated analyses, we identified alterations in Hippo, mTOR, histone methylation, RNA helicase and p53 signaling pathways in MPMs.

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Figure 1: Expression-based mesothelioma subtypes.
Figure 2: Mesothelioma somatic mutations.
Figure 3: Significantly mutated mesothelioma genes.
Figure 4: Multiple molecular mechanisms lead to activation or inactivation of genes.
Figure 5: Mutations in the splicing factor SF3B1 are associated with specific alterations in mRNA splicing.
Figure 6: Integrated analysis of pathway alterations observed in MPM.

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Acknowledgements

We acknowledge Genentech DNA Sequencing, Oligo and Bioinformatics groups for their help with the project. We also acknowledge the personnel of the tumor bank at the Brigham and Women's Hospital. We thank C.S. Rivers and C.J. Harris for the NGS library support. We thank Z. Zhang, P. George, K.V. Paul, P.M. Haverty, S. Jhunjhunwala, S. Sharma, B. Chow, J. Reeder and S. Lipscomb for the bioinformatics and computational support. This research was supported partly by grants to R.B. from the National Cancer Institute (2R01CA120528), The International Mesothelioma Program at Brigham and Women's Hospital and Genentech, Inc.

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Authors

Contributions

R.B. and S.S. conceived the study. R.B., E.W.S. and S.S. designed the experiments. E.W.S. oversaw the bioinformatics analysis and performed mutation and pathway analysis. L.D.G. performed splice variant analysis. S.D. performed gene expression and copy number analysis. F.G. performed whole-genome analysis. T.T.N. performed gene fusion analysis and neoantigen prediction. A.D.R., D.S. and N.D. were responsible for the samples and nucleic acid extractions. L.R.C. performed histological analysis. K.J.M. and W.G.R. managed the tissue repository and clinical annotation that supported the study. C.E.G. provided administrative, technical and material support. Z.M. oversaw collection of genomics data. Z.M. and Y.-J.C. performed validation of the fusions. T.D.W. supported gene fusion predictions. K.T. and C.H. prepared the sequencing libraries. B.S.J., S.C. and N.Z. performed biological validation studies. J.A.H. analyzed immune signatures. A.C. and R.G. were responsible for OncoMD. J.G. and J.S. collected sequencing data. D.J.S. and F.J.d.S. provided scientific and technical support. R.B., E.W.S., L.D.G., S.D., Z.M. and S.S. wrote the manuscript, which was reviewed and edited by the other coauthors.

Corresponding authors

Correspondence to Raphael Bueno, Eric W Stawiski or Somasekar Seshagiri.

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Competing interests

E.W.S., L.D.G., S.D., Z.M., F.G., T.T.N., B.S.J., J.A.H., A.C., R.G., J.G., K.T., C.H., Y.-J.C., J.S., S.C., N.Z., T.D.W., F.J.d.S. and S.S. are employees of Genentech Inc. or MedGenome Labs Pvt. Ltd. E.W.S., S.D., Z.M., F.G., B.J.S., J.A.H., J.G., K.T., C.H., Y.-J.C., J.S., S.C., N.Z., T.D.W., F.J.d.S. and S.S. hold shares in Roche. A.C. and R.G. hold stock options in MedGenome.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–21 (PDF 14921 kb)

Supplementary Table 1

Sample summary and information. (XLS 54 kb)

Supplementary Table 2

Differentially expressed genes in sarcomatoid versus epithelioid clusters. (XLS 1281 kb)

Supplementary Table 3

Sample-level exome coverage statistics. (XLS 18 kb)

Supplementary Table 4

Targeted gene panel. (XLS 17 kb)

Supplementary Table 5

Somatic mutations and germline variants of interest. (XLS 673 kb)

Supplementary Table 6

Mutation consequences. (XLS 8 kb)

Supplementary Table 7

Significantly mutated genes. (XLS 8 kb)

Supplementary Table 8

Hotspot mutations. (XLS 8 kb)

Supplementary Table 9

Meta-analysis–identified hotspot mutations. (XLS 18 kb)

Supplementary Table 10

Gene fusions. (XLS 103 kb)

Supplementary Table 11

Aberrant splice variants. (XLS 10 kb)

Supplementary Table 12

Mutant SF3B1–associated splice variants. (XLS 41 kb)

Supplementary Table 13

Tumor-infiltrating immune cell gene list and neoantigen prediction. (XLS 62 kb)

Supplementary Table 14

Significantly mutated pathways and pathway gene mutation frequencies. (XLS 13 kb)

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Bueno, R., Stawiski, E., Goldstein, L. et al. Comprehensive genomic analysis of malignant pleural mesothelioma identifies recurrent mutations, gene fusions and splicing alterations. Nat Genet 48, 407–416 (2016). https://doi.org/10.1038/ng.3520

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