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James McKay



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    MA12 - New Frontiers from Pathology to Genomics (ID 138)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Mesothelioma
    • Presentations: 1
    • Now Available
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      MA12.01 - Redefining Malignant Pleural Mesothelioma Types as a Continuum Uncovers Immune-Vascular Interactions (Now Available) (ID 1773)

      14:00 - 15:30  |  Author(s): James McKay

      • Abstract
      • Presentation
      • Slides

      Background

      Malignant Pleural Mesothelioma (MPM) is a deadly disease. The current histopathologycal classification recognises three major types (epithelioid, biphasic, and sarcomatoid) with different prognosis, but showes high interobserver variability. This classification also has a role in the clinical decision-making although, ultimately, MPM becomes refractory to all conventional treatment modalities, and alternative therapeutic options have been evaluated with limited success.

      Method

      We have performed unsupervised analyses of publicly available RNA-seq data of 284 MPM tumours1,2 with no assumption of discreteness. We have performed an orthogonal validation in a subset of 187 samples, and we have replicated the findings in an independent series of 77 MPM from the French MESOBANK.

      Result

      A continuum of molecular profiles appeared to explain the prognosis of this disease better than discrete models based on the histopathological classification or on expression data. We identified the immune and vascular pathways as major sources of molecular variation, with strong differences in the expression of immune checkpoints and pro-angiogenic genes across samples; the extrema of this continuum had very specific molecular profiles: a "hot" bad-prognosis profile (median survival of 7 months), with high lymphocyte infiltration, and high expression of immune checkpoints and pro-angiogenic genes; a "cold" bad-prognosis profile (median survival of 10 months), with low lymphocyte infiltration and high expression of pro-angiogenic genes; and a better-prognosis profile (VEGFR2+/VISTA+, median survival of 36 months), with high expression of the immune checkpoint VISTA and the pro-angiogenic VEGFR2 gene. We selected five genes belonging to the immune and vascular pathways (CD8A, PDL1, VEGFR3, VEGFR2, and VISTA), which expression was enough to capture the three molecular profiles, to validate the expression of these genes at the protein level by immunohistochemistry on a subset of 187 samples from the discovery cohort, and to replicate the molecular profiles as well as their prognostic value in an independent series of 77 MPMs.

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      Conclusion

      In this study we found that the prognosis of MPM is best explained by a continuous model, which extremes show characteristic molecular profiles with specific expression patterns of genes involved in the angiogenesis and immune response3. These data may inform future classifications of MPM and provides insights that may assist the clinical management of this disease.

      1Bueno et al., Nat Genet 2016; 2Hmeljak et al., Cancer Discov 2018; 3Alcala et al., under review in Cancer Res; NA and LM equally contributed to this work; MF, FGS, and LFC jointly supervised this work

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