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

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

What do we really know about the Transatlantic Trade and Investment Partnership: Facts versus myths? Trying to understand social expectations

Purpose: The purpose of this work is to confront the social expectations of the TTIP, and how it effects the so-called "expert knowledge". Defining a mismatch between the social expectations and expert knowledge may contribute to better understanding of the controversies related to the TTIP. Using the NAFTA case study, we investigate if there is a significant gap between ex-ante and ex-post analysis of the Free Trade Agreement (FTA). Design/methodology/approach: We rely on Eurobarometer (2014, 2015) and Bertelsmann Foundation (2016) surveys to describe the TTIP-related social expectations. We make a critical overview of the global CGE models, which are the main source of ex-ante estimations of TTIP macro effects. We also use the NAFTA case study as a TTIP reference point that allows for a comparison of ex-ante with ex-post analysis results. Findings: Social expectations regarding the economic effects of the TTIP are ambiguous on both sides of the Atlantic. The CGE models have many limiting assumptions. They are, however, a useful tool for exploring the effects of the TTIP, bearing in mind all restrictions and limitations of ex-ante analyses. The NAFTA case study indicates that most ex-ante models tend to overestimate benefits and underestimate disadvantages arising from free trade. Research limitations/implications: Many such surveys have been conducted recently. The results should be developed upon, for a more detailed, country-specific and time variant understanding of possible sources of social conflicts in the context of the TTIP (or FTA) implementation. Originality/value: The analysis tends to prove the existence of a mismatch between social and expert knowledge on the TTIP, which may result in generating social conflicts. A practical and original outcome of our work is a well-supported recommendation to make the TTIP realistic effects much more transparent to the public, which should be important to those supporting the TTIP (and generally speaking FTA)

Gene fusions during the early evolution of mesothelioma correlate with impaired DNA repair and Hippo pathways

Malignant pleural mesothelioma (MPM), a rare cancer a long latency period (up to 40 years) between asbestos exposure and disease presentation. The mechanisms coupling asbestos to recurrent somatic alterations are poorly defined. Gene fusions arising through genomic instability may create novel drivers during early MPM evolution. We explored the gene fusions that occurred early in the evolutionary history of the tumor. We conducted multiregional whole exome sequencing (WES) of 106 samples from 20 patients undergoing pleurectomy decortication and identified 24 clonal nonrecurrent gene fusions, three of which were novel (FMO9P‐OR2W5, GBA3, and SP9). The number of early gene fusion events detected varied from zero to eight per tumor, and presence of gene fusions was associated with clonal losses involving the Hippo pathway genes and homologous recombination DNA repair genes. Fusions involved known tumor suppressors BAP1, MTAP, and LRP1B, and a clonal oncogenic fusion involving CACNA1D‐ERC2, PARD3B‐NT5DC2, and STAB2‐NT5DC2 fusions were also identified as clonal fusions. Gene fusions events occur early during MPM evolution. Individual fusions are rare as no recurrent truncal fusions event were found. This suggests the importance of early disruption of these pathways in generating genomic rearrangements resulting in potentially oncogenic gene fusions.</p

BAP1 loss induces mitotic defects in mesothelioma cells through BRCA1-dependent and independent mechanisms

This dataset includes the text, figures and supplementary material associated with the Oncogene submission MS#ONC-2022-0172

A gut microbiota rheostat forecasts responsiveness to PD-L1 and VEGF blockade in mesothelioma

Malignant mesothelioma is a rare tumour caused by asbestos exposure that originates mainly from the pleural lining or the peritoneum. Treatment options are limited, and the prognosis is dismal. Although immune checkpoint blockade (ICB) can improve survival outcomes, the determinants of responsiveness remain elusive. Here, we report the outcomes of a multi-centre phase II clinical trial (MiST4, NCT03654833) evaluating atezolizumab and bevacizumab (AtzBev) in patients with relapsed mesothelioma. We also use tumour tissue and gut microbiome sequencing, as well as tumour spatial immunophenotyping to identify factors associated with treatment response. MIST4 met its primary endpoint with 50% 12-week disease control, and the treatment was tolerable. Aneuploidy, notably uniparental disomy (UPD), homologous recombination deficiency (HRD), epithelial-mesenchymal transition and inflammation with CD68+ monocytes were identified as tumour-intrinsic resistance factors. The log-ratio of gut-resident microbial genera positively correlated with radiological response to AtzBev and CD8+ T cell infiltration, but was inversely correlated with UPD, HRD and tumour infiltration by CD68+ monocytes. In summary, a model is proposed in which both intrinsic and extrinsic determinants in mesothelioma cooperate to modify the tumour microenvironment and confer clinical sensitivity to AtzBev. Gut microbiota represent a potentially modifiable factor with potential to improve immunotherapy outcomes for individuals with this cancer of unmet need.</p