For the first time in mesothelioma, a group of researchers sequenced the genome of 74 malignant pleural mesothelioma tumors. According to the authors, the study provides a “deeper understanding of histology-independent 17 determinants of aggressive behavior” and defines “a novel genomic subtype with TP53 and 18 SETDB1 mutations and extensive loss of heterozygosity” and discover “strong 19 expression of the immune checkpoint gene VISTA in epithelioid MPM.” The study was published Cancer Discover, a journal of the American Association for Cancer Research (AACR).
In lay language, this last point is important to those following advances in immunotherapy in mesothelioma because it provides a possible explanation as to why some mesotheliomas respond poorly to such therapies. Other important findings published in this study will help researchers in other areas as well focus their research and future clinical trials.
This study, which began in 2012, covers a number of genomic characteristics. One of the study’s authors, Marc Ladanyi of Memorial Sloan Kettering Cancer Center, explained some of the findings yesterday on Twitter. Some of this information is incredibly complicated and will take some time to digest. But one thing is certain. This is a significant step toward more effective treatments for mesothelioma.
These findings and their significance will be discussed at length during the Meso Foundation’s next Symposium on March 25-27. Learn more about the conference here.
2/ #mesothelioma are low TMB tumors (<2 mut/MB) with few significantly mutated genes (BAP1, NF2, TP53, SETD2, SETDB1)), numerous recurrent losses (BAP1, CDKN2A, NF2, LATS1, LATS2) and no significantly recurrent gains.
— Marc Ladanyi (@MLadanyi) October 15, 2018
4/ Integrative Multi-Platform Analysis of #mesothelioma using iCluster and PARADIGM Defined Novel Prognostic Subsets independent of known prognostic factors such as histology and CDKN2A deletion pic.twitter.com/T2K9x5BL17
— Marc Ladanyi (@MLadanyi) October 15, 2018
5/ #mesothelioma, especially the better differentiated epithelioid type, expresses outlier high levels of VISTA (V-domain Ig Suppressor of T-cell Activation), an immune checkpoint molecule similar to PD-L1. It is also expressed on normal mesothelium. pic.twitter.com/zceXkDBaSa
— Marc Ladanyi (@MLadanyi) October 15, 2018
7/ one more aspect of potential Rx relevance: most #mesothelioma with CDKN2A deletion also have co-deletion of adjacent MTAP. MTAP deficiency reported to lead to lower PRMT5 activity & hypersensitivity to its inhibition, so such pts may be candidates for pathway inhibitor trials. pic.twitter.com/5P0CG2vbAY
— Marc Ladanyi (@MLadanyi) October 15, 2018
8/ There is lots more in the paper (BAP1 genomic correlates, clinical correlates of miRNAs & lncRNAs, other immune checkpoint molecules, etc, etc…), years of work by an enormous and dedicated team. ???? https://t.co/VPbi7fDek0
— Marc Ladanyi (@MLadanyi) October 15, 2018
