Posted: Wednesday, August 3, 2022
Genetic investigation into the pathogenesis of primary mediastinal large B-cell lymphoma (LBCL) revealed a previously underappreciated role of specific chromatin-modifying genes. These findings from Daniel Noerenberg, MD, of the Charité Universitätsmedizin Berlin, and colleagues, which were presented at the European Hematology Association (EHA) 2022 Congress (Abstract S101) during the Presidential Symposium, offer a firm basis for guiding approaches to precision medicine for oncologists treating patients with this type of hematologic malignancy.
A total of 486 patients with previously untreated primary mediastinal LBCL were analyzed by paired tumor/normal whole-genome sequencing, whole-exome sequencing, and targeted sequencing. The analysis focused on specific protein-coding genes. Functional and multiomics analyses were used to combine the data sets from each previously analyzed gene and to apply the required mathematical testing. These analyses were performed in CRISPR/Cas9-engineered cell lines and cultures of cells repeatedly propagated in vitro.
The complex genetics behind primary mediastinal LBCL are well illustrated by the results of whole-genome sequencing and whole-exome sequencing. Investigation revealed 85 structural variants, a 5-mutation/Mb mutational burden, 12 mutated coding candidate driver genes, and 4 focal somatic copy-number aberrations per sample. Aside from the previously known genetic targets, new breakpoints were noticed in the TOX, TP73, and PAX5 genes. These genes had previously not been associated with B-cell lymphomagenesis.
Furthermore, the 10 most frequently mutated candidate driver genes were SOCS1 (86%), B2M (67%), ITPKB (64%), ACTB (58%), STAT6 (58%), IGLL5 (56%), TNFAIP3 (53%), NFKBIE (49%), GNA13 (47%), and ZNF217 (36%). In addition, based on targeted sequencing in nearly 500 samples, using a primary mediastinal LBCL 106-gene panel, recurrent lesions in 25 epigenetic modifiers were found in more than 90% of samples; ZNF217 was identified as the most frequently mutated gene.
Further research efforts point in the direction of analyzing the exact roles of these genes in the pathogenesis of primary mediastinal LBCL. Such study may help to identify novel treatment targets for this patient population.
Disclosure: For full disclosures of the study authors, visit library.ehaweb.org.