Integrating genomic alterations in diffuse large B-cell Lymphoma identifies new relevant pathways and potential therapeutic targets

ABSTRACT: Genome studies of diffuse large B-cell lymphoma (DLBCL) have revealed a large number of somatic mutations and structural alterations that may contribute to their heterogeneous behavior. However, their clinical relevance and potential interest in identifying appropriate candidate drugs for personalized management are not well known. In this study, targeted next generation sequencing and genomic copy number alterations (CNA) were analyzed in 150 cases of diffuse large B-cell lymphoma (DLBCL) to define the clinical significance of recurrent genomic alterations and to identify potential targets for personalized management. An independent cohort of 111 patients was also analyzed to confirm the clinically significant findings. We found a differential profile of mutations, altered pathogenic pathways and CNA in germinal center B (GCB) and activated B-cell (ABC)-DLBCL with some shared alterations in both subtypes. Mutations in genes of the NOTCH pathway and tumor suppressor genes (TP53/CDKN2A), but not individual genes, conferred an unfavorable prognosis that was independent of other parameters and confirmed in the validation cohort. Tumors with NOTCH pathway mutations had a significant overexpression of downstream target genes, emphasizing the relevance of this pathway in DLBCL. We identified other new relevant genes including TMEM30A, RHOA, EBF, and TOX, among others. In silico drug discovery analysis recognized 69 (46%) cases carrying at least one genomic alteration considered a potential target of drug response according to early clinical trials (n=66) or pre-clinical assays (n=3) in DLBCL or other lymphomas. These findings orient future preclinical and clinical intervention strategies in DLBCL.

ORGANISM(S): Homo sapiens

PROVIDER: GSE94705 | GEO | 2018/03/14

REPOSITORIES: GEO