Distinct subtypes of diffuse large B-cell lymphoma defined by hypermutated genes.
Amjad AlkodsiAlejandra CerveraKaiyang ZhangRiku LouhimoLeo MerirantaAnnika PasanenSuvi-Katri LeivonenHarald HolteSirpa LeppaRainer LehtonenSampsa HautaniemiPublished in: Leukemia (2019)
Diffuse large B-cell lymphoma (DLBCL) is a biologically and clinically heterogeneous disease whose personalized clinical management requires robust molecular stratification. Here, we show that somatic hypermutation (SHM) patterns constitute a marker for DLBCL molecular classification. The activity of SHM mutational processes delineated the cell of origin (COO) in DLBCL. Expression of the herein identified 36 SHM target genes stratified DLBCL into four novel SHM subtypes. In a meta-analysis of patients with DLBCL treated with immunochemotherapy, the SHM subtypes were significantly associated with overall survival (1642 patients) and progression-free survival (795 patients). Multivariate analysis of survival indicated that the prognostic impact of the SHM subtypes is independent from the COO classification and the International Prognostic Index. Furthermore, the SHM subtypes had a distinct clinical outcome within each of the COO subtypes, and strikingly, even within unclassified DLBCL. The genetic landscape of the four SHM subtypes indicated unique associations with driver alterations and oncogenic signaling in DLBCL, which suggests a possibility for therapeutic exploitation. These findings provide a biologically driven classification system in DLBCL with potential clinical applications.
Keyphrases
- diffuse large b cell lymphoma
- epstein barr virus
- free survival
- end stage renal disease
- newly diagnosed
- chronic kidney disease
- ejection fraction
- machine learning
- genome wide
- deep learning
- prognostic factors
- peritoneal dialysis
- single cell
- patient reported outcomes
- cell therapy
- single molecule
- mesenchymal stem cells
- data analysis