The aim of the present study was to determine cell of origin (COO) from a platform using a DNA-based method, COO DNA classifier (COODC). A targeted exome-sequencing platform that applies the mutational profile of a sample was used to classify COO subtype. Two major mutational signatures associated with COO were identified: Catalogue of Somatic Mutations in Cancer (COSMIC) signature 23 enriched in activated B cell (ABC) and COSMIC signature 3, which suggested increased frequency in germinal center B cell (GCB). Differential mutation signatures linked oncogenesis to mutational processes during B-cell activation, confirming the putative origin of GCB and ABC subtypes. Integrating COO with comprehensive genomic profiling enabled identification of features associated with COO and demonstrated the feasibility of determining COO without RNA.
Keywords: activated B cell; cell of origin; diffuse large B-cell lymphoma; genomic profiling; germinal center B cell; mutational signature; next-generation sequencing.
Lay abstract To determine subtypes of diffuse large B-cell lymphoma (DLBCL), a cancer with poor survival, we aimed to identify DLBCL subtypes using DNA mutation-based tools. A targeted gene-sequencing platform, which measures the number and types of DNA mutations in a sample, was used to categorize DLBCL subtypes. Two major patterns of mutations associated with subtypes were identified: Catalogue of Somatic Mutations in Cancer (COSMIC) signature 23 and COSMIC signature 3. Differences in how the subtypes developed suggest a link between tumor developments and B cells being activated normally, confirming where the DLBCL subtypes came from. Combining this information with comprehensive genomic profiling, which determines all of the genes that a person has, allowed identification of features that are associated with DLBCL subtypes and showed that a DLBCL subtype can be determined without using RNA.