Abstract
The well-established cell-of-origin (COO) algorithm categorizes diffuse large B-cell lymphoma (DLBCL) into activated B-cell-like (ABC) and germinal center B-cell-like (GCB) subgroups through gene expression profiling. We aimed to develop and validate a qPCR-based gene expression assay to determine the COO subgroups of DLBCL with formalin-fixed paraffin-embedded (FFPE) tissue. We first established a DLBCL transcriptome database of 1,016 samples retrieved from three published datasets (GSE10846, GSE22470, and GSE31312). With this database, we identified a qPCR-based 32-gene expression signature (DLBCL-COO assay) that is significantly associated with the COO subgroups. The DLBCL-COO assay was further validated in a cohort of 160 Chinese DLBCL patients. Biopsy samples from DLBCL patients with paired FFPE and fresh frozen tissue were collected to assign COO subtypes based on the immunohistochemistry (IHC) algorithm (Han's algorithm), DLBCL-COO assay, and global gene expression profiling with RNA-seq. For 111 paired FFPE and fresh DLBCL samples, the concordance between the IHC, qPCR, and RNA-seq methods was 77.5% and 91.9%, respectively. The DLBCL-COO assay demonstrated a significantly superior concordance of COO determination with the “gold standard” RNA-seq compared with the IHC assignment with Han's algorithm (P = 0.005). Furthermore, the overall survival of GCB patients defined by the DLBCL-COO assay was significantly superior to that of ABC patients (P = 0.023). This effect was not seen when the tumors were classified by the IHC algorithm. The DLBCL-COO assay provides flexibility and accuracy in DLBCL subtype characterization. These findings demonstrated that the DLBCL-COO assay might serve as a useful tool for guiding prognostic and therapeutic options for DLBCL patients.
Highlights
Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of malignant lymphomas, accounting for more than 40% of newly diagnosed cases
When the probability predicted by the DLBCLCOO assay that a sample belongs to the activated B-cell-like (ABC) or germinal center B-cell-like (GCB) subgroup is >75%, the specimen is classified as the ABC or GCB subtype
To create a diffuse large B-cell lymphoma (DLBCL) transcriptome database for COO subtype classification, we performed a systematic search of major biological data repositories [e.g., ArrayExpress, Gene Expression Omnibus (GEO), and The Cancer Genome Atlas (TCGA)] to collect gene expression data sets of DLBCL samples with a confirmed COO subtype status
Summary
Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of malignant lymphomas, accounting for more than 40% of newly diagnosed cases. DLBCL has been recognized as a group of heterogeneous diseases with diverse genetic features and variable clinical outcomes. There were at least two distinct groups within DLBCL: the germinal center B-cell-like (GCB) group and the activated B-cell-like (ABC) group. This method is widely recognized as the cellof-origin (COO) classification algorithm. In a series of large randomized clinical studies following the establishment of COO classification, DLBCL patients with the ABC subtype showed significantly inferior characteristics compared with those with the GCB subtype, even in the clinical study evaluating the efficacy of immune chemotherapy [2]
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