Here, DZsig+ and GCB-subtype rrDLBCL tumors demonstrated distinct mutational profiles, observing several mutations in genes with established potential in lymphoma, predominantly impacting DZsig+ (ARID1A, BCL2, BCL6, CREBBP, EZH2, IKZF3, SPEN, TP53) and GCB (CIITA, EP300, KMT2D, SOCS1, STAT6) samples, and CNV events were observed with higher relative frequency in GCB rrDLBCL. This evidence concerns the gene SPEN and lymphoma.