Next Generation Sequencing Highlights the Role of Cell Cycle and Apoptosis Dysregulation and Hepatitis B Infection in Refractory Diffuse Large B Cell Lymphoma

Abstract

About 10-15% DLBCL are primary refractory, the underlying biology aggressiveness contributed to refractoriness remain to be defined. To date, whole-exome (WES) or whole-genome sequences (WGS) obtained from primary or refractory/relapse DLBCL tumors have been published, while the biology study conduct on patients of mixed prognosis failed to characterizing the 10-15% primary refractory cases, and WES or WGS are not applicable in clinical routine practice. To address this issue, we performed target next generation sequencing in 11 primary refractory DLBCL cases. Through pathway enrichment analysis, as expected, the cell cycle/apoptosis and P53 signaling (FDR 10-11~10-9), NF-kB (FDR ~10-9), BCR signaling(FDR ~10-9), PI3K/Akt (FDR ~10-8), MAPK(FDR ~10-10), Wnt (FDR ~10-12), Jak/STAT (FDR ~10-14) signaling were significant mutated. Furthermore, some pathogen infection pathways were also significantly affected, which was not identified as significantly mutated in previous DLBCL WGS studies, including hepatitis B virus infection(HBV) signaling pathway involving BCL-2, MYC, MYD88, CREBBP, FAS, STAT3, TP53, and 4 of the 11 (36.4%) patients were HBsAg-positive. Overall, somatic mutations or copy number aberrations of CD79B (5/11, 45.5%), TP53(4/11, 36.3%), PIM1 (4/11, 36.3%) , MYD88 (3/11, 27.2%), KMT2D (3/11, 27.2%), CREBBP(3/11, 27.2%) and IRF4 (3/11, 27.2%) were the most prevalent aberrations. We separately compared the prevalence of target gene variants in our refractory (ref)-DLBCLs to published cohorts of responsive or de novo or relapse(rel) or relapse/refractory(r/r)-DLBCLs, the profile and frequency was highly concordant to those of relapse ones, while CD79B and cell cycle regulation or apoptosis related genes were more prevalent affected in our refractory cohort than those of responsive or de novo ones(table 2). [Display omitted] DisclosuresNo relevant conflicts of interest to declare.