Biological and Clinical Significance of PIM1 Genetic Alterations in Diffuse Large B-Cell Lymphoma

Background: PIM1 is a somatic hypermutation gene in diffuse large B-cell lymphoma (DLBCL) and its inhibitors exhibit a great value in application in multiple types of lymphoma. Nevertheless, investigation on its genetic alterations, biological characteristics, clinical significance and response to drugs is still lacking. Methods: We integrated the genome sequencing (discovery cohort, n=162; validation cohort, n=1001) and transcriptome sequencing (discovery cohort, n=140; validation cohort, n=928) to capture more detailed insights into the potentially biological functions of PIM1 genetic alterations, and analyzed their relationship with biological characteristics and clinical value which provide a possibility for risk stratification and therapeutic exploitation for patients with DLBCL. Results: PIM1 mutations were identified in 28.4% of DLBCL patients and significantly correlated with higher IPI scores (P=0.013), disease relapse (P=0.031) and CNS and/or testis involvement (P=0.001), as well as inferior PFS (P=0.022) and OS (P=0.0022). Multivariate analysis revealed that PIM1 mutation status was an independent poor prognostic factor (HR=2.86; 95% CI, 1.40-5.84; P=0.004). The most frequent PIM1 mutation type was missense mutations (84.1%), followed by frameshift deletions and nonsense mutations. During the distribution of base substitutions, C > T base substitution was predominant mutation type (54.4%), followed by C >G transversion (29.3%). During different exons, exon 4 of PIM1 was most often mutated. PIM1 mutations significantly co-occurred with the mutations of SETD1B (P Conclusions: PIM1 mutations play a vital role in patient risk stratification and provide novel insights into therapeutic decision making for DLBCL patients with high-risk score. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.