Prognostic Significance ofKMT2DGene Mutation and Its Co-Mutated Genes in Patients with Diffuse Large B-Cell Lymphoma

Abstract:    Objective To explore the clinical characteristics of patients with diffuse large B-cell lymphoma (DLBCL) accompanied by KMT2D gene mutation and the impact of co-mutated genes on prognosis. Methods Clinical data of 155 newly diagnosed DLBCL patients with preserved paraffin-embedded tumor tissue specimens from March 2009 to March 2022 at the People's Hospital of Xinjiang Uygur Autonomous Region were selected. The second-generation sequencing method was used to detect 475 hotspot genes including KMT2D mutation. Patients were divided into KMT2D mutation group and KMT2D wild-type group based on the presence or absence of KMT2D gene mutation. Clinical characteristics, differences in co-mutated genes, and survival differences between the two groups were compared. Results The frequency of KMT2D mutation was 31%, predominantly seen in elderly patients (P=0.07) and less in double expressor phenotype (P=0.07). Compared with the KMT2D wild-type group, KMT2D gene mutation was associated with higher co-mutation rates of CDKN2A (OR=2.82,P=0.01) and BCL2 (OR=3.84, P=0.016), while being mutually exclusive with MYC gene mutation (OR=0.11, P=0.013). In univariate survival analysis, there was no statistically significant difference in overall survival (OS) between the KMT2D mutation group and the wild-type group (P=0.54). Further analysis of the prognostic significance of KMT2D with other gene mutations showed that patients with KMT2D^mutBTG2^mut had poorer OS compared to KMT2D^wt BTG2^mut (P=0.07) and KMT2D^wt BTG2^wt (P=0.05) patients, while patients with KMT2D^mut CD79B^mut showed a trend towards better OS compared to KMT2D^mut CD79B^wt patients (P=0.09), with no prognostic impact observed for other co-mutated genes. Multivariate Cox regression analysis including Ann Arbor stage, LDH level,Ki-67 index, KMT2D^mutBTG2^mut, and KMT2D^mut CD79B^wt revealed that Ann Arbor stage III and IV (HR=2.751, 95% CI 1.169-6.472, P=0.02), elevated LDH levels (HR=2.461, 95% CI 1.396-4.337, P=0.002), Ki-67 index>80% (HR=1.875, 95% CI 1.066-3.299, P=0.029), and KMT2D^mutBTG2^mut (HR=4.566, 95% CI 1.348-15.471, P=0.015) were independent risk factors for OS in DLBCL patients (P<0.05). Conclusion DLBCL patients with KMT2D mutation often have multiple gene mutations, among which patients with co-mutated BTG2 gene have poorer prognosis.