KMT2D基因突变及其共突变基因在弥漫性大B细胞淋巴瘤患者的预后意义

米吉提木提拜尔; 漆小龙; 热那古力·阿不来提; 田文昕; 马卫媛; 刘沙; 王增胜; 安利; 毛敏; 木合拜尔·阿布都尔; 李燕

doi:10.3971/j.issn.1000-8578.2025.24.0557

KMT2D基因突变及其共突变基因在弥漫性大B细胞淋巴瘤患者的预后意义

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

摘要

摘要: 　　目的探讨伴KMT2D基因突变弥漫性大B细胞淋巴瘤（DLBCL）患者的临床特征及其与伴随突变基因对预后的影响。方法选择2009年3月至2022年3月在新疆维吾尔自治区人民医院血液病科确诊，且留存石蜡包埋肿瘤组织标本的初诊155例DLBCL患者资料，采用二代测序方法检测包括KMT2D突变在内的475种热点基因。根据有无KMT2D基因突变将患者分为KMT2D基因突变型组及KMT2D基因野生型组，比较两组患者临床特征及伴随突变基因差异及生存差异。结果 KMT2D突变频率为31%，突变型患者老年患者居多（P=0.07），双表达阳性患者较少（P=0.07）。与KMT2D基因野生型相比, KMT2D基因突变分别与CDKN2A（OR= 2.82, P=0.01）和BCL2（OR =3.84, P=0.016）基因共突变率高，而KMT2D基因突变与MYC（OR =0.11, P=0.013）基因突变为相互排斥。单因素生存分析中，KMT2D基因突变型组和野生型组总生存（OS）差异无统计学意义（P=0.54），进一步分析KMT2D伴随其他基因突变预后意义，结果显示， KMT2D^mutBTG2^mut 突变患者较KMT2D^wt BTG2^mut（P=0.07）、KMT2D^wt BTG2^wt（P=0.05）患者具有较差OS，而 KMT2D^mu^t CD79B^mut 患者较KMT2D^mut CD79B^wt患者具有较好OS趋势（P=0.09），而其他伴随基因未发现预后影响。纳入Ann Arbor分期、LDH水平、Ki-67指数、KMT2D^mutBTG2^mut 、KMT2D^mut CD79B^wt多因素cox回归分析，结果显示，Ann Arbor分期为Ⅲ、Ⅳ（HR＝2.751，95% CI1.169 - 6.472，P=0.02）、LDH水平升高（HR＝2.461，95% CI1.396- 4.337，P=0.002）、Ki-67指数＞80%（HR＝1.875，95% CI 1.066 - 3.299，P=0.029）及KMT2D^mutBTG2^mut（HR＝4.566，95% CI1.348 - 15.471，P=0.015）是DLBCL患者OS的独立危险因素（P＜0.05）。结论 KMT2D突变的DLBCL患者常伴随多种基因突变，其中伴BTG2基因突变患者预后较差。
　　关键词弥漫性大Ｂ细胞淋巴瘤；二代测序；KMT2D基因；共突变；预后；

Abstract: 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^mutshowed a trend towards better OS compared to KMT2D^mut CD79B^wtpatients (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^wtrevealed 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.

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