弥漫性大B细胞淋巴瘤基因变异特征与18F-FDG PET/CT SUVmax的关系解析及其临床意义

doi:10.19401/j.cnki.1007-3639.2025.06.002

摘要/Abstract

摘要：

背景与目的： 弥漫性大B细胞淋巴瘤（diffuse large B cell lymphoma，DLBCL）分子遗传学特征和患者治疗前¹⁸F-FDG PET/CT检查评估的SUV_max值均与患者预后密切相关，但两者的关系及其与R-CHOP治疗方案治疗反应的相关性尚不清楚。本研究旨在分析DLBCL分子遗传学特征与治疗前经¹⁸F-FDG PET/CT检测的SUV_max值的关系及其与临床病理学特征、R-CHOP治疗反应的相关性。方法： 回顾性收集复旦大学附属肿瘤医院2022—2023年同时经淋巴瘤481基因DNA panel二代测序（next-generation sequencing，NGS）和治疗前经PET/CT检查的DLBCL患者225例，本研究通过复旦大学附属肿瘤医院医学伦理委员会的审查（伦理批号：050432-4-2307E）并获得患者知情同意；除基因突变特征外，同时收集荧光原位杂交法检测的BCL2、BCL6和MYC基因易位情况；另收集该组病例的临床病理学参数以及经R-CHOP治疗后的PET/CT检查结果。结果： 总计191例DLBCL患者纳入最终分析，重要基因MYD88突变、TP53突变、CDKN2A/2B拷贝数异常、CD79B突变发生率分别为24.6%、27.2%、32.5%和16.8%。治疗前SUV_max值范围是5.10~63.10（24.44±10.70，中位22.80）。MYD88^L265P突变型DLBCL的治疗前SUV_max值显著高于MYD88野生型DLBCL（P=0.039），SUV_max值与DLBCL其他基因变异类型包括TP53突变、CDKN2A/B拷贝数减少、CD79B突变、KMT2D突变、TNFAIP3突变、B2M突变、EZH2突变、BTG1/2突变、CREBBP突变、MYC、BCL2、BCL6基因重排之间无显著的相关性。治疗前高SUV_max值与高血清乳酸脱氢酶（lactate dehydrogenase，LDH）水平（P=0.012）及非生发中心（non-germinal center B-cell-like，non-GCB）亚型显著相关（P=0.040），但与R-CHOP治疗反应无显著的相关性（P=0.714）。DLBCL中TP53基因突变与R-CHOP治疗反应差显著相关（P=0.001），是R-CHOP治疗后非完全代谢缓解的独立预测因子。联合TP53基因突变、Ann Arbor分期、国际预后指数（International Prognostic Index，IPI）及血清LDH水平能够更好地预测患者对R-CHOP治疗的反应。结论： 在DLBCL中，MYD88^L265P突变型患者具有较高的治疗前SUV_max值。DLBCL治疗前SUV_max值与R-CHOP治疗反应无关，而TP53基因突变与R-CHOP治疗反应差显著相关，并且是独立预测因子。TP53基因突变联合临床病理学参数可更好地预测R-CHOP治疗反应。关于各基因变异特征及SUV_max值与患者预后的关系尚需作进一步随访研究。

关键词: 弥漫性大B细胞淋巴瘤, 基因变异特征, ¹⁸F-FDG PET/CT, SUV_max, R-CHOP, 治疗反应

Abstract:

Background and purpose: Next generation sequencing-identified genetic alterations of diffuse large B cell lymphoma (DLBCL) and baseline SUV_max detected by ¹⁸F-FDG PET/CT were correlated with patients’ prognosis. However, their relationship and the associations with R-CHOP response of DLBCL are still unclear. This study aimed to analyze the association bewteen genetic alterations and ¹⁸F-FDG PET/CT SUV_max and their correlations with clinicopathological characteristics and R-CHOP response of DLBCL. Methods: A total of 225 cases of primary DLBCL detected by next generation sequencing using 481 lymphoma gene panel and examined by ¹⁸F-FDG PET/CT before treatment between 2022 and 2023 were collected. This study was approved by the Ethics Committee of Fudan University Shanghai Cancer Center (Ethical No.: 050432-4-2307E) and acquired the informed consent of the patients. The translocations of BCL2, BCL6 and MYC were identified by fluorescence in situ hybridization. The clinicopathological characteristics and the PET/CT scan after R-CHOP chemotherapy were collected. Results: Finally, 191 patients were enrolled in this study. The frequency of MYD88 mutation, TP53 mutation, copy number variations of CDKN2A/2B, CD79B mutation in the 191 DLBCL patients were 24.6%, 27.2%, 32.5% and 16.8%, respectively. The range of baseline SUV_max was 5.10-63.10 (24.44±10.70, median 22.80). The baseline SUV_max of MYD88^L265P DLBCL was significantly higher than that of MYD88 wild type (P=0.039). There were no significant associations of SUV_max with other gene alterations including TP53 mutation, CDKN2A/B loss, CD79B mutation, KMT2D mutation, TNFAIP3 mutation, B2M mutation, EZH2 mutation, BTG1/2 mutation, CREBBP mutation, gene translocations of MYC, BCL2 and BCL6. The higher SUV_max before treatment was correlated with higher serum lactate dehydrogenase (LDH) level (P=0.012) and non-germinal center B-cell-like (non-GCB) DLBCL (P=0.040). However, there was no significant association of SUV_max with R-CHOP response (P=0.714). TP53 mutation was significantly associated with the poor response of R-CHOP (P=0.001) and was an independent predictor of non-complete metabolic response (non-CMR). TP53 mutation combined with Ann Arbor stage, International Prognostic Index (IPI) score and serum LDH level could better predict R-CHOP response than each factor alone. Conclusion: MYD88^L265P DLBCL had higher baseline ¹⁸F-FDG PET/CT SUV_max. The baseline SUV_max was not associated with R-CHOP response. However, TP53 mutation was significantly correlated with poor response of R-CHOP in DLBCL patients. TP53 mutation combined with clinicopathological characteristics could better predict R-CHOP response. The associations of gene alterations and SUV_max with prognosis of DLBCL patients needed to be explored in the future.

Key words: Diffuse large B cell lymphoma, Genetic alterations, ¹⁸F-FDG PET/CT, SUV_max, R-CHOP, Therapeutic response

中图分类号:

R733.4

田田, 陈晨, 魏然, 包龙龙, 顾丙新, 张群岭, 曹军宁, 于宝华, 李小秋, 周晓燕. 弥漫性大B细胞淋巴瘤基因变异特征与¹⁸F-FDG PET/CT SUV_max的关系解析及其临床意义[J]. 中国癌症杂志, 2025, 35(6): 531-542.

TIAN Tian, CHEN Chen, WEI Ran, BAO Longlong, GU Bingxin, ZHANG Qunling, CAO Junning, YU Baohua, LI Xiaoqiu, ZHOU Xiaoyan. The research on the association between genetic alterations of DLBCLs and ¹⁸F-FDG PET/CT SUV_max and their clinical significance[J]. China Oncology, 2025, 35(6): 531-542.

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参考文献 20

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Clinicopathological characteristics	Case n(%)	SUV_max ($\bar{x}\pm s$)	P value	Mann-Whitney U value
Age/year
≤60	117 (61.2)	24.63±11.39	0.888	4 276
>60	74 (38.7)	24.14±9.57
Gender
Male	105 (55.0)	24.11±9.41	0.837	4 437
Female	86 (45.0)	24.84±12.13
Primary site
Nodal	56 (31.1)	24.15±12.31	0.468	3 237
Extranodal	124 (68.9)	24.50±9.59
Ann Arbor stage
Ⅰ-Ⅱ	70 (39.1)	23.96±10.95	0.678	3 674
Ⅲ-Ⅳ	109 (60.9)	24.66±10.25
IPI
Low (0-2)	106 (59.6)	22.81±10.12	0.408	946
High (3-5)	72 (40.4)	26.75±10.76
Serum LDH level (U·L^-1)
<250	106 (59.1)	22.69±9.68	0.012	2 975
≥250	72 (40.9)	26.67±11.04
Type (IHC)
GCB	84 (47.7)	22.63±9.27	0.040	3 194
Non-GCB	92 (52.3)	26.21±11.32
≥2 extranodal organs involved
Yes	115 (64.6)	24.31±10.71	0.990	3 618
No	63 (35.4)	24.40±10.25

Genetic alterations	Case n(%)	SUV_max ($\bar{x}\pm s$)	P value	Mann-Whitney U value
MYD88^L265P mutation
Positive	47 (24.6)	26.27±8.38	0.039	2 662
Negative	144 (75.4)	23.84±11.31
TP53 mutation
Positive	52 (27.2)	24.43±10.53	0.953	4 569
Negative	139 (72.8)	24.44±10.79
CDKN2A/B
Loss	62 (32.5)	24.2±9.87	0.978	3 989
Without loss	129 (67.5)	24.55±11.11
CD79B mutation
Positive	32 (16.8)	24.84±12.34	0.693	2 431
Negative	159 (83.2)	24.36±10.37
KMT2D mutation
Positive	42 (22.0)	23.52±9.50	0.705	3 009
Negative	149 (78.0)	24.70±11.02
TNFAIP3 mutation
Positive	23 (12.0)	28.13±12.73	0.229	1 632
Negative	168 (88.0)	23.93±10.33
B2M mutation
Positive	15 (7.9)	29.83±11.14	0.059	932
Negative	176 (92.1)	23.98±10.56
EZH2 mutation
Positive	8 (4.2)	22.33±9.44	0.536	635.5
Negative	183 (95.8)	24.53±10.76
BTG1/2 mutation
Positive	23 (12.0)	26.55±12.54	0.557	1 785
Negative	168 (88.0)	24.15±10.43
CREBBP mutation
Positive	13 (6.8)	22.44±9.80	0.423	1 001
Negative	178 (93.2)	24.58±10.77
MYC translocation
Positive	25 (13.1)	23.38±11.12	0.364	2 921
Negative	166 (86.9)	24.48±10.58
BCL6 translocation
Positive	61 (31.9)	24.92±10.17	0.349	4 175
Negative	130 (68.1)	24.03±11.16
BCL2 translocation
Positive	14 (7.3)	23.08±9.18	0.699	1 975
Negative	177 (92.7)	24.64±10.91
Double-hit
Yes	6 (3.1)	22.44±7.31	0.777	6 87.5
No	185 (96.9)	24.53±10.82

Variable	Univariate analysis			Multivariate analysis
Variable	OR	95% CI	P value	OR	95%CI	P value	B value	Std. error	Wald χ²
SUV_max
Low	1[Reference]
High	1.152	0.542-2.448	0.714
Age/year
≤60	1[Reference]
>60	1.268	0.584-2.752	0.548
Gender
Male	1[Reference]
Female	0.954	0.447-2.033	0.902
Primary site
Nodal	1[Reference]
Exnodal	0.510	0.223-1.164	0.111
Ann Arbor stage
Ⅰ-Ⅱ	1[Reference]
Ⅲ-Ⅳ	4.672	1.806-12.084	0.001	6.708	1.987-22.640	0.002	1.920	0.605	10.065
IPI
Low (0-2)	1[Reference]
High (3-5)	2.869	1.300-6.331	0.009	0.835	0.234-2.980	0.781	-0.043	0.535	0.006
Serum LDH level (U·L^-1)
<250	1[Reference]
≥250	2.714	1.252-5.887	0.011	2.377	0.876-6.453	0.089	0.896	0.491	3.333
Type (IHC)
GCB	1[Reference]
Non-GCB	0.871	0.405-1.871	0.723
≥2 extranodal organs involved
No	1[Reference]
Yes	1.519	0.695-3.318	0.295
MYD88 mutation	0.841	0.346-2.046	0.703
TP53 mutation	3.608	1.638-7.946	0.001	6.331	2.404-16.673	<0.001	1.765	0.479	13.598
CDKN2A/B loss	0.853	0.372-1.952	0.706
CD79B mutation	0.696	0.243-1.989	0.498
KMT2D mutation	1.173	0.473-2.905	0.731
TNFAIP3 mutation	0.240	0.030-1.901	0.176
B2M mutation	2.065	0.568-7.509	0.271
EZH2 mutation	2.137	0.485-9.428	0.316
BTG1/2 mutation	1.687	0.590-4.825	0.329
CREBBP mutation	0.841	0.170-4.155	0.832
Double-hit	5.484	0.879-34.238	0.069

弥漫性大B细胞淋巴瘤基因变异特征与¹⁸F-FDG PET/CT SUV_max的关系解析及其临床意义

The research on the association between genetic alterations of DLBCLs and ¹⁸F-FDG PET/CT SUV_max and their clinical significance

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