p53 rs1625895基因多态性与弥漫大B细胞淋巴瘤预后相关性分析

doi:10.19723/j.issn.1671-167X.2019.05.001

摘要/Abstract

摘要：

目的:p53基因是目前研究最广泛的抑癌基因,其生物功能好似“基因组卫士”。既往研究表明大约50%的肿瘤存在P53蛋白功能缺陷,本文旨在回顾性分析p53 rs1625895基因多态性与弥漫大B细胞淋巴瘤(diffuse large B-cell lymphoma, DLBCL)患者预后的相关性。方法:以384例DLBCL患者为研究对象,采用Sanger法测序其p53 rs1625895基因型,分析rs1625895基因多态性与患者临床特征、一线化疗疗效及预后的关系。结果:所有患者中AA型2例(0.5%),AG型34例(8.9%),GG型348例(90.6%)。rs1625895基因型与患者年龄、性别、B症状[指出现以下任一症状:原因不明反复发热(常在38 ℃以上)、盗汗、原因不明6个月内体质量减少10%]、红细胞沉降率(erythrocyte sedimentation rate,ESR)、国际预后指数(international prognostic index,IPI)评分、分子分型等临床病理学特征均无明显相关性(P > 0.05)。AA/AG与GG型患者的一线化疗总有效率(overall response rate,ORR)分别为82.9%和82.8%,差异无统计学意义(P > 0.05)。AA/AG和GG基因型的5年无进展生存率(progression-free survival rate, PFS)分别为71.8%和62.3%(χ ²= 1.351,P = 0.245),5年总生存率(overall survival rate, OS)分别为72.2%和64.1%(χ ²= 1.267,P = 0.260),差异均无统计学意义。亚组分析显示,在生发中心(germinal center B-cell, GCB)亚组中,AA/AG和GG基因型患者的5年PFS分别为91.7%和72.7%(χ ²= 4.493,P = 0.034);5年OS分别为91.7%和76.7%(χ ²= 4.246,P = 0.039),差异均有统计学意义,AA/AG基因型患者预后明显优于GG型患者。而在非生发中心(non-germinal center B-cell, non-GCB)亚组,AA/AG和GG型的5年PFS及OS差异均无统计学意义(P > 0.05)。根据一线方案是否含有利妥昔单抗将患者分为环磷酰胺、多柔比星、长春新碱和泼尼松(cyclophosphoramide, doxorubicin, vincristine, prednisone, CHOP)治疗组及利妥昔单抗联合环磷酰胺、多柔比星、长春新碱和泼尼松(rituximab, cyclophosphoramide, doxorubicin, vincristine, prednisone, R-CHOP)治疗组,结果在不同亚组中,AA/AG和GG型的5年PFS及OS差异也无统计学意义(P > 0.05)。结论:对于一线接受CHOP方案化疗的DLBCL患者,p53 rs1625895不能预测患者的临床疗效和预后,但在GCB型患者中,rs1625895有可能成为判断预后的预测指标。

关键词: 弥漫大B细胞淋巴瘤, p53基因, 单核苷酸多态性

Abstract:

Objective: p53 gene, as “the guardian of the genome”, is the most widely studied tumor suppressor gene. Previous studies have shown that about 50 percent of tumors have P53 dysfunction. This article aims to retrospectively analyze the correlation between p53 rs1625895 polymorphism and the prognosis of patients with diffuse large B-cell lymphoma (DLBCL). Methods: PCR combined with Sanger sequencing were used to detect rs1625895 genotype in 384 DLBCL patients. The relationship between rs1625895 polymorphisms and the clinical characteristics, first-line therapeutic effects and the prognosis of the patients were analyzed. Results: Among all the patients, 2 (0.5%) patients with AA genotype, 34 (8.9%) patients with AG genotype and 348 (90.6%) patients with GG genotype were identified. The patients with different rs1625895 genotypes did not have any difference in terms of age, gender, B symptoms (developing any of the following symptoms: unexplained recurrent fever (often above 38 ℃), night sweats, and unexplained weight loss of 10% within 6 months ), erythrocyte sedimentation rate (ESR), international prognostic index (IPI) and molecular subtype (P>0.05). The overall response rate (ORR) was 82.9% and 82.8% in AA/AG and GG, respectively. There was no significant dif-ference between the first-line therapeutic effects of the two groups (P>0.05). And there was also no difference between A allele carriers and homozygous G allele carriers for the 5-year progression-free survival rate (PFS) (71.8% vs. 62.3%, χ ² = 1.351, P=0.245) and 5-year overall survival rate (OS) (72.2% vs. 64.1%, χ ² = 1.267, P = 0.260). But in the subgroup with Germinal Center B-cell (GCB) type, the patients carrying A allele for rs1625895 had an obviously longer PFS (91.7% vs. 72.7%, χ ² = 4.493,P = 0.034) and OS (91.7% vs. 76.7%, χ ² = 4.246, P = 0.039) compared with the patients homozygous for the G allele. As for the patients with non-GCB subtype, there was no significant difference in PFS and OS between different rs1625895 genotypes (P>0.05). According to whether the first-line regimen contained rituximab or not,the patients were divided into two groups treated with cyclophosphoramide, doxorubicin, vincristine and prednisone (CHOP) or with rituximab and CHOP (R-CHOP). But in both subgroups, there was no significant difference in the 5-year PFS and OS between the AA/AG and GG patients,too (P>0.05). Conclusion: For DLBCL patients receiving CHOP regimen chemotherapy in the first line, p53 rs1625895 cannot predict the clinical efficacy and prognosis of the patients, but in the patients with GCB subtype, this polymorphism may be a prognostic indicator.

Key words: Diffuse large B-cell lymphoma, p53 gene, Single nucleotide polymorphism

中图分类号:

R730.5

田艳,朱军. p53 rs1625895基因多态性与弥漫大B细胞淋巴瘤预后相关性分析[J]. 北京大学学报（医学版）, 2019, 51(5): 791-796.

Yan TIAN,Jun ZHU. Relationship between p53 rs1625895 polymorphism and prognosis in diffuse large B-cell lymphoma[J]. Journal of Peking University(Health Sciences), 2019, 51(5): 791-796.

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参考文献 21

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Clinical parameters	n	Genotype		χ²	P
Clinical parameters	n	AA/AG	GG	χ²	P
Age/years
≤60	241	22	219	0.046	0.830
>60	143	14	129
Gender
Male	197	18	179	0.027	0.870
Female	187	18	169
Subtype (no data were available for 39 patients)
GCB	102	13	89	1.693	0.193
Non-GCB	243	20	223
Ki67 (no data were available for 27 patients)
≤75%	171	16	155	0.062	0.803
>75%	186	16	170
Stage (no data were available for 1 patient)
Ⅰ-Ⅱ	178	19	159	0.635	0.426
Ⅲ-Ⅳ	205	17	188
B symptoms
Negative	252	25	227	0.257	0.612
Positive	132	11	121
ECOG score
0-1	344	32	312	0.021	0.886
2-3	40	4	36
IPI score
0-2	270	26	244	0.069	0.792
3-5	114	10	104
LDH (no data were available for 2 patients)
≤240/ IU/L	221	22	199	0.173	0.677
>240/ IU/L	161	14	147
β₂-MG (no data were available for 15 patients)
Negative	272	28	244	0.789	0.374
Positive	97	7	90
ESR (no data were available for 14 patients)
Negative	162	12	150	0.810	0.368
Positive	208	21	187
Treatment
CHOP	118	11	107	0.001	0.981
R-CHOP	266	25	241

Response	n	Genotype		χ²	P
Response	n	AA/AG, n(%)	GG, n(%)	χ²	P
Grouped by CR
PR+SD+PD	160	12(34.3)	148(43.1)	1.022	0.312
CR	218	23(65.7)	195(56.9)
Grouped by OR
PD+SD	65	6(17.1)	59(17.2)	0.000	0.993
OR(CR+PR)	313	29(82.9)	284(82.8)

Variable	B	SE	Wald	df	P	HR	95%CI
Subtype(non-GCB vs. GCB)	0.546	0.244	4.997	1	0.025	1.727	1.070-2.787
Response(CR vs. PR+SD+PD)	-1.593	0.216	54.159	1	<0.001	0.203	0.133-0.311
B symptoms(positive vs. negative)	0.424	0.194	4.810	1	0.028	1.529	1.046-2.234
β₂-MG(positive vs. negative)	0.637	0.198	10.356	1	0.001	1.890	1.283-2.785