弥漫大B细胞淋巴瘤MYD88 L265P基因突变与R-CHOP方案治疗效果及预后关系的研究

发布时间：2018-06-12 01:54

本文选题：弥漫大B细胞淋巴瘤 + MYD88突变　；参考：《西南医科大学》2016年硕士论文

【摘要】：研究背景及目的:弥漫大B细胞淋巴瘤是成人最常见的非霍奇金淋巴瘤,主要临床表现为无痛性、进行性淋巴结肿大。在老年人的发病率较高,中位发病年龄70岁,偶可见于儿童及青少年。DLBCL是一类高度侵袭性肿瘤,R-CHOP方案一线诱导治疗可使约70%的患者得到治愈,但仍有近三分之一的患者在治疗后短期内复发甚至治疗过程中即出现肿瘤进展。因此,从肿瘤分子生物学及细胞遗传学等方面进一步探寻肿瘤发生、发展及耐药的机制,寻找更能反映肿瘤预后的预测指标,为DLBCL的治疗提供新的治疗靶点及思路已成为目前研究的重点。有研究发现,在多种B细胞肿瘤中有功能活化的MYD88 L265P基因突变,导致下游如NF-κB、JAK-STAT3等信号通路的异常激活,与肿瘤发生、浸润转移、耐药及预后密切相关。本研究通过检测弥漫大B细胞淋巴瘤患者MYD88 L265P基因突变情况,分析突变与DLBCL临床病理特征的关系,初步探讨该基因突变与DLBCL标准治疗方案R-CHOP治疗效果及预后的关系。方法:收集2007年1月至2015年1月四川省肿瘤医院53例弥漫大B细胞淋巴瘤患者的临床资料及存档蜡块,所有入组病例均为CD20+、首诊初治、至少完成3个周期R-CHOP方案化疗的DLBCL。从所收集的石蜡包埋组织中提取DNA,采用半巢式SYBR Green I荧光染料法实时定量等位基因特异性PCR技术对所提取DNA进行MYD88 L265P基因突变检测,分析其与DLBCL临床病理特征、R-CHOP方案治疗效果和预后的关系。采用SPSS20统计软件进行统计学分析,其中计量资料采用Mann-Whitney U检验,计数资料采用卡方检验、Fish确切概率法、Log-rank单因素分析及Cox多因素分析。结果:从入组的53例弥漫大B细胞淋巴瘤患者样本中,成功检测到16例携带MYD88 L265P基因突变,突变率为30.19%。16例突变病例中,GCB型DLBCL 5例,ABC型11例,结外受侵12例(其中1例原发睾丸、2例原发甲状腺),另有原发脾脏及纵膈各1例。统计分析显示,MYD88L265P突变与DLBCL患者年龄及是否有结外受侵具有相关性(X2=5.014,4.520;P=0.025,0.033),对于高龄、有结外受侵的DLBCL患者MYD88L265P突变率较高,在性别、B症状、分期、分型、IPI评分、ECOG评分、LDH及Ki-67水平等临床特征方面,突变组与野生组的分布无明显差异(P0.05)。对DLBCL标准一线R-CHOP方案治疗效果进行对比分析,结果显示性别与治疗反应具有相关性(X2=4.802,P=0.035),女性对R-CHOP方案一线诱导治疗反应较男性好,而MYD88 L265P突变组与野生组对治疗反应的差异性无统计学意义(P0.05),进一步分析一线诱导化疗达到CR/PR患者疾病的复发情况,结果提示MYD88 L265P突变与疾病复发亦无统计学关联(P0.05)。Log-rank单因素生存分析显示,B症状及Ki-67状态与PFS具有相关性(P=0.004,0.030),而Cox多因素分析显示仅B症状与PFS相关(P=0.012)。单因素分析MYD88 L265P基因突变与OS及PFS均无统计学相关性(P0.05)。对所有入组样本采用寿命表法进行生存分析,结果显示,53例DLBCL患者中位OS和PFS分别为58.37和31.71月,MYD88 L265P突变组中位OS和PFS分别为40.16和27.84月,野生组中位OS和PFS分别为72和41.33月,但采用Mann-Whitney U检验对两组样本OS及PFS进行分析,显示差异无统计学意义(P=0.367,0.594)。结论:(1)1、DLBCL患者MYD88 L265P基因突变率高,尤其是高龄、有结外受侵的患者,对于这部分病人的治疗,MYD88及其依赖的信号通路可能是潜在的治疗靶点。(2)MYD88突变与DLBCL对R-CHOP方案治疗反应及一线诱导化疗后疾病进展或复发无统计学相关性,R-CHOP低反应性的DLBCL患者治疗效果差的原因还需更多分子生物学等方面的研究来明确。(3)MYD88 L265P突变与DLBCL疾病预后无明显统计学关联,可能与入组病例数少、随访时间短、选择偏倚或其他影响因素有关,尚需扩大样本量进一步验证。
[Abstract]:Background and purpose: diffuse large B cell lymphoma is the most common non Hodgkin lymphoma in adults. The main clinical manifestations are painless and progressive lymph node enlargement. The incidence is high in the elderly and the median age is 70 years old. I can be seen in children and adolescents with.DLBCL as a type of highly invasive tumor, and R-CHOP regimen is induced by first-line therapy. About 70% of the patients can be cured, but nearly 1/3 of the patients still have a tumor progression in the short term and even in the course of treatment. Therefore, the mechanism of tumor development, development and drug resistance are further explored from the molecular biology and cytogenetics of the tumor to find a prediction index that can better reflect the prognosis of the tumor, for DL BCL therapy provides new targets and ideas for treatment. It has been found that the functional activation of MYD88 L265P gene mutations in a variety of B cell tumors lead to abnormal activation of the downstream signal pathways such as NF- kappa B, JAK-STAT3 and so on, which are closely related to tumor occurrence, invasion, metastasis, drug resistance and prognosis. The mutation of MYD88 L265P gene in the patients with diffuse large B cell lymphoma, the relationship between the mutation and the clinicopathological features of DLBCL, and the relationship between the gene mutation and the R-CHOP treatment effect and prognosis of the DLBCL standard treatment scheme. Methods: 53 patients with diffuse large B cell lymphoma in Sichuan province from January 2007 to January 2015 were collected. All the clinical data and archived wax blocks were all CD20+, first treatment, and at least 3 cycles of R-CHOP chemotherapy for DLBCL. were extracted from the paraffin embedded tissues of the collected DNA, and the semi nested SYBR Green I fluorescent dye method was used for real-time quantitative allele specific PCR technique to detect MYD88 L265P gene mutation of the extracted DNA. The relationship between the DLBCL clinicopathological features, the therapeutic effect and the prognosis of the R-CHOP regimen was analyzed. The statistical analysis was carried out by the SPSS20 statistical software, with the measurement data using the Mann-Whitney U test, the counting data using the chi square test, the exact probability of Fish, the Log-rank single factor analysis and the Cox multifactor analysis. The results were 53 cases from the group. In the sample of diffuse B cell lymphoma, 16 cases of MYD88 L265P gene mutation were detected, the mutation rate was 30.19%.16 case mutation, GCB DLBCL 5 cases, ABC type 11 cases, 12 cases of extranodal invasion (1 cases of primary testis, 2 cases of primary thyroid), and 1 cases of primary spleen and mediastinum. Statistical analysis showed MYD88L265P mutation and DLBCL There was a correlation between patients' age and extranodal invasion (X2=5.014,4.520; P=0.025,0.033). For older patients, there was a higher rate of MYD88L265P mutation in DLBCL patients with extranodal invasion. There was no significant difference between the mutant group and the wild group (P0.05) in sex, B symptoms, staging, typing, IPI score, ECOG score, LDH and Ki-67 levels (P0.05). The results of LBCL standard R-CHOP regimen were compared and analyzed. The results showed that the sex and treatment response had correlation (X2=4.802, P=0.035), the female response to the R-CHOP regimen was better than that of the male, while the difference between the MYD88 L265P mutation group and the wild group was not statistically significant (P0.05), further analysis of the first-line induction. The recurrence of CR/PR patients with chemotherapy showed that there was no statistical correlation between MYD88 L265P mutation and disease recurrence (P0.05).Log-rank single factor survival analysis showed that B symptoms and Ki-67 status were associated with PFS (P=0.004,0.030), while Cox multiple factor analysis showed that B symptoms were associated with PFS. There was no statistical correlation between gene mutation and OS and PFS (P0.05). The survival analysis of all the group samples by life table method showed that the median OS and PFS in 53 DLBCL patients were 58.37 and 31.71 months respectively. The median OS and PFS of the MYD88 L265P mutation group were 40.16 and 27.84 months respectively, and the median OS and PFS were 72 and 41.33 months respectively in the MYD88 L265P mutation group. Nn-Whitney U test analysis of two groups of samples OS and PFS showed no statistically significant difference (P=0.367,0.594). Conclusion: (1) 1, DLBCL patients with high MYD88 L265P gene mutation rate, especially older, patients with extranodal invasion, and for the treatment of this part of the patients, MYD88 and their dependent signal pathways may be potential therapeutic targets. (2) MYD88 process There is no statistical correlation between the response of DLBCL to the treatment of R-CHOP regimen and the progression or recurrence of the first line induced chemotherapy. The reasons for the poor effect of the R-CHOP low reactive DLBCL patients need more molecular biology research. (3) there is no significant correlation between the MYD88 L265P mutation and the prognosis of the DLBCL disease, which may be associated with the group disease. The number of cases is short, the follow-up time is short, and the choice bias or other factors are related. It is necessary to expand the sample size to further verify.
【学位授予单位】：西南医科大学
【学位级别】：硕士
【学位授予年份】：2016
【分类号】：R733.1

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