發(fā)布時(shí)間：2018-06-12 01:54

  本文選題：彌漫大B細(xì)胞淋巴瘤 + MYD88突變　； 參考：《西南醫(yī)科大學(xué)》2016年碩士論文

【摘要】：研究背景及目的:彌漫大B細(xì)胞淋巴瘤是成人最常見的非霍奇金淋巴瘤,主要臨床表現(xiàn)為無痛性、進(jìn)行性淋巴結(jié)腫大。在老年人的發(fā)病率較高,中位發(fā)病年齡70歲,偶可見于兒童及青少年。DLBCL是一類高度侵襲性腫瘤,R-CHOP方案一線誘導(dǎo)治療可使約70%的患者得到治愈,但仍有近三分之一的患者在治療后短期內(nèi)復(fù)發(fā)甚至治療過程中即出現(xiàn)腫瘤進(jìn)展。因此,從腫瘤分子生物學(xué)及細(xì)胞遺傳學(xué)等方面進(jìn)一步探尋腫瘤發(fā)生、發(fā)展及耐藥的機(jī)制,尋找更能反映腫瘤預(yù)后的預(yù)測指標(biāo),為DLBCL的治療提供新的治療靶點(diǎn)及思路已成為目前研究的重點(diǎn)。有研究發(fā)現(xiàn),在多種B細(xì)胞腫瘤中有功能活化的MYD88 L265P基因突變,導(dǎo)致下游如NF-κB、JAK-STAT3等信號通路的異常激活,與腫瘤發(fā)生、浸潤轉(zhuǎn)移、耐藥及預(yù)后密切相關(guān)。本研究通過檢測彌漫大B細(xì)胞淋巴瘤患者M(jìn)YD88 L265P基因突變情況,分析突變與DLBCL臨床病理特征的關(guān)系,初步探討該基因突變與DLBCL標(biāo)準(zhǔn)治療方案R-CHOP治療效果及預(yù)后的關(guān)系。方法:收集2007年1月至2015年1月四川省腫瘤醫(yī)院53例彌漫大B細(xì)胞淋巴瘤患者的臨床資料及存檔蠟塊,所有入組病例均為CD20+、首診初治、至少完成3個(gè)周期R-CHOP方案化療的DLBCL。從所收集的石蠟包埋組織中提取DNA,采用半巢式SYBR Green I熒光染料法實(shí)時(shí)定量等位基因特異性PCR技術(shù)對所提取DNA進(jìn)行MYD88 L265P基因突變檢測,分析其與DLBCL臨床病理特征、R-CHOP方案治療效果和預(yù)后的關(guān)系。采用SPSS20統(tǒng)計(jì)軟件進(jìn)行統(tǒng)計(jì)學(xué)分析,其中計(jì)量資料采用Mann-Whitney U檢驗(yàn),計(jì)數(shù)資料采用卡方檢驗(yàn)、Fish確切概率法、Log-rank單因素分析及Cox多因素分析。結(jié)果:從入組的53例彌漫大B細(xì)胞淋巴瘤患者樣本中,成功檢測到16例攜帶MYD88 L265P基因突變,突變率為30.19%。16例突變病例中,GCB型DLBCL 5例,ABC型11例,結(jié)外受侵12例(其中1例原發(fā)睪丸、2例原發(fā)甲狀腺),另有原發(fā)脾臟及縱膈各1例。統(tǒng)計(jì)分析顯示,MYD88L265P突變與DLBCL患者年齡及是否有結(jié)外受侵具有相關(guān)性(X2=5.014,4.520;P=0.025,0.033),對于高齡、有結(jié)外受侵的DLBCL患者M(jìn)YD88L265P突變率較高,在性別、B癥狀、分期、分型、IPI評分、ECOG評分、LDH及Ki-67水平等臨床特征方面,突變組與野生組的分布無明顯差異(P0.05)。對DLBCL標(biāo)準(zhǔn)一線R-CHOP方案治療效果進(jìn)行對比分析,結(jié)果顯示性別與治療反應(yīng)具有相關(guān)性(X2=4.802,P=0.035),女性對R-CHOP方案一線誘導(dǎo)治療反應(yīng)較男性好,而MYD88 L265P突變組與野生組對治療反應(yīng)的差異性無統(tǒng)計(jì)學(xué)意義(P0.05),進(jìn)一步分析一線誘導(dǎo)化療達(dá)到CR/PR患者疾病的復(fù)發(fā)情況,結(jié)果提示MYD88 L265P突變與疾病復(fù)發(fā)亦無統(tǒng)計(jì)學(xué)關(guān)聯(lián)(P0.05)。Log-rank單因素生存分析顯示,B癥狀及Ki-67狀態(tài)與PFS具有相關(guān)性(P=0.004,0.030),而Cox多因素分析顯示僅B癥狀與PFS相關(guān)(P=0.012)。單因素分析MYD88 L265P基因突變與OS及PFS均無統(tǒng)計(jì)學(xué)相關(guān)性(P0.05)。對所有入組樣本采用壽命表法進(jìn)行生存分析,結(jié)果顯示,53例DLBCL患者中位OS和PFS分別為58.37和31.71月,MYD88 L265P突變組中位OS和PFS分別為40.16和27.84月,野生組中位OS和PFS分別為72和41.33月,但采用Mann-Whitney U檢驗(yàn)對兩組樣本OS及PFS進(jìn)行分析,顯示差異無統(tǒng)計(jì)學(xué)意義(P=0.367,0.594)。結(jié)論:(1)1、DLBCL患者M(jìn)YD88 L265P基因突變率高,尤其是高齡、有結(jié)外受侵的患者,對于這部分病人的治療,MYD88及其依賴的信號通路可能是潛在的治療靶點(diǎn)。(2)MYD88突變與DLBCL對R-CHOP方案治療反應(yīng)及一線誘導(dǎo)化療后疾病進(jìn)展或復(fù)發(fā)無統(tǒng)計(jì)學(xué)相關(guān)性,R-CHOP低反應(yīng)性的DLBCL患者治療效果差的原因還需更多分子生物學(xué)等方面的研究來明確。(3)MYD88 L265P突變與DLBCL疾病預(yù)后無明顯統(tǒng)計(jì)學(xué)關(guān)聯(lián),可能與入組病例數(shù)少、隨訪時(shí)間短、選擇偏倚或其他影響因素有關(guān),尚需擴(kuò)大樣本量進(jìn)一步驗(yàn)證。
[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.
【學(xué)位授予單位】：西南醫(yī)科大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2016
【分類號】：R733.1

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6 程萍;PERK/eIF2а/CHOP信號通路參與新生大鼠壞死性小腸結(jié)腸炎發(fā)病及魚油保護(hù)作用的機(jī)制研究[D];蘇州大學(xué);2016年

7 劉文一;染氟SD大鼠海馬細(xì)胞凋亡的內(nèi)質(zhì)網(wǎng)ATF-6/CHOP途徑研究[D];鄭州大學(xué);2016年

8 劉艷;HBV促進(jìn)thapsigargin致內(nèi)質(zhì)網(wǎng)應(yīng)激中CHOP mRNA的表達(dá)[D];北京協(xié)和醫(yī)學(xué)院;2015年

9 羅光金;敲除CHOP增加小鼠心肌梗死急性期死亡率且不能改善心肌梗死后心室重構(gòu)[D];南方醫(yī)科大學(xué);2016年

10 盧霞;陽和湯加味聯(lián)合R-CHOP治療彌漫大B細(xì)胞淋巴瘤臨床觀察[D];湖南中醫(yī)藥大學(xué);2016年

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