- PDF Free Download

Size: px

Start display at page:

Download ""

馗莫
7 years ago
Views:

1 硕士学位论文论文题目研究生姓名髓系白血病的分子遗传学研究尹佳指导教师姓名孙爱宁陈苏宁专业名称内科学 ( 血液病学 ) 研究方向论文提交日期白血病的基础与临床 2013 年 5 月

3 髓系白血病的分子遗传学研究中文摘要髓系白血病的分子遗传学研究中文摘要本论文包括二部分 :( 一 ) 急性早幼粒细胞白血病的分子遗传学研究 ;( 二 ) 两例非典型慢性髓细胞白血病的临床及实验室特征研究第一部分急性早幼粒细胞白血病的分子遗传学研究目的 : 分析急性早幼粒细胞白血病 (APL) 中多种常见白血病基因的突变情况, 初步探讨这些基因突变是否协同参与急性早幼粒细胞白血病的发病机制及其与 APL 病人的临床表现细胞遗传学和分子危险度分层的关系方法 : 病例来源于年期间在苏州大学附属第一医院住院诊断和治疗的急性早幼粒细胞白血病 84 例, 采用患者的骨髓标本提取基因组 DNA, 再以 PCR 方法扩增目标 DNA, 直接进行 DNA 测序, 分析 FLT3-ITD WT1 FLT3-TKD TET2 N-RAS ASXL1 EZH2 MLL-PTD IDH1 CBL JAK1 DNMT3 c-kit NPM1 IDH2 RUNX1 及 JAK2(V617F) 等基因突变在 AML 中的作用结果 : 1. 在 84 例初治 APL 患者中, 有 23 例 FLT3-ITD 突变阳性 (27.4%),FLT3-ITD 均为框内杂合突变, 重复片段长短不一 ;12 例 WT1 突变阳性 (14.3%),9 例 FLT3-TKD 突变阳性 (10.7%),7 例 TET2 突变阳性 (8.3%),5 例 N-RAS 突变阳性 (6.0%),4 例 ASXL1 突变阳性 (4.8%),2 例 EZH2 突变阳性 (2.4%),MLL-PTD IDH1 及 CBL 各 1 例阳性突变 (1.2%); 而 JAK1 DNMT3 c-kit NPM1 IDH2 RUNX1 JAK2(V617F) 等常见白血病相关基因在样品中未发现突变 84 例 APL 患者发生基因突变的患者总计 51 例, 突变率为 60.7% 2. FLT3-ITD 突变阳性患者较野生型患者相比, 明显具有高白细胞计数特点 (WBC= /L VS WBC= /L), 且差异具有统计学意义 (P=0.004); 而在 I

4 中文摘要髓系白血病的分子遗传学研究中位年龄血小板血红蛋白及原始细胞百分比等方面, 与野生型患者无明显差别 (P>0.05) N-RAS 突变阳性患者具有低血小板计数的特点 (PLT= /L VS PLT= /L), 且与野生型患者相比, 差异有统计学意义 (P=0.012); 突变阳性患者的中位年龄明显偏大, 但统计学无明显差异 (P>0.05); 而白细胞血红蛋白及原始细胞百分比与野生型无明显差别具有 FLT3-ITD 突变或 N-RAS 突变的患者总体生存期 (OS) 较无相关突变组患者明显缩短 (OS=39.1 月 VS OS=71.7 月 / OS=24.79 月 VS OS=68.02 月 ), 且差异有统计学意义 (P=0.01 / P=0.028) WT1 FLT3-TKD TET2 ASXL EZH2 等基因的突变型与野生型患者临床特征无明显差别 ; 而 MLL-PTD IDH1 及 CBL 等基因由于突变例数太少, 和 JAK1 DNMT3 c-kit NPM1 IDH2 RUNX1 JAK2(V617F) 等基因一样, 未与临床资料进行分析 3. 对 84 例 APL 患者均做了染色体核型分析, 单纯 t(15;17) 70 例, 变异型 t(11;17) 1 例,t(15;17) 伴其他染色体异常 13 例, 其中 +8 者 4 例,17 号缺失者 2 例,9 号缺失者 2 例,t(7;12) 者 1 例,+21 者 1 例,+15 者 1 例,-Y 者 1 例,+6 者 1 例,-6 者 1 例,7q+ 者 1 例,11 号缺失者 1 例细胞遗传学与临床特征及突变的关系 : 附加其他核型异常的 APL 患者与单纯 t(15;17) 的患者相比, 初诊原始细胞百分比白细胞血小板血红蛋白及中位年龄等临床特点无明显差异 ; 其总生存期 (OS) 与单纯 t(15;17) 患者有明显缩短 (28.94 月 VS 月 ), 但差异无明显统计学意义 (P=0.576) 附加异常的 APL 患者发生突变的几率 (6/13) 并没有明显高于单纯 t(15;17) 的 APL 患者 (45/71), 且无明显统计学意义 (P=0.219) 结论 : 1. 本实验验证了 FLT3-ITD 基因在 AML 及 APL 患者中的重大意义, 突变率与前人报道大致相同, 与在 AML 中一样,FLT3-ITD 基因突变是 APL 患者的不良预后因素 ; 另外, 我们还发现 N-RAS 与 APL 疾病发生及预后的重要相关性, 有 5 例病人发生了 N-RAS 第 12 号氨基酸的突变, 有 3 种形式的突变形式, 即 c.g35>t/p.gly12val c.g35>a/p.gly12asp c.g34>a/p.gly12ser, 且均为杂合突变 ; 虽然突变例数较少, 突变氨基酸序列发生的变换不一样, 但是经过统计分析发现突变与患者的总体生存期有着明显的相关性 ; 突变患者还有较低的血小板计数等临床特征, 而高白细胞计数及细胞遗传学方面尚未发现有明显联系, 这可能是本研究样本数较少造成的我们的研 II

5 髓系白血病的分子遗传学研究中文摘要究结果表明 FLT3 RAS 基因所致信号转导通路的基因突变与 PML-RARα 致转录因子突变协同参与了急性早幼粒细胞白血病的形成, 即二次打击学说 ; 提示 APL 的临床诊断过程中的分子遗传学水平检测预后危险度分层甚至这些突变发生机制的进一步研究是有必要及重要意义的 2. 通过我们的研究发现,APL 患者细胞遗传学附加异常对患者的预后及生存率无明显影响目前国内外对这一方面研究还尚少, 复杂细胞遗传学异常不影响 APL 患者预后可能与 APL 靶向治疗后缓解率高, 生存期长, 观察时间较短有关, 尚需要继续随访 ; 另外, 本研究患者例数较少, 需要扩大样本量进一步验证结论正确性关键词 : 基因突变 ; 急性早幼粒细胞白血病 ; DNA 突变分析第二部分两例非典型慢性髓细胞白血病的临床及实验室特征研究目的 : 绝大多数慢性髓细胞白血病 (CML, chronic myeloid leukemia) 患者具有特征性染色体易位 t(9;22)(q34;q11), 形成特异性的 BCR-ABL 融合基因, 酪氨酸激酶抑制剂治疗效果良好然而, 极少数 CML 患者中, 不具有此类特异性遗传学特征, 而伴有其他基因可与其他伙伴基因相互易位, 形成新的融合基因, 此种 CML 在 2008WHO 分型中被归入骨髓增殖性肿瘤 (MPN, Myeloproliferative neoplasms) 中的非典型慢性髓细胞白血病 (acml, atypical CML) 为了进一步认识 acml 及探讨其分子靶向治疗机制, 本文对 2 例罕见的伴有 BCR-JAK2 及 ETV6-PDGFRβ 融合基因的 acml 病例进行了临床表现实验室特征靶向治疗及疗效观察等方面研究方法 : 挑选 2 例临床诊断为非典型慢性粒细胞性白血病患者的骨髓细胞, 按常规制备染色体悬液, 经低渗固定后收获细胞,R 显带吉姆萨染色后进行核型分析采用 9p24((5 -D9S1969 和 3 -SHGC )) 红绿双色探针 (KREATECH) 分析细胞分裂间期和分裂期的杂交信号 ; 设计 BCR/JAK2 及 ETV6-PDGFRβ 引物 PCR 扩增产物并序列分析结果 : 患者 1, 男性,28 岁, 因发现白细胞升高四月于 2010 年 8 月就诊, 外周血常规提示 WBC /L,PLT /L,Hb 128g/L 外周血涂片: 中性粒细胞 83%, 淋巴细胞 8%, 单核细胞 8%, 晚幼粒细胞 1% 骨髓形态提示骨髓增生 III

6 中文摘要髓系白血病的分子遗传学研究极度活跃, 粒系明显偏高, 粒红比例偏高骨髓组织活检 ( 塑料包埋 ) 提示 MDS/MPN 骨髓象,aCML 可能性大应用流式细胞术进行骨髓细胞的免疫表型分析, 结果提示未见异常表达, 粒系比例增高伴成熟障碍 R 显带染色体核型分析提示 : 46,XY,ins(22;9)(p11;p13p24)[20] 依据核型分析显示 9p24 断裂点, 分析可能累及位于 9p24 的 JAK2 基因, 应用 9p24/JAK2 探针进行的 FISH 检测结果显示, 大约 50% 的细胞出现阳性分离信号, 证实存在 JAK2 基因的重排 RT-PCR 提示 BCR-ABL 融合基因阴性, 而 BCR-JAK2 引物进行 PCR 扩增得到特异性条带, 测序证实为 BCR/JAK2 融合基因该例患者诊断为伴有 ins(22;9)(p11;p13p24)/bcr-jak2 的非典型慢性髓细胞性白血病, 予以 α 干扰素及羟基脲治疗, 随访至 2012 年 5 月仍处于血液学缓解中患者 2, 男性,55 岁, 因发现白细胞升高半月于 2012 年 6 月来诊, 外周血常规提示 WBC /L,PLT /L,Hb 145g/L 外周血涂片: 中性粒细胞 82%, 淋巴细胞 3%, 单核细胞 2%, 嗜酸性粒细胞 1%, 嗜碱性粒细胞 2%, 晚幼粒细胞 10% 骨髓形态提示粒系比例增高, 粒红比例偏高, 红系可见类巨幼样变应用流式细胞术进行骨髓细胞的免疫表型分析, 结果提示 1% 幼稚群体, 髓系表型, 粒系比例增高伴成熟障碍 R 显带染色体核型分析提示 :46,XY, t(5;12)(q33;p13)[20] RT-PCR 提示 ETV6- PDGFR β 融合基因阳性该例患者诊断为伴有 t(5;12)(q33;p13)/etv6-pdgfrβ 的非典型慢性髓细胞性白血病, 予以羟基脲及甲磺酸伊马替尼 400mg/ 天治疗 3 月达 CR 后改 100mg 维持治疗, 随访至 2013 年 3 月仍处于分子遗传学缓解中结论 : 发现新的伴有 BCR-JAK2 融合基因及 ETV6-PDGFRβ 融合基因的非典型慢性髓细胞白血病患者各 1 例, 该两种融合基因分别由 ins(22;9)(q11;p13p24) 导致 BCR 基因和 JAK2 基因并置及 t(5;12)(q33;p13) 导致 ETV6 基因和 PDGFRβ 基因并置形成关键词 : 白血病, 髓细胞, 慢性 ; 融合基因 ; 非典型作导者 : 尹佳师 : 孙爱宁教授指导老师 : 陈苏宁教授 IV

7 Molecular genetics research on myeloid leukemia Abstract Molecular genetics research on myeloid leukemia Abstract This thesis will comprise two parts:part I: Molecular genetics research on gene mutations in acute promyelocytic leukemia; Part II: Clinical and laboratory characteristics of two cases of atypical chronic myeloid leukemia. PART I Molecular genetics research on gene mutations in acute promyelocytic leukemia Objective : To analyze the mutation incidence of multiple common leukemia-related genes in acute promyelocytic leukemia (APL), to explore whether these mutations synergestically involved in the leukemogenesis of APL and their relevance with clinical features, cytogenetics and molecular risk stratification. Methods : A total of 84 specimens of admitted de novo APL patients in the First Affiliated Hospital of Soochow University from February 2005 to October 2010 was recruited in this research to assess the genetic mutation patterns. The genomic DNA is extracted from bone marrow mononuclear cells and amplified by PCR( polymerase chain reaction ). The analysis of TET2, DNMT3A, IDH1, IDH2, EZH2, CBL, ASXL1, MLL-PTD, NPM1, WT1, RUNX1, c-kit, FLT3-ITD, FLT3-TKD, N-RAS and JAK2V617F gene mutations and clinical features of mutation-positive patients were analyzed by massively DNA sequencing and statistical methods. Results : 1. We demonstrate the presence of 66 cryptic genomic aberrations in 84 patients (78.6%) consisting of mutations (51 patients), in which the mutations with the highest incidence were found as FLT3-ITD, reaching 27.4%(23/84). All the duplications of FLT3 V

8 Abstract Molecular genetics research on myeloid leukemia were heterozygosis and sustained in open reading frame, which differ in length and insertion sites. Next, there were 12 cases WT1 mutations, 9 for FLT3-TKD, 7 for TET2, 5 for N-RAS, 4 for ASXL1, 2 for EZH2 mutation and 1 positive in MLL-PTD, IDH1 and CBL respectively. No mutation was found in other JAK1, DNMT3A, c-kit, NPM1, IDH2, RUNX1 and JAK2 (V617F) common leukemia-related genes. 2. Median age of our patients was 34 years (range, 8 to 79 years) and 44 patients (52.4%) were male and 40 (47.6%) were female. Combined analysis with clinical data demonstrated that the patients with FLT3-ITD mutation displayed higher white blood cell counts (WBC= /L VS WBC= /L, P=0.004), which displayed no significant difference compared with wild-type in median age, platelets counts, hemoglobin and blast percentage. The patients with N-RAS mutation showed lower platelet counts (PLT= /L VS PLT= /L, P=0.012), which displayed no significant difference compared with wild-type in median age, white blood cell counts, hemoglobin and blast percentage. The median age of NRAS-positive patients is significantly larger, but there was no significant difference (P>0.05). Overall survival of these patients was obviously shorten as compared with wild-type (for FLT3-ITD, 39.1 months vs 71.7 months; p=0.010; for NRAS, months vs months; p=0.028). The difference of OS between mutant and wild-type of all above mentioned cases was statistically significance (P<0.05). There were no significant correlations between age, sex, WBC and mutations in WT1, FLT3-TKD, TET2, ASXL1, EZH2, MLL-PTD, IDH1 or CBL. 3. In the cytogenetic analysis of 84 APL patients, recurrent chromosomal abnormalities that are the cytogenetic hallmarks of genetically except simple t(15;17) entities were identified in 13 cases, namely +8 (4/84), 17abnormal (2/84), 9 abnormal (2/84); while t (7;12) (1/84), +21, +15, - Y, +6, -6, 7q + and 11 abnormal were in 1 case respectively. The difference between APL with simple t(15;17) and additional abnormal karyotype did not show a significant statistically variant OS (28.94 months vs months; p=0.576) or a mutation incidence of leukemia-related genes (6/13 vs 45/71; p=0.219) as other clinical features. VI

9 Molecular genetics research on myeloid leukemia Abstract Conclusion: The FLT3-ITD mutation is recurring genetic change in APL, together with N-RAS mutation indicates poor prognosis. Additional abnormal karyotype does not associate with prognosis and mutation incidence of APL. Key words : gene mutation; acute promyelocytic leukemia (APL); DNA mutation analysis PART II Clinical and laboratory characteristics of two atypical chronic myeloid leukemia cases. Object: Patients with clinical features of chronic myeloid leukemia (CML) who lack the Philadelphia chromosome and/or the BCR-ABL fusion gene are generally considered as having atypical CML (acml) or, more broadly, an unclassifiable myeloproliferative or myelodysplastic/myeloproliferative disease. Here we report two acml patient with rare genetic abnormality and research on clinical manifestations, laboratory features and individual targeted therapy. Methods: Mononuclearcells of two patients with atypical chronic myeloid leukemia by bone marrow aspiration were disposed with conventional chromosome suspension preparation of hypotension, fixation, harvest, RHG banding, Giemsa-staining and karyotype analysis. 9p24 probe (5'-D9S1969 and 3'-SHGC , KREATECH) was investigated by dual-color Fluorescence in situ hybridization (FISH). BCR-JAK2 and ETV6-PDGFRβ primers were designed and amplificated PCR product were sequenced. Results: Patient 1: A 28-years-old Chinese male was admitted to our hospital with the routine examination finding WBC increased four months on July 10th, Physical examination revealed skin pallor, and splenomegaly were observed. Examination of peripheral blood (PB) indicated a white blood cell count of /L (83% neutrophil, 8% lymphocytes, VII

10 Abstract Molecular genetics research on myeloid leukemia 8% monocytes, 1% metamyelocytes and 2% eosinophil), a platelet count of /L, and 128 g/l hemoglobin. Bone marrow (BM) aspirate was markedly with granulocytic hyperplasia and characterized by increasing eosinocytes. Flow cytometric immunophenotyping identified granuloid cells with dysmaturity and no evidence of an increase in myeloid blasts. Cytogenetic analysis (RHG banding) demonstrated a karyotype of ins(22;9)(q11;p13p24). Reversetranscription polymerase chain reaction (RT-PCR) analysis failed to detect BCR-ABL fusion transcripts as well as JAK2 V617F mutation from the bone marrow cells. The BM biopsy tissue was considered as acml. Based on above datas, diagnosis of acml was made. Since this patient had negative BCR/ABL fusion gene, low-dose interferon alpha and hydroxyurea therapy was given upon remained until now. Patient 2: The patient was a 55-year-old male who presented with the routine examination finding white blood cells increased half months in June A complete blood count revealed leukocytosis (WBC= /L), hemoglobin (145g/L) and thrombocyte ( /L). Examination of his peripheral blood film revealed nucleated red blood cells, and the differential consisted primarily of neutrophils and neutrophil precursors, ranging from metamyelocytes to bands. There was an increased number of metamyelocytes (10%), but relatively few monocytes (2%) and lymphocytes (3%). Eosinophils and basophils are also visible. A bone marrow aspirate revealed hypercellularity, an increased M:E ratio and megaloblastic degeneration of erythroid. Blasts were normal in number. The original cytogenetics were reported as a t(5;12)(q33;p13) in 20 of 20 spreads. Testing by RT-PCR demonstrated the ETV6-PDGFRB fusion gene. Treatment with hydrea and imatinib mesylate (formerly STI571; now Gleevec in the UnitedStates and Glivec in Europe) was started at 400mg per day. At this dose, a complete hematologic and cytogenetic response was attained within three month. Then low-dose 100mg/d maintenance treatment was adopted. Minimal residual disease analysis by nested RT-PCR was still negative at this juncture. Until March 2013 the patient is still in molecular genetics remission. Conclusion: VIII

11 Molecular genetics research on myeloid leukemia Abstract Atypical chronic myeloid leukemia patients with BCR-JAK2 and ETV6-PDGFRβ fusion gene were resulted from the ins (22;9)(q11;p13p24) resulting in the BCR gene and the JAK2 gene juxtaposed and t(5;12)(q33;p13) causing the ETV6 genes and PDGFRβ genes juxtaposition.. Key words: Atypical chronic myeloid leukemia (acml); fusion gene Written by : Yin Jia Supervised by : Professor Sun Aining Professor Chen Suning IX

13 目录第一部分急性早幼粒细胞白血病的分子遗传学研究引言材料和方法结果讨论参考文献第二部分两例非典型慢性髓细胞白血病的临床及实验室特征研究引言材料和方法结果讨论参考文献总结...42 综述...43 参考文献攻读学位期间公开发表的论文...71 英文缩略词表...72 致谢...75

15 髓系白血病的分子遗传学研究第一部分第一部分急性早幼粒细胞白血病的分子遗传学研究 1.1 引言急性早幼粒细胞白血病 (Acute Promyelocytic Leukemia,APL) 是急性髓细胞白血病 (Acute Myeloid Leukemia,AML) 中极为特殊的亚型, 在以形态学为基础的 FAB 分型中归为急性髓细胞白血病 -M3 型 ; 遗传学上,t(15;17)(q22;q21) 的平衡型染色体易位是急性早幼粒细胞白血病的特征性改变, 从而导致了早幼粒细胞白血病基因 (PML) 与维甲酸受体基因 (RARα) 形成 PML-RARα 融合基因, 也有不到 2% 的 APL 患者检测到 t(15;17) 变异型 1, 如 t(11;17) 或 t(5;17) 等 APL 患者以弥漫性血管内凝血 (Disseminated Intravascular Coagulation, DIC) 或纤溶亢进所致严重出血倾向为主要突出表现, 使 AML-M3 患者发病凶险, 死亡率高近年来, 随着以维甲酸砷剂联合蒽环类抗生素为基础的化疗药物的普遍应用, 该类患者的长期生存率提高到了 90-95% 1 近 10 年来, 国内外众多学者研究发现,FMS 样的酪氨酸激酶 3- 内部串联重复 (Fms-Like Tyrosine kinase-3 Intenal Tandem Duplication, FLT3-ITD) FLT3- 激酶区点突变 (FLT3-Tyrosine Kinase Domain mutation, FLT3-TKD) TET 癌基因家组成员 2(the 2nd member of TET oncogene family, TET2) 神经母细胞 -RAS(Neuroblastoma RAS, N-RAS) DNA 甲基化转移酶 3(DNA methyltransferase3, DNMT3) c-kit 核仁磷酸蛋白 1(Nucleophosmin, NPM1) 等常见白血病基因突变 1 2 广泛存在于 AML 患者中欧洲 APL 工作组报道认为,FLT3-ITD 在 APL 中的突变率为 35% 3, 与其在 AML 中一样是不良预后因素, 具有 FLT3-ITD 突变的 APL 的患者具有较短的总生存 (Overall survival, OS) 期 ; 而 RAS 基因突变病例数过少 (4/119), 其预后影响不能进行统计学评估, 目前国内外尚未见大规模的 APL 原代标本来验证哪些常见白血病基因突变能够协同参与 APL 的发病机制, 以及这些基因突变与 APL 患者的的临床表现预后及其他遗传学异常的关系本研究采用基因组 DNA-PCR 结合基因组测序技术, 评估了 FLT3-ITD WT1 FLT3-TKD TET2 N-RAS 带附加性梳样 1(Additional sex comb-like 1, ASXL1) 果蝇 Zeste 基因增强子人类同源物 2(Enhancer of Zeste Homolog 2, EZH2)

16 第一部分髓系白血病的分子遗传学研究 MLL-PTD 异柠檬酸脱氢酶 1(Isocitrate Dehydrogenase 1, IDH1) CBL JAK1 DNMT3A c-kit NPM1 IDH2 转录调节因子 1(Runt-related protein 1, RUNX1) 及 JAK2(V617F) 等常见白血病相关基因突变在 84 例 APL 患者中的发生频率和对预后的影响, 并探讨这些基因突变的发生与患者的临床特征及细胞遗传学的关系, 以进一步研究其与白血病发病机制中两次打击 ( 信号转导通路的基因突变和转录因子突变 ) 所致协同突变的相关性 1.2 材料和方法病例资料共收集初治 APL 患者 84 例, 均为 2005 年 2 月至 2010 年 1 月苏州大学附属第一医院门诊或住院病例, 其中男 44 例, 女 40 例, 中位年龄 34.5(8-79) 岁, 其中 9 例未成年患者 ( 18 岁 ), 成人 (18 岁 -60 岁 )72 例, 老年患者 ( 60 岁 ) 为 3 例所有患者均为初发的急性早幼粒细胞白血病, 排除了具有其他造血系统疾病,MDS 转化及治疗相关性白血病, 所采取的样本均为患者进行诱导治疗前的骨髓细胞 ( 详细信息见表 1) 所有 APL 患者均根据临床表现血常规骨髓细胞形态学白血病免疫分型融合基因及染色体核型等检查明确诊断, 诊断标准符合参照血液病诊断及疗效标准 4 所有患者均按照 AML 中国诊疗指南进行, 随访时间从 1 到 97 个月, 中位随访时间为 13 个月表例 APL 患者的临床及实验室特征编号性别年龄 HB WBC PLT blast(%) 染色体随访结果 EFS OS 1 女 ,xx,t(15;17) 死亡男 14 N/A N/A N/A ,xy,t(15;17)(q22;q21)[14]/46,xy[1] 存活男 32 N/A N/A N/A ,xy,+8,t(15;17)(q22;q12)[4] 失访 4 男 51 N/A N/A N/A ,xy,t(15;17) 失访 5 女 29 N/A N/A N/A N/A 46,xy,t(15;17)[4]/46,xx[18] 失访 6 男 15 N/A N/A N/A N/A 46,xy,t(15;17)[7]/46,xy[3] 失访 7 女 N/A 46,xx,t(15;17) 失访 8 男 50 N/A N/A N/A ,xy,t(15;17)(q22;q21) 存活男 57 N/A N/A N/A 90 46,xy,t(15;17)(q22;q21) 失访 10 女 35 N/A N/A N/A ,xx,t(15;17)(q22;q21)i(17q-)(p11;q21)[ 失访 10]/47,idem,+6[1] 11 男 52 N/A N/A N/A ,XY,t(15;17)(q22;q12). 失访 2

<4D6963726F736F667420576F7264202D20ECFAD0C0D0C0C2DBCEC4CCE1BDBB6F7665722E646F63>

<4D6963726F736F667420576F7264202D20ECFAD0C0D0C0C2DBCEC4CCE1BDBB6F7665722E646F63> 硕士专业学位论文论文题目鲍温病临床病理特征和几种治疗方法比较的分析研究研究生姓名指导教师姓名禚欣欣康定华专业名称皮肤性病学研究方向皮肤肿瘤与皮肤病理论文提交日期 2013 年 4 月 I 鲍温病临床病理特征和几种治疗