【摘要】：研究目的探討慢性中性粒細(xì)胞白血病(CNL)患者臨床表現(xiàn)、形態(tài)學(xué)、細(xì)胞遺傳學(xué)、基因突變的特點(diǎn)及轉(zhuǎn)歸。研究方法對臨床疑診“CNL”的27例患者按2008年WHO診斷分型標(biāo)準(zhǔn)進(jìn)行回顧性診斷,回顧分析患者形態(tài)學(xué)及細(xì)胞遺傳學(xué)特點(diǎn),隨訪患者判定預(yù)后。利用等位基因特異性聚合酶鏈?zhǔn)椒磻?yīng)(AS-PCR)檢測JAK2 V617F突變,直接測序法檢測CSF3R第14-17外顯子、ASXL1第12外顯子、SETBP1第4外顯子、CALR第9外顯子、MPL第10外顯子突變狀態(tài),對有突變的樣本進(jìn)行克隆后測序鑒定突變類型。或者應(yīng)用二代測序方法對血液腫瘤常見的112種基因進(jìn)行突變分析,篩選以上6個(gè)基因的突變進(jìn)行分析。分析CNL患者臨床表現(xiàn)、形態(tài)學(xué)、細(xì)胞遺傳學(xué)及基因突變的特點(diǎn)及其臨床意義。結(jié)果27例疑診“CNL"的患者中,最終16例患者診斷為CNL,1例攜帶CSF3R T618I突變但不符合WHO (2008) CNL的診斷標(biāo)準(zhǔn),2例診斷為意義未明的單克隆免疫球蛋白病(MGUS)伴CNL表現(xiàn),感染及腫瘤繼發(fā)的反應(yīng)性中性粒細(xì)胞增多各4例。16例CNL患者發(fā)病中位年齡64(43-80)歲,男性占75%(12/16),確診時(shí)中位血紅蛋白水平為114(81-154)g/L,中位白細(xì)胞計(jì)數(shù)為41.20(26.05-167.70)×10g/L,中位血小板計(jì)數(shù)為238(91-394)×109/L。中位周血幼稚粒細(xì)胞比例2(0-9)%,中位周血原始細(xì)胞比例0(0-0.5)%,中位骨髓原始細(xì)胞比例1(0-4.5)%,中位骨髓纖維化水平為1(0-3)級。除1例t(1,7)(p32,q11)、1例+21克隆異常及1例14,ps+外,余患者未檢測到異常核型。16例CNL患者中，CSF3R T618I突變檢出率為100%(16/16),1例合并CSF3R W791X突變；ASXL1突變檢出率為81%(13/16),依據(jù)檢出頻率依次為G646WfsX12(8例)、Y591X (2例)、S871SfsX4(1例)、R404X(1例)及Q976X(1例)；SETBP1突變檢出率為63%(10/16),依據(jù)檢出頻率依次為D868N(4例)、1871T(3例)、G870S(1例)、G870D(1例)及D874N(1例)。同時(shí)有CSF3R T618I、ASXL1及 SETBP1突變的患者為9例,同時(shí)有CSF3R T618I及ASXL1突變的患者為4例,同時(shí)有CSF3R T618I及SETBP1突變的患者為1例,僅有CSF3R T618I突變并且不伴有ASXL1 及 SETBP1突變的患者為2例。此外,我們還通過直接測序得到了僅有1例患者攜帶CALRK385fs*47突變。所有CNL患者均無JAK2 V617F突變及MPL突變。1例攜帶 CSF3RT618I突變但不符合WHO (2008) CNL診斷標(biāo)準(zhǔn)的患者伴有SETBP1突變但未檢測到ASXL1、JAK2 V617F、CALR 及 MPL突變。MGUS伴CNL表現(xiàn)及反應(yīng)性中性粒細(xì)胞增多患者均未檢出以上6種基因突變。除SETBP1基因發(fā)現(xiàn)1例G870S純合突變外,余基因突變均為雜合突變。ASXL1突變及SETBP1突變型與其對應(yīng)的野生型相比,在性別比例、年齡分布、血紅蛋白水平、白細(xì)胞計(jì)數(shù)、血小板計(jì)數(shù)、周血幼稚粒細(xì)胞比例、周血原始細(xì)胞比例、骨髓原始細(xì)胞比例、骨髓纖維化是否≥1級各項(xiàng)指標(biāo)均無明顯差異。ASXL1突變與SETBP1突變的發(fā)生無相關(guān)性。16例CNL患者中位生存期為26(95%CI 20-32)月。去除了1例接受異基因造血干細(xì)胞移植患者的生存數(shù)據(jù)后,我們發(fā)現(xiàn)影響CNL患者預(yù)后的因素：初診WBC≥50×109/L生存期較50×109/L者短(11月vs.39月,P=0.005)。而性別、年齡≥60歲、初診是否有貧血(貧血標(biāo)準(zhǔn)以男性＜120g/L,貧血標(biāo)準(zhǔn)以女性110g/L計(jì)算,P=0.063)、是否有ASXL1突變、是否有SETBP1突變、周血是否有幼稚粒細(xì)胞、骨髓原始細(xì)胞是否≥2%、骨髓纖維化是否≥1級及初診染色體核型是否異常對預(yù)后影響無統(tǒng)計(jì)學(xué)差異。結(jié)論1. CSF3R T618I基因突變可以作為診斷CNL的主要標(biāo)準(zhǔn)。CNL患者還常合并ASXL1及SETBP1基因突變。2.CNL患者確診時(shí)染色體核型異常的比例不高,這些染色體異常在髓系腫瘤中并沒有特異性。初診染色體核型的異常并非預(yù)后不良因素。3.CNL患者中位生存期26月,確診時(shí)WBC≥50×109/L是不良預(yù)后因素。研究目的探討慢性粒單核細(xì)胞白血病(CMML)患者ASXL1、SETBP1、TET2及SRSF2基因突變及其臨床意義。研究方法對141例CMML患者按2008年WHO診斷分型標(biāo)準(zhǔn)進(jìn)行回顧性診斷,隨訪患者判定預(yù)后。應(yīng)用直接測序法檢測ASXL1第12外顯子、SETBP1第4外顯子、TET2第3-11外顯子和SRSF2第1外顯子突變狀態(tài),克隆后測序鑒定突變類型。比較基因突變患者與野生型患者的臨床及實(shí)驗(yàn)室特征、分析影響CMML患者預(yù)后的因素。結(jié)果141例CMML患者中位年齡63(18-85)歲,男性95例(67%)。確診時(shí)中位血紅蛋白水平為88(43-166)g/L,中位白細(xì)胞計(jì)數(shù)為21.88(3.01-117.57)×109/L,中位中性粒細(xì)胞絕對值為7.07(0.30-66.91)×109/L,中位單核細(xì)胞絕對值為3.72(1.02-57.72)×109/L,中位血小板計(jì)數(shù)為78(4-1001)×109/L。141例CMML患者中共發(fā)現(xiàn)65例(46%)ASXL1基因(僅無義突變及移碼突變被視為有突變)突變、25例(18%)SETBP1基因突變,46例(33%)TET2基因突變及41例(29%) SRSF2基因突變患者。ASXL1基因突變類型以移碼突變?yōu)橹?其中移碼突變59例(G646WfsX12為38例)、無義突變7例,同時(shí)存在移碼突變及無義突變1例。SETBP1基因突變類型均為錯(cuò)義突變,其中D868N 12例(48%)、G870S 9例(36%), I871S、R867S、S869I及S869R各1例(各占4%)。TET2基因突變類型包含移碼突變22例、錯(cuò)義突變19例及無義突變7例,其中1例患者存在錯(cuò)義突變及無義突變,1例患者同時(shí)存在錯(cuò)義、無義及移碼突變。SRSF2基因突變錯(cuò)義突變?yōu)橹?P95H、P95L、 P95R及移碼突變例數(shù)分別為18例(44%)、13例(32%)、7例(17%)及3例(7%)。以上所有基因突變均為雜合突變。ASXL1與SETBP1基因突變的存在具有相關(guān)性；TET2與SRSF2基因突變的存在具有相關(guān)性。TET2突變患者和野生型患者比較：年齡≥65歲比例較高、骨髓原始細(xì)胞≥10%比例較低；SRSF2突變患者和野生型患者比較：年齡≥65歲比例較高、血紅蛋白水平、白細(xì)胞計(jì)數(shù)、中性粒細(xì)胞絕對值、單核細(xì)胞絕對值較高。ASXL1、SETBP1突變患者和野生型患者在臨床特征無明顯差異。多因素分析141例CMML總生存,血紅蛋白水平、周血幼稚髓系細(xì)胞(IMCs)有無及ASXL1突變是CMML獨(dú)立預(yù)后因素。依據(jù)Mayo預(yù)后模型各組中位生存(median overall survival, MS):低危組未達(dá)到、中危組28月和高危組18月。依據(jù)分子Mayo預(yù)后模型各組MS：低危組未達(dá)到、中危-1組55月、中危-2組25月和高危組15月。對兩個(gè)預(yù)后積分系統(tǒng)進(jìn)行似然比檢驗(yàn),分子Mayo預(yù)后模型優(yōu)于Mayo預(yù)后模型(-2 log似然比分別為627和654,P=0.001)。將基因突變與Mayo預(yù)后模型同時(shí)納入COX回歸,相對于ASXLlwt/TET2wt患者,ASXLlmut/TET2mut. ASXLlmut/TET2wt和ASXLlwt/TET2mut患者的相對危險(xiǎn)度分別為4.7(95％CI 2.2-10.3；P=0.000)、2.2(95%CI 1.1-4.2；P=0.025)和1.3(95%CI O.6-2.5；P=0.521)。結(jié) 論1.CMML患者中ASXL1、SETBP1、TET2及SRSF2基因突變頻率分別為46%、18%、33%及29%。約3/4患者至少能檢測到1種以上基因突變。2.SRSF2基因突變CMML患者表現(xiàn)為髓系細(xì)胞獲得增殖優(yōu)勢,但與CMML患者總體生存及疾病進(jìn)展無明顯相關(guān)性。3.ASXL1基因突變是CMML患者總體生存的獨(dú)立不良預(yù)后因素。將ASX L1突變納入預(yù)后積分系統(tǒng),有助于更好區(qū)分預(yù)后危險(xiǎn)度。4.有ASXL1突變的CMML患者中檢測出TET2突變,提示更差的預(yù)后。
[Abstract]:Objective To investigate the clinical manifestations, morphology, cytogenetics, and gene mutation characteristics and prognosis of chronic neutrophil leukemia (CNL) patients.Methods 27 suspected patients with CNL were retrospectively diagnosed according to the WHO classification criteria in 2008. To determine the prognosis, JAK2 V617F mutation was detected by allele-specific polymerase chain reaction (AS-PCR), CSF3R exon 14-17, ASXL1 exon 12, SETBP1 exon 4, CALR exon 9 and MPL exon 10 were directly sequenced to identify the mutation type. Generation sequencing was used to analyze the mutations of 112 common genes in hematological malignancies. The clinical manifestations, morphology, cytogenetics and gene mutations of CNL patients were analyzed. Two patients were diagnosed as unidentified monoclonal immunoglobulin disease (MGUS) with CNL. The median age of onset was 64 (43-80) years in 16 patients with CNL, and 75 (12/16) in males. The median hemoglobin level at diagnosis was 114 (81-154) g/L. The median white blood cell count was 41.20 (26.05-167.70)*10 g/L, and the median platelet count was 238 (91-394)*109/L. The median percentage of peripheral blood immature granulocytes was 2 (0-9)%, the median percentage of peripheral blood primitive cells was 0 (0-0.5)%, the median percentage of bone marrow primitive cells was 1 (0-4.5)%, and the median level of bone marrow fibrosis was 1 (0-3). Except for 1 (1 (1,7) (p32, q11), 1 + 21 clonal abnormality. Among the 16 CNL patients, the detection rate of CSF3R T618I mutation was 100% (16/16), one with CSF3R W791X mutation, ASXL1 mutation was 81% (13/16), G646WfsX12 (8 cases), Y591X (2 cases), S871SfsX4 (1 case), R404X (1 case) and Q976X (1 case), respectively. 63% (10/16), according to the detection frequency, were D868N (4 cases), 1871T (3 cases), G870S (1 case), G870D (1 case) and D874N (1 case). There were 9 cases with CSF3R T618I, ASXL1 and SETBP1 mutations, 4 cases with CSF3R T618I and ASXL1 mutations, 1 case with CSF3R T618I and SETBP1 mutations, and 1 case without CSF3R T618I and SETBP1 mutations. Two patients had mutations in ASXL1 and SETBP1. In addition, only one patient with CALRK385fs * 47 mutation was obtained by direct sequencing. All CNL patients had no JAK2 V617F mutation and MPL mutation. One patient with CSF3RT618I mutation but did not meet the WHO (2008) CNL diagnostic criteria had mutations in SETBP1 but did not detect mutations in ASXL1, JAK2 V617. All the mutations were heterozygous except one G870S homozygous mutation found in SETBP1 gene. The ASXL1 mutation and SETBP1 mutation were compared with the corresponding wild type in terms of sex ratio, age distribution, hemoglobin level. There were no significant differences in white blood cell count, platelet count, peripheral blood immature granulocyte ratio, peripheral blood primitive cell ratio, bone marrow primitive cell ratio, and whether myelofibrosis was above grade 1. There was no correlation between ASXL1 mutation and SETBP1 mutation. The median survival time of 16 CNL patients was 26 (95% CI 20-32) months. After the survival data of the patients undergoing blood stem cell transplantation, we found that the prognostic factors of CNL patients were WBC (>50 *109/L) survival time was shorter than that of 50 *109/L patients (vs. 39 months in November, P = 0.005). Sex, age (>60 years old), anemia (anemia < 120g/L for men, 110g/L for women, P = 0.063), and ASXL1 protrusion. Conclusion 1. CSF3R T618I gene mutation can be used as the main criteria for the diagnosis of CNL. CNL patients are often associated with ASXL1 and SETBP1 gene processes. Chromosome karyotype abnormalities were not specific in myeloid tumors. Chromosome karyotype abnormalities were not a poor prognostic factor. 3. The median survival time of CNL patients was 26 months. WBC (>50 *109/L) at diagnosis was a poor prognostic factor. Methods 141 patients with CMML were retrospectively diagnosed according to WHO classification criteria in 2008. The prognosis was determined by follow-up. The mutations of ASXL1 exon 12, SETBP1 exon 4, TET2 exon 3-11 and SRSF2 exon 1 were detected by direct sequencing. Results The median age of 141 CMML patients was 63 (18-85) years, and 95 (67%) were male. The median hemoglobin level was 88 (43-166) g/L at diagnosis, and the median white blood cell count was 21.88 (3.01-117). 57 *109/L, median neutrophil absolute value was 7.07 (0.30-66.91) *109/L, median monocyte absolute value was 3.72 (1.02-57.72) *109/L, median platelet count was 78 (4-1001) *109/L. A total of 65 (46%) patients with CMML had mutations in the ASXL1 gene (only senseless mutations and frameshift mutations were considered to be mutations), 25 (18%) had mutations in the SETBP1 gene. 46 patients (33%) had mutations in TET2 gene and 41 patients (29%) had mutations in SRSF2 gene. The mutations in ASXL1 gene were mainly frameshift mutations, of which 59 were frameshift mutations (38 were G646WfsX12), 7 were nonsense mutations, and 1 was frameshift mutation and nonsense mutation. There were 22 frameshift mutations, 19 missense mutations and 7 nonsense mutations in TET2 gene. One patient had missense mutations and nonsense mutations. One patient had both missense, nonsense and frameshift mutations. SRSF2 mutations were mainly missense mutations, P95H, P95L, P95R and frameshift mutations. All of the above mutations were heterozygous. ASXL1 was associated with SETBP1 gene mutation. TET2 was associated with SRSF2 gene mutation. Compared with wild-type patients, patients with TET2 mutation had a higher proportion of age (> 65 years) and bone marrow primordial cells (> 10%). There was no significant difference in clinical characteristics between patients with SRSF2 mutation and those with wild type. Multivariate analysis showed that 141 patients with CMML survived, hemoglobin levels, and weeks. The presence or absence of IMCs and ASXL1 mutation were independent prognostic factors for CMML. According to the Mayo prognostic model, the median overall survival (MS) was not achieved in the low-risk group, 28 months in the medium-risk group and 18 months in the high-risk group. Month. A likelihood ratio test for the two prognostic score systems showed that the molecular Mayo prognostic model was superior to the Mayo prognostic model (-2 log likelihood ratio was 627 and 654 respectively, P = 0.001). The relative risk of ASXLlmut/TET2mut. The degree of mutation was 4.7 (95% CI 2.2-10.3; P = 0.000), 2.2 (95% CI 1.1-4.2; P = 0.025) and 1.3 (95% CI 0.6-2.5; P = 0.521). Conclusion 1. The mutation frequencies of ASXL1, SETBP1, TET2 and SRSF2 genes in CMML patients were 46%, 18%, 33% and 29%, respectively. ASXL1 mutation is an independent and unfavorable prognostic factor for the overall survival of CMML patients. Incorporating ASXL1 mutation into the prognostic score system helps to better distinguish the prognostic risk. 4. TET2 mutation was detected in CMML patients with ASXL1 mutation, suggesting worse prognosis. Prognosis.
【學(xué)位授予單位】：北京協(xié)和醫(yī)學(xué)院
【學(xué)位級別】：博士
【學(xué)位授予年份】：2016
【分類號(hào)】：R733.72

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