常规核型分析联合多重荧光原位杂交确定急性白血病复杂核型异常
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摘要
[目的](1)建立多重荧光原位杂交(M-FISH)技术平台。(2)探讨联合常规核型分析、位点特异性的荧光原位杂交及多重荧光原位杂交技术在确定急性白血病(AL)患者复杂核型异常(CCA)和标记染色体中的应用价值。(3)结合文献复习及数据库检索以发现未报道过和少见的异常,并探讨这些异常可能的预后意义。
[方法](1)收集患者骨髓标本,采用R显带的方法行常规染色体核型分析。(2)对11例常规R显带显示具有CCA和／或标记染色体的AL患者标本应用M-FISH技术确定复杂染色体重排和标记染色体的组成,识别并确定微小易位和隐匿易位。(3)对M-FISH显示或怀疑有涉及某些特定基因如MLL扩增或P53基因缺失的患者进一步用位点特异性的荧光原位杂交技术进行进一步确证或排除。
[结果](1)成功建立M-FISH技术平台。(2)常规细胞遗传学(CC)技术检测发现11例AL患者具有CCA或未识别的结构异常。11例AL患者中,应用CC共检出27种染色体数目异常和41种结构异常,包括17种标记染色体,其组成及来源不明。(3)M-FISH分析明确CC未识别结构异常的来源与性质：M-FISH检测确定了CC未能明确的异常。CC检出的3种染色体增加和9种染色体丢失以及12种结构异常与M-FISH分析结果一致；CC技术检出的15种染色体丢失,经M-FISH证实为衍生染色体；M-FISH还检出3种CC未发现的染色体数目增加。CC所检出的其余29种结构异常包括17种标记染色体的性质被M-FISH进一步明确。对部分患者进行的位点特异性FISH检测进一步验证了M-FISH的结果。(4)文献复习及数据库检索结果：M-FISH共检出33种结构重排,有6种异常未见文献报道,分别是t(5q-;16)(?q14;q24),der(9)(Y::9::Y::9)>der(7)(7::8::9)、ins(20;21)、der(11)(11::21::20)和der(3)t(3p-;13)(3p-;q21),这些复杂染色体重排主要由染色体不平衡易位所致。另有一些异常比较罕见,目前报道不超过百例,分别是：der(15)t(Y;15)、dic (16; 17)、der(12)t(8;12)、t(2;4)、der(10)t(10;17)、der(14)t(14;15)、der(12)t(6;12)、der(1)t(1;5)、der(15)t(1;15)、der(17)t(5;17)、der(3)t(3p-;13)、t(9;15)以及der(13)t(10;13)。(5)分析CCA在AL中所涉及的染色体种类：CCA几乎涉及所有染色体,在AML患者以涉及17号、5号、7号、15号和11号染色体的异常较为常见；在ALL患者则以涉及8号、9号、14号和22号染色体的异常较为多见。
[结论]M-FISH不仅可以证实CC已明确的异常,还可确定CC所不能辨认的复杂核型异常以及标记染色体的来源和组成,二者联合应用在部分患者可进一步明确断裂位点,可以提高核型分析的分辨率,且有助于发现未报道过的异常以及少见异常,对伴复杂核型和标记染色体的AL具有一定的临床应用价值。
Objective:(1) To set up the technical system of multiplex fluorescence in situ hybridization (M-FISH) technique. (2) To explore the value of combination of conventional cytogenetics, locus specific FISH and M-FISH in the detection of the complex chromosomal aberrations (CCAs) and marker chromosomes in acute leukemia (AL). (3) To find out unreported or very rare abnormalities by reviewing literature and checking the Mitelman database of Chromosome Aberrations in Cancer and to discuss the possible prognostic relevance of these abnormalities.
Methods:(1) Bone marrow specimens of patients with acute leukemia were collected, cultured, prepared and R-banded for conventional cytogenetic analysis. (2) M-FISH was performed on specimens of the 11 AL cases whose conventional cytogenetic analysis showed CCAs or marker chromosomes in order to define the unrecognized chromosomal aberrations and the constitution of marker chromosomes, and to identify small and cryptic translocations. (3) Locus specific FISH with specific probes was performed on specimens whose M-FISH results showed or suspected involvement of specific genes, such as MLL amplification or P53 deletion, for verification or exclusion.
Results:(1) The M-FISH technical system was successfully established, with all of the 11 M-FISH experiments being successful and with good images. (2) Conventional cytogenetics (CC) showed CCAs and/or marker chromosomes in the 11 AL cases studied. Altogether CC detected 27 numerical and 41 structural chromosomal abnormalities, including 17 marker chromosomes, whose constitution and resources were undetermined. (3) M-FISH analysis determined the resources and chatacteristics of the structural abnormalities undetermined by CC. Among the 27 numerical and 41 structural chromosomal abnormalities detected by CC,3 chromosome gains and 9 chromosome losses as well as 12 structural abnormalities were confirmed by M-FISH. The other 15 chromosome losses detected by CC were revised by M-FISH as derivative chromosomes. M-FISH also detected 3 chromosome gains that were undetected by CC. The other 29 structural abnormalities including 17 marker chromosomes were characterized by M-FISH. The locus specific FISH performed on certain patients further verified the M-FISH results. (4) Results of literature reviewing and database searching:A total of 33 structural abnormalities were detected by M-FISH, among which 6 have never been reported before, i.e. t(5q-;16)(?ql4;q24), der(9)(Y::9::Y::9), der(7) (7::8::9), ins(20;21), der(11) (11::21::20) and der(3)t(3p-;13)(3p-;q21) and most of them resulted from unbalanced translocations. Some of the abnormalities are very rare, with no more than 100 cases reported world wide up to now, including der(15)t(Y;15), dic(16;17), der(12)t(8;12), t(2;4), der(10)t(10;17), der(14)t(14;15), der(12)t(6;12), der(1)t(1;5), der(15)t(1;15), der(17)t(5;17), der(3)t(3p-;13), t(9;15) and der(13)t(10;13). (5) Analyzing the distribution of chromosomes involved in CCA of AL:Almost all chromosomes were involved in CCAs, the more common ones were chromosome 17,5,7,15,11 in AML and 8,9,14,22 in ALL.
Conclusion:Not only can M-FISH verify the abnormalities determined by CC, but the technique can also determine the complex chromosomal abnormalities and recognize the resources and constitution of marker chromosomes undetermined by CC. Combination of these two kinds of technique can also help further determine the breakpoint in some patients, raise resolution of karyotyping, and help discover unreported abnormalities and very rare abnormalities, which justifies its clinical application for the detection of CCAs and marker chromosomes in AL.
[方法](1)收集患者骨髓标本,采用R显带的方法行常规染色体核型分析。(2)对11例常规R显带显示具有CCA和／或标记染色体的AL患者标本应用M-FISH技术确定复杂染色体重排和标记染色体的组成,识别并确定微小易位和隐匿易位。(3)对M-FISH显示或怀疑有涉及某些特定基因如MLL扩增或P53基因缺失的患者进一步用位点特异性的荧光原位杂交技术进行进一步确证或排除。
[结果](1)成功建立M-FISH技术平台。(2)常规细胞遗传学(CC)技术检测发现11例AL患者具有CCA或未识别的结构异常。11例AL患者中,应用CC共检出27种染色体数目异常和41种结构异常,包括17种标记染色体,其组成及来源不明。(3)M-FISH分析明确CC未识别结构异常的来源与性质：M-FISH检测确定了CC未能明确的异常。CC检出的3种染色体增加和9种染色体丢失以及12种结构异常与M-FISH分析结果一致；CC技术检出的15种染色体丢失,经M-FISH证实为衍生染色体；M-FISH还检出3种CC未发现的染色体数目增加。CC所检出的其余29种结构异常包括17种标记染色体的性质被M-FISH进一步明确。对部分患者进行的位点特异性FISH检测进一步验证了M-FISH的结果。(4)文献复习及数据库检索结果：M-FISH共检出33种结构重排,有6种异常未见文献报道,分别是t(5q-;16)(?q14;q24),der(9)(Y::9::Y::9)>der(7)(7::8::9)、ins(20;21)、der(11)(11::21::20)和der(3)t(3p-;13)(3p-;q21),这些复杂染色体重排主要由染色体不平衡易位所致。另有一些异常比较罕见,目前报道不超过百例,分别是：der(15)t(Y;15)、dic (16; 17)、der(12)t(8;12)、t(2;4)、der(10)t(10;17)、der(14)t(14;15)、der(12)t(6;12)、der(1)t(1;5)、der(15)t(1;15)、der(17)t(5;17)、der(3)t(3p-;13)、t(9;15)以及der(13)t(10;13)。(5)分析CCA在AL中所涉及的染色体种类：CCA几乎涉及所有染色体,在AML患者以涉及17号、5号、7号、15号和11号染色体的异常较为常见；在ALL患者则以涉及8号、9号、14号和22号染色体的异常较为多见。
[结论]M-FISH不仅可以证实CC已明确的异常,还可确定CC所不能辨认的复杂核型异常以及标记染色体的来源和组成,二者联合应用在部分患者可进一步明确断裂位点,可以提高核型分析的分辨率,且有助于发现未报道过的异常以及少见异常,对伴复杂核型和标记染色体的AL具有一定的临床应用价值。
Objective:(1) To set up the technical system of multiplex fluorescence in situ hybridization (M-FISH) technique. (2) To explore the value of combination of conventional cytogenetics, locus specific FISH and M-FISH in the detection of the complex chromosomal aberrations (CCAs) and marker chromosomes in acute leukemia (AL). (3) To find out unreported or very rare abnormalities by reviewing literature and checking the Mitelman database of Chromosome Aberrations in Cancer and to discuss the possible prognostic relevance of these abnormalities.
Methods:(1) Bone marrow specimens of patients with acute leukemia were collected, cultured, prepared and R-banded for conventional cytogenetic analysis. (2) M-FISH was performed on specimens of the 11 AL cases whose conventional cytogenetic analysis showed CCAs or marker chromosomes in order to define the unrecognized chromosomal aberrations and the constitution of marker chromosomes, and to identify small and cryptic translocations. (3) Locus specific FISH with specific probes was performed on specimens whose M-FISH results showed or suspected involvement of specific genes, such as MLL amplification or P53 deletion, for verification or exclusion.
Results:(1) The M-FISH technical system was successfully established, with all of the 11 M-FISH experiments being successful and with good images. (2) Conventional cytogenetics (CC) showed CCAs and/or marker chromosomes in the 11 AL cases studied. Altogether CC detected 27 numerical and 41 structural chromosomal abnormalities, including 17 marker chromosomes, whose constitution and resources were undetermined. (3) M-FISH analysis determined the resources and chatacteristics of the structural abnormalities undetermined by CC. Among the 27 numerical and 41 structural chromosomal abnormalities detected by CC,3 chromosome gains and 9 chromosome losses as well as 12 structural abnormalities were confirmed by M-FISH. The other 15 chromosome losses detected by CC were revised by M-FISH as derivative chromosomes. M-FISH also detected 3 chromosome gains that were undetected by CC. The other 29 structural abnormalities including 17 marker chromosomes were characterized by M-FISH. The locus specific FISH performed on certain patients further verified the M-FISH results. (4) Results of literature reviewing and database searching:A total of 33 structural abnormalities were detected by M-FISH, among which 6 have never been reported before, i.e. t(5q-;16)(?ql4;q24), der(9)(Y::9::Y::9), der(7) (7::8::9), ins(20;21), der(11) (11::21::20) and der(3)t(3p-;13)(3p-;q21) and most of them resulted from unbalanced translocations. Some of the abnormalities are very rare, with no more than 100 cases reported world wide up to now, including der(15)t(Y;15), dic(16;17), der(12)t(8;12), t(2;4), der(10)t(10;17), der(14)t(14;15), der(12)t(6;12), der(1)t(1;5), der(15)t(1;15), der(17)t(5;17), der(3)t(3p-;13), t(9;15) and der(13)t(10;13). (5) Analyzing the distribution of chromosomes involved in CCA of AL:Almost all chromosomes were involved in CCAs, the more common ones were chromosome 17,5,7,15,11 in AML and 8,9,14,22 in ALL.
Conclusion:Not only can M-FISH verify the abnormalities determined by CC, but the technique can also determine the complex chromosomal abnormalities and recognize the resources and constitution of marker chromosomes undetermined by CC. Combination of these two kinds of technique can also help further determine the breakpoint in some patients, raise resolution of karyotyping, and help discover unreported abnormalities and very rare abnormalities, which justifies its clinical application for the detection of CCAs and marker chromosomes in AL.
引文
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[58]Zwaan CM, Kaspers GJL, Pieters R, et al. Cellular drug resistance in childhood acute myeloid leukemia is related to chromosomal abnormalities. Blood,2002,100(9): 3352-3360.
[59]Wang Y, Xue Y, Chen S, et al. A clinical and laboratory study on acute myeloid leukemia with t(6;9)(p23;q34). Zhonghua Yi Xue Yi Chuan Xue Za Zhi.2010,27(1): 34-37.
[60]Chi Y, Lindgren V, Quigley S, et al. Acute myelogenous leukemia with t(6;9)(p23;q34) and marrow basophilia:an overview. Arch Pathol Lab Med,2008, 132(11):1835-1837.
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[45]Seifert H, Mohr B, Thiede C, et al. The prognostic impact of 17p (p53) deletion in 2272 adults with acute myeloid leukemia. Leukemia,2009,23(4):656-663..
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[52]Streubel B, Sauerland C, Heil G, et al. Correlation of cytogenetic, molecular cytogenetic, and clinical findings in 59 patients with ANLL or MDS and abnormalities of the short arm of chromosome 12. Br J Haematol,1998,100(3):521-533.
[53]Schoch C, Haferlach T, Haase D, et al. Patients with de novo acute myeloid leukaemia and complex karyotype aberrations show a poor prognosis despite intensive treatment:a study of 90 patients. Br J Haematol,2001,112(1):118-126.
[54]Visani G, Bernasconi P, Boni M, et al. The prognostic value of cytogenetics is reinforced by the kind of induction/consolidation therapy in influencing the outcome of acute myeloid leukemia-analysis of 848 patients. Leukemia,2001,15(6):903-909.
[55]Swansbury GJ, Lawler SD, Alimena G, et al. Long-term survival in acute myelogenous leukemia:a second follow-up of the Fourth International Workshop on Chromosomes in Leukemia. Cancer Genet Cytogenet,1994,73(1):1-7.
[56]Mrozek K, Heinonen K, Lawrence D, et al. Adult patients with de novo acute myeloid leukemia and t(9;11)(p22;q23) have a superior outcome to patients with other translocations involving band 11q23:a Cancer and Leukemia Group B study. Blood, 1997,90(11):4532-4538.
[57]Rubnitz JE, Raimondi SC, Tong X, et al. Favorable impact of the t(9;11) in childhood acute myeloid leukemia. J Clin Oncol,2002,20(9):2302-2309.
[58]Zwaan CM, Kaspers GJL, Pieters R, et al. Cellular drug resistance in childhood acute myeloid leukemia is related to chromosomal abnormalities. Blood,2002,100(9): 3352-3360.
[59]Wang Y, Xue Y, Chen S, et al. A clinical and laboratory study on acute myeloid leukemia with t(6;9)(p23;q34). Zhonghua Yi Xue Yi Chuan Xue Za Zhi.2010,27(1): 34-37.
[60]Chi Y, Lindgren V, Quigley S, et al. Acute myelogenous leukemia with t(6;9)(p23;q34) and marrow basophilia:an overview. Arch Pathol Lab Med,2008, 132(11):1835-1837.
[61]Slovak ML, Gundacker H, Bloomfield CD, et al. A retrospective study of 69 patients with t(6;9)(p23;q34) AML emphasizes the need for a prospective, multicenter initiative for rare'poor prognosis'myeloid malignancies. Leukemia,2006,20(7): 1295-1297.
[62]Grim wade D, Hills RK, Moorman AV, et al. Refinement of cytogenetic classification in acute myeloid leukemia:determination of prognostic significance of rare recurring chromosomal abnormalities amongst 5,876 younger adult patients treated in the UK Medical Research Council trials. Blood,2010, [Epub ahead of print].
[1]Nowell PC, Hungerford DA. A minute chromosome in human chronic granulocytic leukemia. Science,1960,132(3438):1497-1497. Abstract.
[2]Caspersson T, Gahrton G, Lindsten J, Zech L. Identification of the Philadelphia chromosome as a number 22 by quinacrine mustard fluorescence analysis. Exp Cell Res, 1970,63(1):238-240.
[3]Rowley JD. A new consistent chromosomal abnormality in chronic myelogenous leukaemia identified by quinacrine fluorescence and Giemsa staining. Nature,1973, 243(5405):290-293.
[4]Kantarjian HM, Smith TL, O'Brien S, et al. Prolonged survival in chronic myelogenous leukemia after cytogenetic response to interferon-alpha therapy. The Leukemia Service. Ann Intern Med,1995,122(4):254-261.
[5]Takahashi N, Miura I, Saitoh K, Miura AB. Lineage involvement of stem cells bearing the Philadelphia chromosome in chronic myeloid leukemia in the chronic phase as shown by a combination of fluorescence-activated cell sorting and fluorescence in situ hybridization. Blood,1998,92(12):4758-4763.
[6]Ren R. Mechanisms of BCR-ABL in the pathogenesis of chronic myelogenous leukaemia. Nat Rev Cancer,2005,5(3):172-183.
[7]Gribble SM, Sinclair PB, Grace C, et al. Comparative analysis of G-banding, chromosome painting, locus-specific fluorescence in situ hybridization, and comparative genomic hybridization in chronic myeloid leukemia blast crisis. Cancer Genet Cytogenet, 1999,111(1):7-17.
[8]Lim TH, Tien SL, Lim P, Lim AS. The incidence and patterns of BCR/ABL rearrangements in chronic myeloid leukaemia (CML) using fluorescence in situ hybridisation (FISH). Ann Acad Med Singapore,2005,34(9):533-538.
[9]Sinclair PB, Nacheva EP, Leversha M, et al. Large deletions at the t(9;22) breakpoint are common and may identify a poor-prognosis subgroup of patients with chronic myeloid leukemia. Blood,2000,95(3):738-743.
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