9q34 rearrangements in BCR/ABL fusion-negative acute lymphoblastic leukemia

The t(9;22)(q11.2;q34) translocation is found in a subset of acute lymphoblastic leukemia (ALL). The presence of this translocation involving the fusion of BCR/ABL genes represents a poor prognostic group. Because of the importance in detecting t(9;22) in ALL patients and because occasionally a cytogenetically cryptic BCR/ABL fusion is detected with fluorescence in situ hybridization (FISH), our laboratory routinely performs BCR/ABL FISH tests on all newly diagnosed ALL patients. In the past year, 25 consecutive, newly diagnosed, untreated ALL cases were analyzed. We report the cytogenetics and FISH findings of three cases containing a rearranged 9q34 region with an intact BCR (22q11.2) region and an absence of the BCR/ABL fusion. A split ABL signal representing a translocation of the 9q34 region with chromosome segments other than 22q11.2 (BCR) was observed in 3 cases. Two of these patients were 3 years old; one was 21 at the time of diagnosis. A split ABL FISH signal without the involvement of BCR does not represent a t(9;22) translocation, and prognostic implications of this apparent subgroup of ALL cases have not been determined. Cytogenetic, pathologic, and clinical aspects of these three cases are presented.     

Isodicentric 20q- in two cases of B-cell acute lymphocytic leukemia with the respective t(9;20)(p11;q11.2) and t(9;22)(q34;q11.2)

The cytogenetic anomaly der(20)del(20)(q11.2q13.3)idic(20)(p11), or idic(20q-) in short form, has been reported in 13 cases of myelodysplastic syndrome, one case of chronic myelomonocytic leukemia, and one case of acute myeloid leukemia since 2004. To our knowledge, it has not previously been described in lymphoid diseases. Here we report the cases of two patients with B-cell acute lymphocytic leukemia (ALL) having a novel idic(20q-). One was a 34-year-old man with B-cell ALL whose leukemic cells at presentation had a karyotype of 45,XY,dic(9;20)(p11;q11.2); at relapse, a small marker chromosome was found coexisting with the dic(9;20). The other was a 39-year-old woman with Ph-positive B-cell-ALL whose leukemic cells contained both t(9;22)(q34;q11.2) and a small marker chromosome. A series of FISH analyses using the appropriate probes revealed the small marker chromosome in both patients to be an idic(20q-), confirming the dic(9;20)(p11;q11.2) in one case and revealing a BCR/ABL fusion gene in the other. One patient achieved complete remission but relapsed; the other did not achieve complete remission. Both patients died with a short survival time, despite receiving intensive chemotherapy. These two cases show that idic(20q-) can appear not only in myeloid diseases but also in lymphoid diseases.     

Chromosome abnormalities in a pancreatic adenocarcinoma

Short-term cultures initiated from a pancreatic adenocarcinoma were cytogenetically investigated. The composite karyotype was 74-76,XX,+X,+2,+3,+del(3)(p21),+5,+5,+der(7) t(1;7)(q21;p22),+der(7),del(8)(p21),+del(8)(p21),+der(8)t(8;?)(q24; +),+9,+9,+10,+10,+11,+11,+12,+13,+14,+der(14)t(14; +)(p11;?),+der(16)t(15;16)(q11;p13),+der(16),+der(17)t(17;?) (p11;?),+der(17),+18,+20,+20,-21,-21,+22,+22,+1-3mar. A comparison with the few previously cytogenetically characterized cases of this tumor type reveals no consistent abnormalities.     

Therapy-related acute leukemia with mixed phenotype and t(9;22)(q32;q11.2): a case report and review of the literature

Therapy-related acute leukemia showing mixed phenotype is extremely rare. We report a 49-year-old woman who presented with palpable masses in her neck and back. She had received systemic chemotherapy (adriamycin and cisplatin) and radiotherapy for endometrial adenocarcinoma 7 years before. Her peripheral blood and bone marrow showed increased blasts, which coexpressed myeloid (CD13, CD33, and myeloperoxidase) and B-lymphoid antigens (CD19 and CD79a). Cytogenetic analysis showed a karyotype of 46,XX,dup(1)(q21q32),add(5)(q33),t(9;22)(q34;q11.2)[12]/47,idem,+der(22)t(9;22)[8], and BCR/ABL1 rearrangement was detected. Leukemic infiltration was also confirmed in her back mass. After induction chemotherapy with idarubicin, cytarabine, and imatinib, she achieved complete remission. Only 2 cases of therapy-related acute leukemia with mixed phenotype have been reported so far: one with hyperploidy and the other with t(1;21)(p36;q22). To the best of our knowledge, this is the first case of therapy-related acute leukemia with mixed phenotype and t(9;22) as well as extramedullary leukemic infiltrations.     

Complex karyotype in a low grade phyllodes tumor of the breast

Cytogenetic analysis of a phyllodes tumor of low grade malignancy disclosed the karyotype 52-55,XX, -1,+5,+7,+9,+10,+11,-15,+18,-19,+20,der(21)t(1;21)(p13;q22),+mar1x 2-4,+mar2[cp18]/46,XX. This study shows that a complex chromosome karyotype can be found in low-grade phyllodes tumors and is not necessarily a sign of extreme malignancy of these neoplasms.     

两例Turner综合征患者微小额外标记染色体来源鉴定

目的 为指导遗传咨询和临床治疗,对两例特纳综合征患者微小额外标记染色体(small supernumerary marker chromosome,sSMC)来源进行鉴定.方法 高分辨染色体G显带和C显带核型分析;PCR扩增SRY基因;中期染色体荧光原位杂交.结果 两例患者核型分析结果分别为45,X[29]/46,X,+mar[31]和45,X[71]/46,X,+mar[29].病例1 SRY基因检测阳性,其sSMC来源于Y染色体,通过荧光原位杂交最终确定其核型为45,X[29]/46,X,idic(Y)(q10)[31].ish idic(Y)(q10)(RP11-115 H13 ×2)(SRY+).病例2 sSMC来源于X染色体,核型最终确定为45,X[713/46,X,r(X)(p11.23q21)[29]ish r(X)(p11.23q21)(AL591394.11+,AC 092268.3-).结论 联合应用多种遗传学检测技术,准确鉴定了两例特纳综合征患者微小额外标记染色体的来源,以正确指导临床诊断和治疗.     

Four cases with complex Philadelphia translocations, including one with appearance de novo of a "masked" Ph

Four cases of chronic myelogenous leukemia (CML) with complex Philadelphia (Ph) translocations are described. The first case was that of a 50-year-old woman in the chronic phase of CML. Her leukemic cells showed a complex Ph translocation involving chromosomes #9, #11, and #22 [i.e., t(9;9;22;11)(11qter----11q11::9q11----9q34:: 9p11----9pter;22qter----22q11::9q34?;11 pter----11q11::22q11----22qter)]. In addition to the complex Ph translocation, the leukemic cells contained del(10)(p13). The second case was that of a 21-year-old man whose leukemic cells contained a translocation involving chromosomes #5, #9, and #22 [i.e., t(5;22;9)(q31;q11;q34)], resulting in a "masked" Ph chromosome. The third case was that of a 37-year-old man whose leukemic cells had a complex Ph translocation involving chromosomes #8, #9, and #22 [i.e., t(8;9;22)(q13;q34;q11)]. The fourth patient was a 41-year-old woman diagnosed as having CML in myeloid blastic phase, at which time the first specimen was examined by us. This blood sample showed a karyotype of 45,XX, -9, -17, -22, +mar1, +mar2,9q+. No Ph chromosome was present. A standard Ph translocation was detected in the cells obtained from the spleen, when the patient underwent splenectomy for treatment of the blastic crisis. Subsequent specimens obtained from the blood and bone marrow showed that the leukemic cells contained three clones: 45,XX, -9, -17, -22, +mar1, +mar2,9q+/46,XX, -17, +mar1,t(9;22)(q34;q11)/46,XX,t(9;22)(q34;q11). Cells with the "masked" Ph chromosome were thought to have been derived from the clone with the standard Ph translocation. We postulate that some variant Ph translocations, including those with a "masked" Ph chromosome, may be generated by a stepwise process following the genesis of a standard Ph translocation.     

A near‐haploid clone harboring a BCR/ABL1 gene fusion in an adult patient with newly diagnosed B‐lymphoblastic leukemia

The detection of recurrent genetic abnormalities in B‐lymphoblastic leukemia (B‐ALL) is critical for risk stratification and therapy‐related decisions. Near‐haploidy (24‐30 chromosomes), a subgroup of hypodiploidy (<46 chromosomes), and BCR/ABL1 gene fusions are both recurrent genetic abnormalities in B‐ALL and are considered adverse prognostic findings, although outcomes in BCR/ABL1‐positive patients have improved with tyrosine kinase inhibitor therapy. While near‐haploid clones are primarily observed in children and rarely harbor structural abnormalities, BCR/ABL1‐positive B‐ALL is primarily observed in adults. Importantly, recurrent genetic abnormalities are considered mutually exclusive and rarely exist within the same neoplastic clone. We report only the second case to our knowledge of a near‐haploid clone that harbors a BCR/ABL1 fusion in an adult with newly diagnosed B‐ALL. Conventional chromosome studies revealed a near‐haploid clone (27 chromosomes) along with a der(22)t(9;22)(q34.1;q11.2) in 17 of 20 metaphases analyzed. Our B‐ALL fluorescence in situ hybridization (FISH) panel confirmed the BCR/ABL1 fusion and monosomies consistent with chromosome studies in approximately 95% of interphase nuclei. Moreover, no evidence of a “doubled” near‐haploid clone was observed by chromosome or FISH studies. This highly unusual case illustrates that while rare, recurrent genetic abnormalities in B‐ALL can exist within the same neoplastic clone.     

两种BCR/ABL探针在Ph阳性白血病荧光原位杂交检测中的不同信号模式及其意义

目的 比较BCR/ABL双色额外信号探针(dual color extra-signal BCR/ABL probe,ESFISH探针)及BCR/ABL双色双融合探针(dual color dual fusion BCR/ABL probe,D-FISH探针)在Ph阳性白血病荧光原位杂交(fluorescence in situ hybridization,FISH)检测中信号模式的差异,探讨它们的诊断价值.方法 分别采用D-FISH和ES-FISH探针对74例伴有单纯t(9;22)(q34;q11)及37例伴有变异Ph易位或复杂核型异常的Ph阳性白血病患者骨髓细胞进行间期FISH检测.结果 所有单纯t(9;22)(q34;q11)易位的白血病患者应用两种探针均检测到BCR/ABL阳性信号,ES-FISH探针显示2个橙色信号、1个绿色信号和1个黄色信号模式,而D-FISH探针显示1个橙色信号、1个绿色信号和2个黄色信号模式.ES-FISH探针在9例(12.2%)Ph阳性白血病患者中识别次要BCR断裂位点(1个橙色信号、1个绿色信号和2个黄色信号),而D-FISH探针不能识别主要BCR和次要BCR断裂位点;D-FISH探针在8例(10.8%)Ph阳性白血病中区分ABL基因单独缺失(1个橙色信号、2个绿色信号、1个黄色信号)和ABL、BCR基因共同缺失(1个橙色信号、1个绿色信号和1个黄色信号),ES-FISH则不能区分之.检测变异Ph易位和含Ph易位的复杂核型异常时,两种探针的信号模式分别有4种和6种之多,且以不典型者居多,对于它们的精确解释必须依赖常规染色体分析和中期FISH结果 .结论 ES-FISH及D-FISH探针由于BCR探针大小及覆盖区域不同,在Ph阳性白血病的FISH检测中显示不同信号模式,可分别作为Ph+急性淋巴细胞白血病和慢性髓系白血病患者FISH检测的首选.若采用伊马替尼治疗,主要BCR断裂点和次要BCR断裂点、伴或不伴有衍生9号染色体部分序列缺失均不影响预后,但鉴于ES-FISH探针性价比优于D-FISH探针,推荐其作为Ph阳性白血病FISH检测的首选.     

两种BCR/ABL探针在Ph阳性白血病荧光原位杂交检测中的不同信号模式及其意义

目的 比较BCR/ABL双色额外信号探针(dual color extra-signal BCR/ABL probe,ESFISH探针)及BCR/ABL双色双融合探针(dual color dual fusion BCR/ABL probe,D-FISH探针)在Ph阳性白血病荧光原位杂交(fluorescence in situ hybridization,FISH)检测中信号模式的差异,探讨它们的诊断价值.方法 分别采用D-FISH和ES-FISH探针对74例伴有单纯t(9;22)(q34;q11)及37例伴有变异Ph易位或复杂核型异常的Ph阳性白血病患者骨髓细胞进行间期FISH检测.结果 所有单纯t(9;22)(q34;q11)易位的白血病患者应用两种探针均检测到BCR/ABL阳性信号,ES-FISH探针显示2个橙色信号、1个绿色信号和1个黄色信号模式,而D-FISH探针显示1个橙色信号、1个绿色信号和2个黄色信号模式.ES-FISH探针在9例(12.2%)Ph阳性白血病患者中识别次要BCR断裂位点(1个橙色信号、1个绿色信号和2个黄色信号),而D-FISH探针不能识别主要BCR和次要BCR断裂位点;D-FISH探针在8例(10.8%)Ph阳性白血病中区分ABL基因单独缺失(1个橙色信号、2个绿色信号、1个黄色信号)和ABL、BCR基因共同缺失(1个橙色信号、1个绿色信号和1个黄色信号),ES-FISH则不能区分之.检测变异Ph易位和含Ph易位的复杂核型异常时,两种探针的信号模式分别有4种和6种之多,且以不典型者居多,对于它们的精确解释必须依赖常规染色体分析和中期FISH结果 .结论 ES-FISH及D-FISH探针由于BCR探针大小及覆盖区域不同,在Ph阳性白血病的FISH检测中显示不同信号模式,可分别作为Ph+急性淋巴细胞白血病和慢性髓系白血病患者FISH检测的首选.若采用伊马替尼治疗,主要BCR断裂点和次要BCR断裂点、伴或不伴有衍生9号染色体部分序列缺失均不影响预后,但鉴于ES-FISH探针性价比优于D-FISH探针,推荐其作为Ph阳性白血病FISH检测的首选.     

两种BCR/ABL探针在Ph阳性白血病荧光原位杂交检测中的不同信号模式及其意义

目的 比较BCR/ABL双色额外信号探针(dual color extra-signal BCR/ABL probe,ESFISH探针)及BCR/ABL双色双融合探针(dual color dual fusion BCR/ABL probe,D-FISH探针)在Ph阳性白血病荧光原位杂交(fluorescence in situ hybridization,FISH)检测中信号模式的差异,探讨它们的诊断价值.方法 分别采用D-FISH和ES-FISH探针对74例伴有单纯t(9;22)(q34;q11)及37例伴有变异Ph易位或复杂核型异常的Ph阳性白血病患者骨髓细胞进行间期FISH检测.结果 所有单纯t(9;22)(q34;q11)易位的白血病患者应用两种探针均检测到BCR/ABL阳性信号,ES-FISH探针显示2个橙色信号、1个绿色信号和1个黄色信号模式,而D-FISH探针显示1个橙色信号、1个绿色信号和2个黄色信号模式.ES-FISH探针在9例(12.2%)Ph阳性白血病患者中识别次要BCR断裂位点(1个橙色信号、1个绿色信号和2个黄色信号),而D-FISH探针不能识别主要BCR和次要BCR断裂位点;D-FISH探针在8例(10.8%)Ph阳性白血病中区分ABL基因单独缺失(1个橙色信号、2个绿色信号、1个黄色信号)和ABL、BCR基因共同缺失(1个橙色信号、1个绿色信号和1个黄色信号),ES-FISH则不能区分之.检测变异Ph易位和含Ph易位的复杂核型异常时,两种探针的信号模式分别有4种和6种之多,且以不典型者居多,对于它们的精确解释必须依赖常规染色体分析和中期FISH结果 .结论 ES-FISH及D-FISH探针由于BCR探针大小及覆盖区域不同,在Ph阳性白血病的FISH检测中显示不同信号模式,可分别作为Ph+急性淋巴细胞白血病和慢性髓系白血病患者FISH检测的首选.若采用伊马替尼治疗,主要BCR断裂点和次要BCR断裂点、伴或不伴有衍生9号染色体部分序列缺失均不影响预后,但鉴于ES-FISH探针性价比优于D-FISH探针,推荐其作为Ph阳性白血病FISH检测的首选.     

Cytogenetic abnormalities in hepatoblastoma: report of two new cases and review of the literature suggesting imbalance of chromosomal regions on chromosomes 1, 4, and 12

Two cases of hepatoblastoma with unique karyotypic changes are described. One case was that of a 2-year-old boy with an unbalanced chromosomal translocation involving 4q35 as the sole chromosomal abnormality. The clonal karyotype of this tumor was 46,XY,add(4)(q35)[3]/46,XY[9]. In the other case, that of a 2-year-old boy, karyotypic analyses revealed the clonal karyotype as 57,XY,+del(1)(p22),+2,+5,+6,+7,+8,+del(12)(p12),+18,+19,+20,+22[4]/46,XY[12]. Review of these two cases, together with previous reports, underscored the significance of numerical and/or structural chromosomal abnormalities of 1q, 4q, 2, 8, and 20 in the development of hepatoblastoma. The present results show that imbalance of the terminal region of 4q could be the sole chromosomal abnormality in a hepatoblastoma. We also found that imbalance of chromosomal regions on chromosomes 1 and 12 may contribute to the development of hepatoblastoma.     

Characterization of two supernumerary marker chromosomes in a patient with signs of Klinefelter syndrome, mild facial anomalies, and severe speech delay

A boy with signs of Klinefelter syndrome, mild facial dysmorphic features, and severely retarded speech development displayed a female karyotype with mosaicism for two marker chromosomes 48,XX,+mar1,+mar2[68]/47,XX,+mar1[19]/47,XX,+mar2[6]/46,XX[8]. Using chromosomal microdissection, locus-specific fluorescence in situ hybridization (FISH), and PCR with several Y-chromosome markers, the larger supernumerary marker chromosome (SMC) was characterized as a ring Y-chromosome. Detection of the SRY-region explained the male phenotype. The smaller second marker chromosome contained the pericentromeric region of chromosome 8. We suggest that the co-occurrence of a partial Y-chromosome and partial trisomy 8 explain the severe speech delay and the facial dysmorphic features.     

IGH gene involvement in two cases of acute lymphoblastic leukemia with t(14;14)(q11;q32) identified by sequential R-banding and fluorescence in situ hybridization

Translocation (14;14)(q11;q32) or inv(14)(q11q32) is a common cytogenetic aberration in T-cell leukemia associated with ataxia-telangiectasia (AT); however, rare reports have indicated that this abnormality also occurs in B-lineage acute lymphoblastic leukemia (ALL). We report here two cases with common-type ALL exhibiting the chromosomal aberration t(14;14)(q11;q32). The immunophenotype showed the blasts were positive for CD9, CD10, CD38, CD22, and CD15 in case 1 and positive for CD2, CD9, CD10, CD19, CD38, CD20, and CD22 in case 2, but negative for CD3, CD4, and CD8 expression in both cases. The cytogenetic analysis revealed del(6)(q22), and t(14;14)(q11;q32) in case 1 and t(14;14)(q11;q32),+mar in case 2. Fluorescence in situ hybridization (FISH) and sequential R-banding FISH assay with dual-color break-apart IGH probe confirmed that t(14;14)(q11;q32) involved the IGH gene in our cases. The results indicate that the t(14;14)(q11;q32) involving IGH at 14q32 in B-lineage ALL in our cases differ from those reported to involve the TCL1 gene on 14q32.1 in T-cell leukemia associated with AT. Sequential R-banding and FISH provide precise analysis of alterations of chromosomes and genes involved.