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1.
Genes Chromosomes Cancer ; 46(5): 478-86, 2007 May.
Article in English | MEDLINE | ID: mdl-17311319

ABSTRACT

The t(1;19)(q23;p13.3) is one of the most common chromosomal abnormalities in B-cell precursor acute lymphoblastic leukemia (BCP-ALL) and usually gives rise to the TCF3-PBX1 fusion gene. Additional rare, and sometimes cytogenetically cryptic, translocations involving the TCF3 gene have also been described. Using a dual color split-signal fluorescence in situ hybridization (FISH) probe, we have investigated the involvement of this gene in a series of BCP-ALLs harboring 19p13 translocations, as well as an unselected patient cohort. The TCF3 gene was shown to be involved in the majority of cases with a cytogenetically visible t(1;19) translocation, while the remaining TCF3-negative ALLs demonstrated breakpoint heterogeneity. Although most "other" 19p13 translocations did not produce a split-signal FISH pattern, a novel t(13;19)(q14;p13) involving TCF3 was discovered. A prospective screen of 161 children with BCP-ALL revealed a cryptic t(12;19)(p13;p13), another novel TCF3 rearrangement, and a series of patients with submicroscopic deletions of TCF3. These results demonstrate the utility of a split-signal FISH strategy in confirming the involvement of the TCF3 gene in 19p13 rearrangements and in identifying novel and cryptic TCF3 translocations. In addition to its role as a fusion partner gene, we propose that TCF3 can also act as a tumor suppressor gene in BCP-ALL.


Subject(s)
Basic Helix-Loop-Helix Transcription Factors/genetics , Burkitt Lymphoma/genetics , Chromosomes, Human, Pair 19 , Chromosomes, Human, Pair 1 , Translocation, Genetic , Burkitt Lymphoma/pathology , Chromosome Mapping , Gene Rearrangement , Humans , In Situ Hybridization, Fluorescence , Interphase , Karyotyping , Precancerous Conditions/genetics , Precancerous Conditions/pathology , Sequence Deletion
2.
Cancer Genet Cytogenet ; 167(1): 78-81, 2006 May.
Article in English | MEDLINE | ID: mdl-16682292

ABSTRACT

A chance observation of a tiny constitutional variant for the centromere of chromosome 21 in two patients with acute lymphoblastic leukemia (ALL), suggested a possible correlation with the cytogenetic findings in their leukemic cells. Interphase FISH revealed three 13/21 centromeric signals and a single MLL signal in the blast cells of each patient. Metaphase FISH with dual-color application of whole-chromosome paint (wcp) and centromeric probes for chromosome 21 showed two copies of chromosome 21, one with a tiny centromeric signal which corresponded to the invisible centromere in the interphase cells. Patient 2700 had a normal karyotype in his bone marrow at diagnosis. All metaphases from his stimulated peripheral blood also had the tiny chromosome 21 centromere, proving it to be a constitutional variant. Patient 3314 showed the abnormal karyotype 46,XY,inv(1)(p?q?),del(11)(q?),del(12)(p?),inc in his bone marrow. Interphase FISH revealed only one copy each of the ABL and ETV6 genes, in addition to the loss of the MLL signal. The question arises, is there an association between the diminutive centromeric signals for chromosome 21 and the chromosomal instability demonstrated by the deletions of key genes from the leukemic blasts of these two patients?


Subject(s)
Centromere , Chromosomes, Human, Pair 21 , Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics , Adolescent , Child , Chromosome Deletion , Chromosome Painting , Chromosomes, Human, Pair 11 , Chromosomes, Human, Pair 12 , Genes, abl , Genetic Variation , Humans , Interphase , Karyotyping , Male
3.
Br J Haematol ; 129(4): 520-30, 2005 May.
Article in English | MEDLINE | ID: mdl-15877734

ABSTRACT

Summary Interphase fluorescence in situ hybridization (iFISH) was used independently to reveal chromosomal abnormalities of prognostic importance in a large, consecutive series of children (n = 2367) with acute lymphoblastic leukaemia (ALL). The fusions, TEL/AML1 and BCR/ABL, and rearrangements of the MLL gene occurred at frequencies of 22% (n = 447/2027) (25% in B-lineage ALL), 2% (n = 43/2027) and 2% (n = 47/2016) respectively. There was considerable variation in iFISH signal patterns both between and within patient samples. The TEL/AML1 probe showed the highest incidence of variation (59%, n = 524/884), which included 38 (2%) patients with clustered, multiple copies of AML1. We were thus able to define amplification of AML1 as a new recurrent abnormality in ALL, associated with a poor prognosis. Amplification involving the ABL gene, a rare recurrent abnormality confined to T ALL patients, was identified for the first time. The use of centromeric probes revealed significant hidden high hyperdiploidy of 33% and 59%, respectively, in patients with normal (n = 21/64) or failed (n = 32/54) cytogenetic results. The iFISH contributed significantly to the high success rate of 91% (n = 2114/2323) and the remarkable abnormality detection rate of 89% (n = 1879/2114). This study highlights the importance of iFISH as a complementary tool to cytogenetics in routine screening for significant chromosomal abnormalities in ALL.


Subject(s)
Chromosome Aberrations , Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics , Adolescent , Child , Child, Preschool , Core Binding Factor Alpha 2 Subunit , Cytogenetic Analysis , DNA-Binding Proteins/genetics , Fusion Proteins, bcr-abl/genetics , Gene Amplification , Gene Rearrangement , Genes, abl , Histone-Lysine N-Methyltransferase , Humans , In Situ Hybridization, Fluorescence , Infant , Interphase , Myeloid-Lymphoid Leukemia Protein , Oncogene Proteins, Fusion/genetics , Prognosis , Proto-Oncogenes/genetics , Reverse Transcriptase Polymerase Chain Reaction , Transcription Factors/genetics
4.
Genes Chromosomes Cancer ; 43(1): 54-71, 2005 May.
Article in English | MEDLINE | ID: mdl-15704129

ABSTRACT

This study was undertaken in order to compare the interphase and metaphase cytogenetics of 28 patients with ETV6/RUNX1 positive acute lymphoblastic leukemia, at diagnosis and relapse. The median time to relapse was 26 months. The significant fusion positive population heterogeneity revealed at interphase by a commercial probe for ETV6/RUNX1 fusion has not been described before. Six diagnostic samples had a single abnormal population; others had up to five each, which differed in the numbers of RUNX1 signals, and in the retention or loss of the second ETV6 signal. In contrast, the number of fusion signals was more constant. At relapse, there were fewer populations; the largest or unique clone was sometimes a re-emergence of a minor, diagnostic one, with a retained copy of ETV6 and the most RUNX1 signals. Abnormal, fusion negative clones were identified in bone marrow samples at extra-medullary relapse. Variant three or four-way translocations, which involved chromosomes 12 and 21, were prominent among the complex rearrangements revealed by metaphase FISH. The frequency of their occurrence at diagnosis and reappearance at relapse, sometimes accompanied by minor clonal evolution, was another new observation. Other recurrent cytogenetic features included a second copy of the fusion signal in six cases, partial duplication of the long arm of the X chromosome in two cases, and trisomy 10 in three cases. In comparing our data with previously reported cases, a picture is beginning to emerge of certain diagnostic features, which may provide circumstantial evidence of an increased risk of relapse.


Subject(s)
Artificial Gene Fusion , DNA-Binding Proteins/genetics , Nuclear Proteins/genetics , Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics , Proto-Oncogene Proteins/genetics , Repressor Proteins/genetics , Transcription Factors/genetics , Adolescent , Adult , Child , Child, Preschool , Chromosome Mapping , Core Binding Factor Alpha 2 Subunit , Female , Humans , In Situ Hybridization, Fluorescence , Infant , Karyotyping , Male , Middle Aged , Precursor Cell Lymphoblastic Leukemia-Lymphoma/diagnosis , Prognosis , Proto-Oncogene Proteins c-ets , Recurrence , ETS Translocation Variant 6 Protein
5.
Br J Haematol ; 126(3): 307-12, 2004 Aug.
Article in English | MEDLINE | ID: mdl-15257702

ABSTRACT

Prenatal acquisition of leukaemia-associated gene rearrangements is a well-established phenomenon. This is the first report of a complex cytogenetic clone, in association with an ETV6/AML1 fusion, developing in utero. Identical twin girls, aged 4 years, developed ETV6/AML1-positive acute lymphoblastic leukaemia (ALL) within 3 months of one another. Both demonstrated an identical four way, variant t(12;21). There was gain of an AML1 signal in twin 1 and loss of an ETV6 one in twin 2 at interphase. This unique case study demonstrates that ETV6/AML1 fusion and the associated complex chromosomal rearrangements occurred in utero. Clonal expansion of the abnormal cell in one twin was followed by metastasis to the other. There was a prolonged preleukaemic phase, which lasted well into childhood. The short time between the two diagnoses of ALL suggests a common precipitating event. The significance of the different secondary markers remains unclear.


Subject(s)
Diseases in Twins/embryology , Diseases in Twins/genetics , Precursor Cell Lymphoblastic Leukemia-Lymphoma/embryology , Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics , Translocation, Genetic , Child, Preschool , Chromosomes, Human, Pair 12 , Chromosomes, Human, Pair 21 , Clone Cells , Core Binding Factor Alpha 2 Subunit , Female , Humans , In Situ Hybridization, Fluorescence , Karyotyping , Oncogene Proteins, Fusion/genetics , Preleukemia/embryology , Preleukemia/genetics , Twins, Monozygotic
6.
Br J Haematol ; 125(5): 552-9, 2004 Jun.
Article in English | MEDLINE | ID: mdl-15147369

ABSTRACT

This study of children and adults with acute lymphoblastic leukaemia (ALL) is the largest series of patients with hypodiploidy (<46 chromosomes) yet reported. The incidence of 5% was independent of age. Patients were subdivided by the number of chromosomes; near-haploidy (23-29 chromosomes), low hypodiploidy (33-39 chromosomes) and high hypodiploidy (42-45 chromosomes). The near-haploid and low hypodiploid groups were characterized by their chromosomal gains and a doubled hyperdiploid population. Structural abnormalities were more frequent in the low hypodiploid group. Near-haploidy was restricted to children of median age 7 years (range 2-15) whereas low hypodiploidy occurred in an older group of median age 15 years (range 9-54). Patients with 42-45 chromosomes were characterized by complex karyotypes involving chromosomes 7, 9 and 12. The features shared by the few patients with 42-44 chromosomes and the large number with 45 justified their inclusion in the same group. Survival analysis showed a poor outcome for the near-haploid and low hypodiploid groups compared to those with 42-45 chromosomes. Thus cytogenetics, or at least a clear definition of the modal chromosome number, is essential at diagnosis in order to stratify patients with hypodiploidy into the appropriate risk group for treatment.


Subject(s)
Aneuploidy , Chromosomes, Human/genetics , Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics , Adolescent , Adult , Child , Disease-Free Survival , Female , Follow-Up Studies , Humans , Karyotyping , Male , Middle Aged , Prognosis , Survival Analysis
7.
Blood ; 102(8): 2756-62, 2003 Oct 15.
Article in English | MEDLINE | ID: mdl-12829593

ABSTRACT

High hyperdiploidy (HeH) (51 to 65 chromosomes) is found in one third of children with acute lymphoblastic leukemia and is associated with a good prognosis. Cytogenetic features may further refine this prognosis and identify patients with a poor outcome. We examined the effect of sex, age, individual trisomies, modal number, and structural abnormalities on survival among 700 children with HeH. Univariate analysis showed that age. sex, +4, +10, +18, and a high modal number were associated with survival. Multivariate analysis however, revealed that only age, sex, +4, and +18 were independent indicators. Hazard scores for predicting relapse and mortality were constructed. Three risk groups with 5-year event-free survival (EFS) rates of 86%, 75%, and 50% (P <.0001) were identified. The high-risk group comprised boys older than 9 years, boys aged 1 through 9 years without +18, and girls older than 9 years without +18, while girls aged 1 through 9 years with +18 had the best EFS. In terms of mortality, those younger than age 10 years with both +4 and +18 had an improved survival (96% vs 84% at 5 years, P <.0001). These findings confirm that the outcome of children with HeH is heterogeneous and that specific trisomies can identify patients with the greatest and least risk of treatment failure.


Subject(s)
Diploidy , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics , Adolescent , Age Factors , Child , Child, Preschool , Disease-Free Survival , Female , Humans , In Situ Hybridization, Fluorescence , Infant , Karyotyping , Male , Multivariate Analysis , Precursor Cell Lymphoblastic Leukemia-Lymphoma/mortality , Prognosis , Proportional Hazards Models , Sex Factors , Time Factors , Treatment Outcome , Trisomy
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