RESUMO
Fluorescence in situ hybridization (FISH) studies were performed in three cases of acute lymphoblastic leukemia (ALL) with marker chromosomes to analyze the contribution of chromosome 21 in these markers. FISH with a chromosome 21 painting probe confirmed that chromosome 21 was involved in all three cases. FISH with YAC probes showed that the number of extra copies varied according to their location on chromosome 21. Attention was focused on the AML1 gene, which was present as five copies in most of the cells exhibiting the marker chromosomes. As controls, 11 cases of childhood ALL were studied with PAC probes covering AML1. The results agreed with the banded karyotypes in 10 patients. FISH uncovered a clone with four copies of AML1 which were only observed by FISH analysis of interphase nuclei in one patient. No point mutation was detected in exons 3-5, encoding the runt domain of AML1, in the three cases, suggesting an oncogenic role of wild-type AML1 amplification.
Assuntos
Aberrações Cromossômicas , Cromossomos Humanos Par 21/genética , Proteínas de Ligação a DNA/genética , Amplificação de Genes/genética , Proteínas de Neoplasias/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Proteínas Proto-Oncogênicas , Fatores de Transcrição/genética , Adolescente , Criança , Pré-Escolar , Subunidade alfa 2 de Fator de Ligação ao Core , Análise Mutacional de DNA , Feminino , Humanos , Cariotipagem , MasculinoRESUMO
A patient with acute myeloblastic leukemia (AML) and karyotypic abnormality mimicking t(8;21) is reported. Because of the uncommon morphology of blasts for AML with t(8;21), and absence of AML1-ETO fusion in the RT-PCR analysis, fluorescence in situ hybridization (FISH) was applied to precise the abnormality. FISH revealed a complex rearrangement involving chromosomes 7, 21 and 8, and involvement of the AML1 gene without evidence of AML1-ETO fusion. This case of unusual AML illustrates the necessity of collecting all hematologic, cytogenetic, and eventual FISH and RT-PCR data to analyse genetic rearrangements in leukemic patients.
Assuntos
Aberrações Cromossômicas , Transtornos Cromossômicos , Cromossomos Humanos Par 21 , Cromossomos Humanos Par 8 , Leucemia Mieloide Aguda/genética , Translocação Genética , Adulto , Aberrações Cromossômicas/genética , Mapeamento Cromossômico , Cromossomos Humanos Par 7 , Feminino , Humanos , Hibridização in Situ Fluorescente , CariotipagemRESUMO
Cytogenetic and fluorescence in situ hybridization studies have shown the presence of telomeric repeats in translocation present in three patients with hematopoietic malignancies. One had jumping translocations, involving 1q12 and 2q, 16p, and 19q. These sequences were detected by FISH only in derivative chromosomes t(1;16) and t(1;19) in the first patient, and t(1;7) in the second. They were not seen in derivative t(1;2) and t(7;8), respectively. Interstitial telomeric sequences were observed in der(2)t(1;2) in about half of the metaphases in the third patient. The instability of interstitial telomeric DNA repeats in translocations is shown by the present findings. Moreover it supports the hypothesis that the presence of interstitial telomere repeats is not sufficient to make it functional.
Assuntos
Neoplasias Hematológicas/genética , Telômero/genética , Translocação Genética , Idoso , Idoso de 80 Anos ou mais , Cromossomos Humanos Par 1 , Cromossomos Humanos Par 16 , Cromossomos Humanos Par 19 , Cromossomos Humanos Par 2 , Feminino , Humanos , Cariotipagem , Masculino , Sequências Repetitivas de Ácido Nucleico/genéticaAssuntos
Cromossomos Humanos Par 16 , Cromossomos Humanos Par 21 , Leucemia Mieloide/genética , Proteínas de Fusão Oncogênica/genética , Fatores de Transcrição/genética , Translocação Genética/genética , Doença Aguda , Adulto , Sequência de Aminoácidos , Sequência de Bases , Subunidade alfa 2 de Fator de Ligação ao Core , Feminino , Humanos , Cariotipagem , Dados de Sequência MolecularRESUMO
Cytogenetic study of a young child with acute megakaryocytic leukaemia (AML-M7) has shown a karyotype with 49-50 chromosomes with one and two acquired extra chromosomes 21. Fluorescence in situ hybridization detected a minor clone with translocation t(1;21) and loss of a part of chromosome band 1p36. Trisomy and polysomy 21 are not uncommon in AML-M7. A more systematic search for chromosome 21 rearrangements in AML-M7 using FISH techniques is proposed.
Assuntos
Cromossomos Humanos Par 1/genética , Cromossomos Humanos Par 21/genética , Síndrome de Down , Leucemia Megacarioblástica Aguda/genética , Translocação Genética/genética , Medula Óssea/patologia , Medula Óssea/ultraestrutura , Aberrações Cromossômicas/genética , Bandeamento Cromossômico , Análise Citogenética , Humanos , Hibridização in Situ Fluorescente/métodos , Lactente , Cariotipagem , MasculinoRESUMO
The TEL/ETV6 gene is located at 12p13 and encodes a member of the ETS family of transcription factors. Translocated ETS leukemia (TEL) is frequently involved in chromosomal translocations in human malignancies, usually resulting in the expression of fusion proteins between the amino-terminal part of TEL and either unrelated transcription factors or protein tyrosine kinases. We have characterized a t(1;12)(q21;p13) translocation in an acute myeloblastic leukemia (AML-M2). At the protein level, the untranslocated TEL copy and, as a result of the t(1;12) translocation, a fusion protein between TEL and essentially all of aryl hydrocarbon receptor nuclear translocator (ARNT) are expressed. The involvement of ARNT in human leukemogenesis has not been previously described. The ARNT protein belongs to a subfamily of the "basic region helix-loop-helix" (bHLH) protein that shares an additional region of similarity called the PAS (Per, ARNT, SIM) domain. ARNT is the central partner of several heterodimeric transcription factors, including those containing the aryl hydrocarbon (dioxin) receptor (AhR) and the hypoxia-inducible factor 1alpha (HIF1alpha). Our results show that the TEL-ARNT fusion protein is the crucial product of the translocation and suggest that interference with the activity of AhR or HIF1alpha can contribute to leukemogenesis.
Assuntos
Cromossomos Humanos Par 12 , Cromossomos Humanos Par 1 , Proteínas de Ligação a DNA/genética , Leucemia Mieloide Aguda/genética , Receptores de Hidrocarboneto Arílico , Proteínas Repressoras , Fatores de Transcrição/genética , Translocação Genética , Fusão Gênica Artificial , Translocador Nuclear Receptor Aril Hidrocarboneto , Pré-Escolar , Humanos , Masculino , Proteínas Proto-Oncogênicas c-ets , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Variante 6 da Proteína do Fator de Translocação ETSRESUMO
Using fluorescence in situ hybridization analysis, breakpoints involving the long arm of chromosome 1 (1q) were localized in 36 patients with various hematopoietic disorders and rearrangements of the proximal part of 1q, as ascertained with banding techniques. The breakpoint was localized within the satellite II (sat II) domain in 14 patients with various abnormalities, between the sat II domain and the BCL9 locus in eight, between the BCL9 and ARNT loci in two, between sat II and ARNT in two others, and distal to ARNT in seven. A dicentric chromosome 1 was present in two patients. A high incidence of heterochromatin heteromorphism of chromosome 1 was present in this series. Two recurrent translocations were identified, t(1;2)(q12;q37) in three patients suffering from three different acute leukemia subtypes, and t(1;16)(q12;q24) in two patients with different diseases. Two patients had jumping translocations. Most of the rearrangements of 1q were secondary abnormalities, included in complex karyotypes. The roles of methylation, interactions with the proteins interfering with heterochromatin and possible gene silencing due to heterochromatin rearrangements are discussed.
Assuntos
Cromossomos Humanos Par 1 , DNA Satélite , Rearranjo Gênico , Hibridização in Situ Fluorescente , Translocação Genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , RecidivaRESUMO
Two patients with chromosome 16 inversion-associated translocation were studied with conventional cytogenetic and fluorescence in situ hybridization (FISH) techniques. The same chromosome 16 was involved in inversion and translocation in both patients. The chromosome translocation breakpoint was located within the heterochromatin of chromosome 16 but outside the alpha satellite domain in the t(10;16) of the first patient, whereas it was outside the heterochromatin area in the second case with t(1;16). These two types of rearrangements may be due to different mechanisms and illustrate the possible difficulties in recognizing the chromosome 16 inversion without FISH studies.
Assuntos
Inversão Cromossômica , Cromossomos Humanos Par 16/genética , Eosinofilia/genética , Leucemia Mielomonocítica Aguda/genética , Translocação Genética/genética , Adulto , Células da Medula Óssea/metabolismo , Células da Medula Óssea/patologia , Bandeamento Cromossômico , Quebra Cromossômica/genética , Cromossomos Humanos Par 1/genética , Cromossomos Humanos Par 10/genética , Eosinofilia/patologia , Feminino , Variação Genética/genética , Humanos , Hibridização in Situ Fluorescente , Cariotipagem , Leucemia Mielomonocítica Aguda/patologia , Masculino , Mapeamento Físico do CromossomoRESUMO
The TEL gene is involved in several chromosomal abnormalities of human hematopoietic malignancies. The chromosome 12 breakpoints frequently lie within the fifth intron of the gene, particularly in the most frequent translocation involving TEL, the t(12;21)(p13;q22). In order to search for a peculiar mechanism involved in the genesis of these translocations, we have established the sequence of two t(12;21) and a t(9;12)(q24;p13) breakpoints. Our data do not reveal the involvement of VDJ recombinase activity or Alu sequences but favor the occurrence of staggered breaks and DNA repair activity in the genesis of these translocations.
Assuntos
Linfoma de Burkitt/genética , Quebra Cromossômica/genética , Cromossomos Humanos Par 12/genética , Proteínas de Ligação a DNA/genética , Leucemia-Linfoma de Células T do Adulto/genética , Proteínas Repressoras , Fatores de Transcrição/genética , Translocação Genética/genética , Alelos , Elementos Alu/genética , Sequência de Bases , Criança , Cromossomos Humanos Par 21/genética , Cromossomos Humanos Par 9/genética , Análise Mutacional de DNA , DNA Nucleotidiltransferases/metabolismo , Reparo do DNA/genética , Éxons/genética , Humanos , Íntrons/genética , Leucemia-Linfoma de Células T do Adulto/patologia , Mapeamento Físico do Cromossomo , Proteínas Proto-Oncogênicas c-ets , Recidiva , VDJ Recombinases , Variante 6 da Proteína do Fator de Translocação ETSRESUMO
Cytogenetic and fluorescence in situ hybridization (FISH) analysis of 10 patients with various hematopoietic malignancies revealed the presence of dicentric chromosomes or pericentric chromosome rearrangements. Dicentrics were only ascertained by FISH studies in six patients. Two types of pericentric chromosome rearrangements have been observed: 'classical' dicentrics with two clearly separated centromeric regions, and more unusual rearrangements with a breakpoint within the centromeric or heterochromatic area, but outside the alphoid domain. FISH analysis of partial chromosome 1 q duplications present in three Burkitt lymphoma cell lines confirmed the partial involvement of the non-alphoid centromeric domain in the duplicated chromosome segment. The incidence of centromeric and pericentromeric rearrangements in hematopoietic malignancies may be higher than hitherto admitted. The chromosomal localization of these rearrangements suggests several mechanisms possibly involved in the malignant process and deserves more systematic study.
Assuntos
Aberrações Cromossômicas , Neoplasias Hematológicas/genética , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Hibridização in Situ Fluorescente , Lactente , Masculino , Pessoa de Meia-Idade , Células Tumorais CultivadasRESUMO
Two patients with acute myeloid leukemia (AML-M7 and AML-M4) and trisomy 10 as the sole chromosome abnormality are reported. In the first patient, all karyotypes were abnormal. A karyotypically normal cell population was present in the second patient and the trisomic cells were less numerous than the normal ones at diagnosis. A review of the literature shows the rarity of isolated trisomy 10 in hematopoietic disorders and the diversity of the involved diseases. Moreover, in some patients, the trisomic cell population was less numerous than the normal one. These data are discussed in relation with the hypothesis that cells with trisomy 10 can belong to nonmalignant clones, at least in some cases, as previously shown for trisomy 7 in other conditions.
Assuntos
Cromossomos Humanos Par 10 , Leucemia Megacarioblástica Aguda/genética , Leucemia Mielomonocítica Aguda/genética , Trissomia , Idoso , Feminino , Humanos , Cariotipagem , MasculinoRESUMO
Cytogenetic studies of two patients with acute myeloblastic leukemia, classified as M1 and M2, showed a partial duplication of the distal part of the long arm of chromosome 12 (12q24) as the sole detectable chromosome abnormality. High white blood cell count was common to the two leukemic children. Fluorescence in situ hybridization analysis with the use of a whole-chromosome 12 painting probe and a telomeric probe confirmed the apparent absence of any translocation. The genes involved in the duplication could not be ascertained, but several candidate genes such as growth-factor receptors or genes encoding transcription factors localized to 12q22-q24 should be investigated in the molecular analysis of these duplications.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Aberrações Cromossômicas , Transtornos Cromossômicos , Cromossomos Humanos Par 12 , Leucemia Mieloide Aguda/genética , Adolescente , Criança , Mapeamento Cromossômico , Humanos , Cariotipagem , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/patologia , MasculinoRESUMO
The MLL gene, located on chromosome band 11q23 is fused to different partner genes as a result of various chromosomal translocations in hematopoietic malignancies. A t(1;11) (q21;q23) resulting in a MLL-AF1q fusion gene has previously been reported. Cytogenetic studies on six cases are reported, including one three-way translocation. FISH analysis using a YAC encompassing the MLL gene and a YAC encompassing the AF1q locus showed splitting in three cases and two patients, respectively. PCR analysis of two cases confirmed that AF1q is specifically associated with t(1;11)(q21;q23). The MLL-AF1q fusion mRNA was similar to that previously described in one case and involved MLL exon 7 in the other. This study confirms the specific involvement of AF1q in t(1;11) (q21;q23)-positive acute leukemia with monocytic involvement.
Assuntos
Fusão Gênica Artificial , Cromossomos Humanos Par 11 , Cromossomos Humanos Par 1 , Leucemia Mielomonocítica Aguda/genética , Translocação Genética , Sequência de Bases , Pré-Escolar , Feminino , Humanos , Hibridização in Situ Fluorescente , Lactente , Cariotipagem , Masculino , Dados de Sequência MolecularRESUMO
The BCMA gene is a new gene discovered by the molecular analysis of a t(4;16) translocation, characteristic of a human T cell lymphoma. It has no significant similarity with any known protein or motif, so that its function was unknown. This report describes the cloning of murine BCMA cDNA and its genomic counterpart. The mouse gene is organized into three exons, like the human gene, and lies in murine chromosome 16, in the 16B3 band, the counterpart of the human chromosome 16p13 band, where the human gene lies. Murine BCMA cDNA encodes a 185 amino acids protein (184 residues for the human), has a potential central transmembrane segment like the human protein and is 62% identical to it. The murine BCMA mRNA is found mainly in lymphoid tissues, as is human BCMA mRNA. Alignment of the murine and human BCMA protein sequences revealed a conserved motif of six cysteines in the N-terminal part, which strongly suggests that the BCMA protein belongs to the tumor necrosis factor receptor (TNFR) superfamily. Human BCMA is the first member of the TNFR family to be implicated in a chromosomal translocation.
Assuntos
Proteínas de Membrana/genética , Sequência de Aminoácidos , Animais , Antígeno de Maturação de Linfócitos B , Linfócitos B/metabolismo , Sequência de Bases , Mapeamento Cromossômico , Clonagem Molecular , DNA Complementar , Humanos , Hibridização in Situ Fluorescente , Proteínas de Membrana/química , Camundongos , Dados de Sequência Molecular , Receptores do Fator de Necrose Tumoral/química , Receptores do Fator de Necrose Tumoral/genética , Mapeamento por Restrição , Alinhamento de Sequência , Análise de Sequência de DNA , Translocação GenéticaRESUMO
Chromosomal translocations involving the human 12p13 band frequently affect the TEL gene, usually resulting in gene fusion between TEL and genes encoding proteins of various types. The most frequent 12p13 translocation is the t(12;21)(p13;q22), which recombines TEL with the AML1 gene on chromosome 21 and is frequently associated with deletion of the untranslocated TEL allele. Using antisera against different parts of TEL and against the AML1 proteins, we undertook Western blot and immunofluorescence analyses of leukemic samples with and without 12p13 abnormalities. In t(12;21) samples, TEL-AML1 was detected as several protein species in the nuclei, whereas the AML1-TEL protein, was inconsistently expressed. AML1 was found to be expressed but no normal TEL proteins were detected. A survey of the TEL proteins in a panel of human leukemic samples without t(12;21) revealed a variation in the ratio of TEL protein isoforms. We also analysed a leukemic cell line bearing a t(12;22)(p13;q11) that was found to affect the 5' untranslated (UT) region of TEL and to be associated with inactivation of the untranslocated TEL allele. No MN1-TEL fusion could be detected upon RT-PCR analysis, in contrast to the previously investigated t(12;22). Strikingly, extremely low levels of apparently normal TEL proteins, expressed from the translocated allele, were detected by Western blot analysis. These results suggest that the level of TEL expression can be important for leukemogenesis.
Assuntos
Cromossomos Humanos Par 12 , Cromossomos Humanos Par 21 , Proteínas de Ligação a DNA/metabolismo , Leucemia Mielomonocítica Aguda/metabolismo , Proteínas de Neoplasias/metabolismo , Proteínas de Fusão Oncogênica , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Proteínas Proto-Oncogênicas , Proteínas Repressoras , Fatores de Transcrição/metabolismo , Adulto , Animais , Criança , Pré-Escolar , Subunidade alfa 2 de Fator de Ligação ao Core , Células HL-60 , Células HeLa , Humanos , Isomerismo , Leucemia Mielomonocítica Aguda/patologia , Proteínas de Neoplasias/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Proteínas Proto-Oncogênicas c-ets , Coelhos , Frações Subcelulares , Translocação Genética , Células Tumorais Cultivadas , Variante 6 da Proteína do Fator de Translocação ETSRESUMO
Abnormalities of the short arm of chromosome 12 are nonrandom events in T cell prolymphocytic leukemia (T-PLL). Fluorescence in situ hybridization (FISH) studies were performed in three patients with T-PLL and one patient with T cell peripheral lymphoma and rearrangement of 12p. Whereas the rearrangements of 12p were different in the four patients, a breakpoint centromeric to the ETV6 gene was present in the three T-PLL patients. In addition, loss of heterozygosity for a chromosomal segment telomeric to ETV6 with loss of the RAD52 locus was also shown by FISH studies. In contrast, the breakpoint was telomeric to ETV6 in the patient with peripheral lymphoma.
Assuntos
Aberrações Cromossômicas , Cromossomos Humanos Par 12 , Leucemia Prolinfocítica/genética , Leucemia de Células T/genética , Idoso , Proteínas de Ligação a DNA/genética , Feminino , Humanos , Hibridização in Situ Fluorescente , Masculino , Pessoa de Meia-IdadeRESUMO
A new case of translocation t(6;11)(q21;q23) in a patient with therapy-related acute myeloblastic leukemia is reported. The translocation results in fusion of the MLL and AF6q21 genes. The breakpoint with AF6q21 is located within the sequences encoding the AF6q21 fork head motif. The similar location of the localization of the chromosome 6 breakpoints in the present case and in the first case reported suggests their nonrandom localization. In addition, treatment for Hodgkin's disease prior to leukemia in both t(6;11)(q21;q23) cases suggests an association of this translocation with therapy-related leukemias, as reported for the recently described.
Assuntos
Cromossomos Humanos Par 11/genética , Cromossomos Humanos Par 6/genética , Proteínas de Ligação a DNA/genética , Leucemia Mieloide Aguda/genética , Proteínas Nucleares/genética , Proto-Oncogenes , Fatores de Transcrição/genética , Translocação Genética/genética , Adulto , Sequência de Aminoácidos , Sequência de Bases , Bandeamento Cromossômico , Análise Mutacional de DNA , Fatores de Transcrição Forkhead , Histona-Lisina N-Metiltransferase , Humanos , Hibridização in Situ Fluorescente , Leucemia Mieloide Aguda/induzido quimicamente , Masculino , Dados de Sequência Molecular , Proteína de Leucina Linfoide-Mieloide , Reação em Cadeia da PolimeraseRESUMO
Fusion genes implicating the MLL gene have been recently demonstrated in various 11q23 chromosomal abnormalities in human hematopoietic malignancies. We analyzed a t(6;11)(q21;q23) translocation detected in a secondary acute myeloblastic leukemia. This translocation results in fusion of the MLL gene on 11q23 to a previously unknown gene on chromosome 6 that differs from the previously reported MLL partner gene AF6q. The novel gene, named AF6q21, encodes a forkhead (FH) protein with strong similarities to the two FH family members whose genes are already known to be involved in chromosomal translocations of human malignancies, AFX and FKHR. Strikingly, in these translocations the breakpoints are located at the same position within the FH domains. Therefore, AF6q21, AFX, and FKHR could define a new FH subfamily particularly involved in human malignancies.
Assuntos
Cromossomos Humanos Par 11 , Cromossomos Humanos Par 6 , Proteínas de Ligação a DNA/genética , Neoplasias Hematológicas/genética , Proteínas Nucleares/genética , Proto-Oncogenes , Fatores de Transcrição/genética , Translocação Genética , Sequência de Aminoácidos , Fusão Gênica Artificial , Sequência de Bases , DNA Complementar/análise , DNA Complementar/genética , Fatores de Transcrição Forkhead , Histona-Lisina N-Metiltransferase , Humanos , Dados de Sequência Molecular , Proteína de Leucina Linfoide-Mieloide , Alinhamento de SequênciaRESUMO
A wide variety of abnormalities of the short arm of chromosome 12 has been reported in hematologic malignancies. The most frequent rearrangements result from t(12;21)(p13;q22) of childhood acute lymphoblastic leukemia, a translocation cryptic when leukemic cells are analyzed with chromosome banding techniques. This translocation results in a fusion of the TEL/ETV6 and AML1 genes. In this report, examples of rearrangements of 12p are presented. Study of two complex chromosome abnormalities associated with t(12;21) emphasizes the importance of using FISH in detection of such translocations. Three novel translocations involving the TEL/ETV6 gene localized on 12p13 are also reported: t(X;12)(q28;p13), t(1;12)(q21;p13), and t(9;12)(p23-24;p13). Finally, the presentation of two translocations with breakpoints located centromeric to TEL/ETV6 highlights the not uncommon involvement of genes other than TEL/ETV6 on 12p.
Assuntos
Anemia Refratária com Excesso de Blastos/genética , Aberrações Cromossômicas/genética , Cromossomos Humanos Par 12 , Proteínas de Ligação a DNA/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Proteínas Repressoras , Fatores de Transcrição/genética , Adolescente , Criança , Pré-Escolar , Transtornos Cromossômicos , Cromossomos Humanos Par 1 , Cromossomos Humanos Par 9 , Feminino , Humanos , Hibridização in Situ Fluorescente , Masculino , Proteínas Proto-Oncogênicas c-ets , Translocação Genética , Cromossomo X , Variante 6 da Proteína do Fator de Translocação ETSRESUMO
Deletion of the short arm of chromosome 9 (9p), resulting in the loss of the p16INK4a/MTS1 gene, now called CDKN2, has been found to occur frequently in acute lymphoblastic leukemia, even in the absence of a microscopically visible deletion. In this study, we have used YAC probes encompassing the CDKN2 locus to analyze by fluorescence in situ hybridization patients with leukemia and lymphoma and translocations involving 9p in order to establish the CDKN2 status in relation to the karyotype. We found that, in leukemic cells exhibiting loss of heterozygosity at the CDKN2 locus, the deleted allele was from the cytogenetically normal chromosome 9, whereas the other allele was located on a rearranged chromosome. This finding suggests that CDKN2 gene loss is nonrandomly associated with 9p translocation in lymphoid proliferations. Genes Chromosom.