Molecular cytogenetic analysis discloses complex genetic imbalance in a t(11;21) myelodysplastic syndrome

Three cases of t(11;21)(q24;q11.2) myelodysplastic syndromes (MDS) showed karyotypic evolution resulting in the presence of two der(11)t(11;21) without normal chromosome 11 and with partial trisomy 21q. In one of these, we performed further molecular cytogenetic investigations which showed 1) that this rearrangement led to changes in the dosage and location of both c-ets 1 and c-ets 2 protooncogenes; and 2) that the presence of two 11q + chromosomes did not result from a nondisjunction, but that a second chromosome rearrangement had occurred. The final genetic imbalance resulting from this cytogenetic change involves at least hemizygosity for some sequences on the long arm of chromosome 11, including c-ets 1, plus trisomy for the most part of the long arm of chromosome 21, including c-ets 2.     

A marginal zone phenotype in follicular lymphoma with t(14;18) is associated with secondary cytogenetic aberrations typical of marginal zone lymphoma

Marginal zone differentiation of follicular lymphomas (FL), sometimes referred to as monocytoid B-cell differentiation, is a relatively uncommon phenomenon. Recently, this type of differentiation was also linked to secondary cytogenetic aberrations of chromosome 3 in a small number of patients. We have analysed 131 primary nodal FL with t(14;18)(q32;q21) for secondary cytogenetic aberrations previously described as recurrent in marginal zone lymphomas (MZL) to identify their frequency and possible association with morphological evidence of marginal zone differentiation. We searched for trisomy of chromosomes 3, 12, and 18, gains of chromosome arm 3q, deletions of chromosome arm 7p, structural anomalies with break-points in 1q21 and 1p34, as well as the t(1;2)(p22;p12), t(1;14)(p22;q32), t(3;14)(q27;q32), t(6;14)(p21;q32), and t(11;18)(q21;q21) translocations. At least focal morphological evidence of marginal zone differentiation occurred in 35/131 (27%) FL with t(14;18)(q32;q21) as the primary chromosomal abnormality. None of the recurrent balanced translocations characteristic of extranodal MZL were seen secondarily in the nodal FLs with t(14;18)(q32;q21). However, 43/131 (33%) cases had at least one of the above secondary cytogenetic aberrations previously reported as recurrent aberrations in MZL and, when combined, these were significantly more frequent in FL with morphological evidence of marginal zone differentiation (p<0.0001, two-sided Fisher's exact test). Aberrations of chromosome 3 and, in particular, trisomy 3 occurred frequently in FL with marginal zone differentiation (p=0.002 and p<0.0001, respectively, two-sided Fisher's exact test), while chromosome 21, 22, and X chromosome aberrations, which have not been described previously as recurrent in MZL, were also significantly associated with marginal zone differentiation in FL (p=0.002, p=0.037, p=0.039, respectively, two-sided Fisher's exact test).     

Predominance of trisomy 1q in myelodysplastic syndromes in Korea: is there an ethnic difference? A 3-year multi-center study

A predominance of total or partial chromosomal losses and the rarity of translocations are characteristics of myelodysplastic syndrome (MDS), and 5q,-5, -7 and +8 are known to be the most predominant chromosomal changes. To investigate whether the incidence and the pattern of chromosomal changes in MDS varies by location in Korea, we reviewed the cytogenetic results of 205 MDS cases from three medical centers. Distribution of MDS subtypes and the incidence of chromosomal aberration (44.8%) of MDS in Korea were similar to those found in other countries, however, their patterns were different. Translocations (40.4%) predominated over partial or total deletions (36.3%) in Korea. The most common abnormalities in MDS were trisomy 8, trisomy 1q, -5/5q-, and -7/7q-, which occurred in 18(19.5%), 14(15.2%), 12(13.0%), and 11(11.9%) patients, respectively. It is of note that trisomy 1q, which is rarely reported in hematologic malignancies, was the second most common change associated with MDS in Korea, and that structural anomalies of chromosomes 1(19.6%) exceeded that of chromosome 5(15.2%). The most common sole anomalies were trisomy 8(7.6%) and 14(78%) of 18 cases with chromosome 1 anomalies accompanied by other chromosomal abnormalities, suggesting that the changes of chromosome 1 may be evolutionary events rather than sporadic events. In conclusion, trisomy 1q and trisomy 8 predominate in Korean MDS, suggesting the likelihood of ethnic differences.     

Molecular cytogenetics localizes two new breakpoints on 11q23.3 and 21q11.2 in myelodysplastic syndrome with t(11;21) translocation.

Translocation t(11;21)(q24;q11.2) is a rare but recurrent chromosomal abnormality associated with myelodysplastic syndrome (MDS) that until now has not been characterized at the molecular level. We report here results of a molecular cytogenetic analysis of this translocation in a patient with refractory anemia. Using FISH with a panel of 11q and 21q cosmid/YAC probes, we localized the chromosome 11 breakpoint at q23.3 in a region flanked by CP-921G9 and CP-939H3 YACs, distal to the HRX/MLL locus frequently involved in acute leukemias. The chromosome 21 breakpoint was mapped in a 800-kb fragment inserted into the CP-145E3 YAC at 21q11.2, proximal to the AML1 gene. It is noteworthy that in all four cases with a t(11;21) reported until now, a second der(11)t(11;21) and loss of normal chromosome 11 could be observed either at diagnosis or during the course of the disease. Since in our case heteromorphism was detected by FISH on the centromeric region of the two der(11), the second der(11) chromosome could be the result of a mitotic recombination that had occurred on the long arm of chromosome 11, rather than of duplication of the original der(11). Constancy of secondary karyotypic changes resulting in an extra copy of the putative chimeric gene at der(11), loss of 11 qter sequences, and partial trisomy 21 suggest that neoplastic progression of MDS cases with a t(11;21) may be driven by the same mechanism(s).     

Partial trisomy 14q -- and parental translocation of No. 14 chromosome. Report of a case and review of the literature.

A case of partial trisomy 14 (47, + 14q-) is presented. The proband's mother had a balanced translocation of 14q with the long arm of a No. 3 chromosome. Clinical and cytogenetic findings of this case are compared with 5 other cases of 47, + 14q-, in which one parent had a balanced translocation of the distal part of the No. 14 long arm to another chromosome. It appears that this chromosomal aneuploidy produces a fairly typical clinical picture.     

Analysis of selected oncogenes (AKT1, FOS, BCL2L2, TGFbeta) on chromosome 14 in granulosa cell tumors (GCTs): a comprehensive study on 30 GCTs combining comparative genomic hybridization (CGH) and fluorescence-in situ-hybridization (FISH)

In previous studies, we have demonstrated a number of cytogenetic alterations in granulosa cell tumors (GCTs), especially on chromosomes X, 12, 14, and 22. However, little is known about specific loci on 14q, which could play an important role in tumor pathology. Therefore, we assessed four important genes in 30 GCTs using fluorescence-in situ-hybridization (FISH). Comparative genomic hybridization (CGH) was performed on paraffin-embedded material. Then, we applied FISH with gene-specific DNA probes for AKT1 (14q32.32), FOS (14q24.3), BCL2L2 (14q11.2-q12), and TGFbeta3 (14q24), and tried to find a correlation between CGH, FISH, tumor stage, and survival. In CGH, 7 of 30 cases (23.3%) showed complete gains on chromosome 14. FISH of the four loci revealed gains of hybridization signals in 8 of 30 cases (26.6%), indicating trisomy of the whole chromosome arm. The same aberration was detected by FISH in 2 of 30 cases (6.6%), which were negative using CGH. One case (1 of 30; 3.3%) was found to have a gain on chromosome 14 by CGH, which could not be confirmed by FISH. A correlation with tumor stage or survival could not be established. Our results suggest that GCTs may be characterized by trisomy of chromosome 14. A specific oncogene that could play a particular role in the tumorigenesis of GCTs was not identified on chromosome 14.     

Trisomy rescue by postzygotic unbalanced (X;14) translocation in a girl with dysmorphic features

In this report we present the clinical features and molecular and cytogenetic findings in a female with partial trisomy 14q. Molecular and cytogenetic studies allowed us to determine that the extra 14q material (of paternal origin) was translocated postzygotically onto the maternal X chromosome. Consequently, only the derivative X chromosome was inactivated, although inactivation apparently did not spread over the entire chromosome 14q. This partial inactivation makes the present case unusual, giving rise to phenotypic features absent in other patients with partial trisomy 14q, typically restricted to the distal part of the chromosome.     

Partial trisomy of chromosome 10(q22-q24) due to maternal insertional translocation (15;10)

Interchromosomal insertional translocations are rare chromosome rearrangements with an incidence of about 1:80,000 live births. We report on the clinical and cytogenetic findings of a newborn baby with partial trisomy 10q22-10q24 due to a maternal insertional translocation 15;10. Partial trisomy of the long arm of chromosome 10 is a distinctive chromosome aberration characterized by prenatal-onset growth retardation and craniofacial, skeletal, and other somatic anomalies. Most cases are unbalanced products from reciprocal chromosome translocations, and insertional translocations are rarely involved. The proband was initially referred because of severe intrauterine growth retardation, and fluorescence in situ hybridization (FISH) using painting probes confirmed the maternal balanced (15;10) insertion.     

Risk factor analysis in myelodysplastic syndrome patients with del(20q): prognosis revisited

The deletion of the long arm of chromosome 20, or del(20q), is a common cytogenetic abnormality in various myeloid disorders and is known to be a favorable prognostic factor in myelodysplastic syndromes (MDS) when it is the sole change. However, del(20q) occurs with one or more cytogenetic changes when it is associated with disease progression. Here, we analyzed 33 patients with MDS and del(20q) to ascertain the risk factors in MDS. We categorized del(20q) into two groups: one with the del(20q) clone (> or =50% marrow metaphases), corresponding to genomic integrity, and the other with a late appearance of a minor del(20q) clone (<50% metaphases) with additional cytogenetic changes, representing genomic instability. Of the MDS patients with del(20q) at initial presentation, the negative factors in predicting prognosis on survival are (i) INT-2/High risk according to the International Prognostic Scoring System, (ii) any additional cytogenetic changes, or (iii) minor del(20q) clone. The late appearance of del(20q) at any phase is linked to a significantly unfavorable prognosis, thus indicating the clinical and biological heterogeneity of del(20q) in MDS.     

Four patients with myelodysplastic syndrome with translocation (1;7)(p11;p11) including one patient with independent clones del(7)q22) [corrected] and t(1;7)(q21;q11)

A translocation involving the short arm of chromosome #1 and the short arm of chromosome #7, [t(1;7)(p11;p11)] was present in four patients with myelodysplastic syndrome (MDS). Two of these patients had prior lymphoproliferative disorders and developed MDS following prolonged therapy with alkylating agents. One of the patients with prior therapy history has two additional independent abnormal clones: one with a partial deletion of the long arm of #7 and the other with t(1;7)(q21;q11). A third patient had a family history of leukemia in both the father and a brother, both of whom developed acute nonlymphocytic leukemia following an MDS phase. The last patient was an elderly woman with no predisposing features.     

Partial trisomy 14q24 leads to qter.

A newborn male with partial trisomy for the distal part of the long arm of chromosome 14 (14q24 leads to qter) is described. The anomaly arose as an adjacent 1 meiotic segregation product from a balanced translocation t(11;14) (q25;q24) in the mother (figure). To our knowledge only one previous case involving the same segment has been reported. The karyotype was confirmed as 46,XY,der(11),t(11;14)(q25;q24) mat.     

A der(13)t(7;13)(p13;q14) with monoallelic loss of RB1 and D13S319 in myelodysplastic syndrome

Deletions or translocations of chromosome band 13q14, the locus of the retinoblastoma gene (RB1), have been observed in a variety of hematological malignancies including myelodysplastic syndrome (MDS). We describe here a novel unbalanced translocation der(13)t(7;13)(p13;q14) involving 13q14 in a patient with MDS. A 66-year-old woman was diagnosed as having MDS, refractory anemia with excess of blasts (RAEB-1) because of 7.4% blasts and trilineage dysplasia in the bone marrow cells. G-banding and spectral karyotyping analyses showed complex karyotypes as follows: 46,XX,der(6)t(6;7)(q11;?),der(7)del(7)(?p13)t(6;7)(q?;q11)t(6;13)(q?;q?),der(13)t(7;13)(p13;q14). Fluorescence in situ hybridization (FISH) analyses demonstrated that one allele of the RB1 gene and the microsatellite locus D13S319, located at 13q14 and telomeric to the RB1 gene, was deleted. Considering other reported cases, our results indicate that submicroscopic deletions accompanying 13q14 translocations are recurrent cytogenetic aberrations in MDS. The RB1 gene or another tumor suppressor gene in the vicinity of D13S319, or both, may be involved in the pathogenesis of MDS with 13q14 translocations by monoallelic deletion.     

A novel dic(1;10) in a patient with myelodysplastic syndrome

We report on a case of refractory anemia with trilineage dysplasia and an unbalanced der(1)t(1;10) that resulted in trisomy of the long arm of chromosome 1 (1q) and monosomy of the short arm of chromosome 10 (10p). Fluorescence in situ hybridization showed that the rearranged chromosome contained the centromeres of both chromosomes 1 and 10, leading to a dic(1;10). To our knowledge, a dicentric chromosome involving chromosomes 1 and 10 has never been described in hematological malignancies.     

Subtelomeric FISH uncovers trisomy 14q32: lessons for imprinted regions,cryptic rearrangements and variant acrocentric short arms

The recent development of a set of chromosome-specific, subtelomeric probes has proved useful in diagnosis and recurrence risk counseling of patients and families with mental retardation and in further characterization of known chromosomal abnormalities. Cases of cryptic, subtelomeric rearrangements may account for up to 7.5% of cases of idiopathic moderate-severe mental retardation. We present the molecular cytogenetic studies of trisomy 14q detected by subtelomeric fluorescence in situ hybridization (FISH). Our patient is a 3-year-old girl with growth and developmental delay, myelomeningocele, partial agenesis of the corpus callosum, hypertelorism, tented mouth, simple ears, small mandible, and congenital heart disease (atrial and ventricular septal defects with subaortic conus). G-banded chromosome analysis was apparently normal. A set of FISH-based, subtelomeric, region-specific probes revealed trisomy for 14q in the child. Parental FISH studies established that the mother is a balanced carrier for a half-cryptic translocation between the distal long arm of chromosome 14 and the short arm of chromosome 22. FISH analysis using two BAC clones that contain the imprinted genes MEG3 and DLK1, which localize to 14q32, established that our patient has two maternal copies of these genes. Because the child does not have features of the maternal UPD 14 syndrome, this case suggests that it is absence of expression of a paternally expressed gene, rather than overexpression of a maternally expressed gene, that is responsible for the maternal UPD 14 phenotype.     

Subtelomeric FISH uncovers trisomy 14q32: Lessons for imprinted regions,cryptic rearrangements and variant acrocentric short arms

The recent development of a set of chromosome‐specific, subtelomeric probes has proved useful in diagnosis and recurrence risk counseling of patients and families with mental retardation and in further characterization of known chromosomal abnormalities. Cases of cryptic, subtelomeric rearrangements may account for up to 7.5% of cases of idiopathic moderate–severe mental retardation. We present the molecular cytogenetic studies of trisomy 14q detected by subtelomeric fluorescence in situ hybridization (FISH). Our patient is a 3‐year‐old girl with growth and developmental delay, myelomeningocele, partial agenesis of the corpus callosum, hypertelorism, tented mouth, simple ears, small mandible, and congenital heart disease (atrial and ventricular septal defects with subaortic conus). G‐banded chromosome analysis was apparently normal. A set of FISH‐based, subtelomeric, region‐specific probes revealed trisomy for 14q in the child. Parental FISH studies established that the mother is a balanced carrier for a half‐cryptic translocation between the distal long arm of chromosome 14 and the short arm of chromosome 22. FISH analysis using two BAC clones that contain the imprinted genes MEG3 and DLK1, which localize to 14q32, established that our patient has two maternal copies of these genes. Because the child does not have features of the maternal UPD 14 syndrome, this case suggests that it is absence of expression of a paternally expressed gene, rather than overexpression of a maternally expressed gene, that is responsible for the maternal UPD 14 phenotype. © 2002 Wiley‐Liss, Inc.     

Spreading of inactivation in an (X;14) translocation

In the KOP translocation, t(X;14) (q13; q32), virtually the entire long arm of the X has been translocated to the end of the long arm of chromosome 14. Meiotic secondary nondisjunction in a female balanced carrier of the translocation has led to a son with two der(14) or 14-X chromosomes. The normal X chromosome is late replicating in the mother. One of the two 14-X Chromosomes is late replicating in the son, with heavy terminal labeling of all but the centromeric end of the chromosome. This suggests that genetic inactivation has spread from the Xq segment of the translocation chromosome to at least two thirds of the segment derived from chromosome 14, and that the remaining proximal segment of chromosome 14 is possibly still genetically active. These findings provide an explanation for the phenotype: Klinefelter syndrome plus a few mild malformations that are sometimes seen in this syndrome but are also seen in duplication of the proximal portion of chromosome 14. Although the proband has a duplication of virtually an entire chromosome 14, 14(pter→q32), the phenotypic effect of the autosomal duplication has been mostly nullified by the spread of inactivation.     

Shwachman syndrome as mutator phenotype responsible for myeloid dysplasia/neoplasia through karyotype instability and chromosomes 7 and 20 anomalies

An investigation of 14 patients with Shwachman syndrome (SS), using standard and molecular cytogenetic methods and molecular genetic techniques, showed that (1) the i(7)(q10) is not, or not always, an isochromosome but may arise from a more complex mechanism, retaining part of the short arm; (2) the i(7)(q10) has no preferential parental origin; (3) clonal chromosome changes, such as chromosome 7 anomalies and del(20)(q11), may be present in the bone marrow (BM) for a long time without progressing to myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML); (4) the del(20)(q11) involves the minimal region of deletion typical of MDS/AML; (5) the rate of chromosome breaks is not significantly higher than in controls, from which it is concluded that SS should not be considered a breakage syndrome; (6) a specific kind of karyotype instability is present in SS, with chromosome changes possibly found in single cells or small clones, often affecting chromosomes 7 and 20, in the BM. Hence, we have confirmed our previous hypothesis that the SS mutation itself implies a mutator effect that is responsible for MDS/AML through these specific chromosome anomalies. This conclusion supports the practice of including cytogenetic monitoring in the follow-up of SS patients.     

Del(14)(q22) in diffuse B-cell lymphocytic lymphoma

Some recurrent chromosomal abnormalities have recently been found to be associated with distinctive histologic subtypes of non-Hodgkin's lymphoma (NHL). In a study of 62 patients with NHL whose karyotypes was determined at diagnosis, 3 patients were found to have a deletion of the long arm of chromosomes 14 at band 22 (del[14][q22]). All had a diffuse lymphoma with generalized lymphadenopathy and bone marrow involvement. All three lymphomas were of B-cell origin, as shown by the presence of surface immunoglobulin and monoclonal antibody phenotyping. For each patient, a trisomy 12 was associated with del(14)(q22) in a clone. These data suggest that del(14)(q22), perhaps in association with trisomy 12, could identify a subtype of NHL and that band 22 of chromosome 14 may be implicated in the B-cell ontogeny.     

Direct cytogenetic analysis of primary neuroblastoma

In this paper the results of cytogenetic analysis of a metastatic neuroblastoma from a 14-month-old boy are described. Direct cytogenetic analysis was performed on tumor pieces obtained from surgery prior to therapy. Consistent numerical and structural chromosome aberrations were identified. The modal chromosome number was 48, with 9.4% of the cell population being in the near-tetraploid range. In all karyotyped cells, the Y chromosome was missing and additions of chromosomes 7 and 14 were identified. Two rearranged #1 were observed: del(1)(p22 or p31) and t(1;18)(p22 or p31;q11-12), resulting in monosomy of the distal segment of the short arm and trisomy of the long arm. In two cells, single minutes were found; this chromosomal aberration has been previously described in a case of metastatic neuroblastoma.     

Spreading of inactivation in an (X;14) translocation.

In the KOP translocation, t(X;14)(q13;q32), virtually the entire long arm of the X has been translocated to the end of the long arm of chromosome 14. Meiotic secondary nondisjunction in a female balanced carrier of the translocation has led to a son with two der(14) or 14-X chromosomes. The normal X chromosome is late replicating in the mother. One of the two 14-X chromosomes is late replicating in the son, with heavy terminal labeling of all but the centromeric end of the chromosome. This suggests that genetic inactivation has spread from the Xq segment of the translocation chromosome to at least two thirds of the segment derived from chromosome 14, and that the remaining proximal segment of chromosome 14 is possibly still genetically active. These findings provide an explanation for the phenotype: Klinefelter syndrome plus a few mild malformations that are sometimes seen in this syndrome but are also seen in duplication of the proximal portion of chromosome 14. Although the proband has a duplication of virtually an entire chromosome 14, 14(pter leads to q32), the phenotypic effect of the autosomal duplication has been mostly nullified by the spread of inactivation.