Recurrent Chromosomal Imbalances Research Articles

Recurrent chromosomal imbalances and structurally abnormal breakpoints within complex karyotypes of malignant peripheral nerve sheath tumour and malignant triton tumour: a cytogenetic and molecular cytogenetic study

Background: Cytogenetic studies of malignant peripheral nerve sheath tumours (MPNSTs) and malignant triton tumours (MTTs) are rare. Aims: To undertake cytogenetic analysis of these tumours. Methods: Conventional cytogenetic analysis of...

Molecular cytogenetic analysis of recurrent unbalanced t(11;17) in neuroblastoma

Loss of 11q material occurs in approximately 30% of advanced stage neuroblastoma and defines a distinct genetic subtype of this disease. These tumors almost always possess unbalanced gain of the 17q, along with many additional recurrent chromosomal imbalances. Loss of 11q and gain of 17q is often the consequence of an unbalanced translocation between the long arms of both chromosomes, but because of the involvement of other chromosomal mechanisms, the actual frequency of t(11;17) is unknown. In addition, chromosomal breakpoint positions for the t(11;17) are variable in different tumors, with breakpoints on neither the 11q nor 17q being well defined. We have used interphase fluorescence in situ hybridization analysis to detect a der(11)t(11;17) in a series of neuroblastomas with 11q loss/17q gain using a statistical approach which could be applicable to the detection of translocations in other solid tumors. The frequency of der(11)t(11;17) was approximately 90% in our neuroblastoma series. A balanced t(11;17) was also detected in a MYCN amplified tumor, which is a distinctly different genetic subtype from the 11q− tumors. Breakpoint positions on 11q were determined to be variable, whereas all breakpoints on 17q appeared to cluster proximal to position 43.1 Mb on the DNA sequence map. The majority of tumors had large numbers of nuclei with 2 or more copies of der(11)t(11;17), which led to unbalanced gain of 11p, and further increases in 17q imbalance. The prevalence of t(11;17) in neuroblastoma warrants additional studies to further define the range in variation in breakpoint positions on both chromosomes and to elucidate the molecular mechanisms that lead to this important and interesting recurrent genetic abnormality.

Genetic diagnosis by comparative genomic hybridization in adult de novo acute myelocytic leukemia

A total of 127 adult de novo acute myelocytic leukemia (AML) patients were analyzed by comparative genomic hybridization (CGH) at diagnosis. Conventional cytogenetic analysis (CCA) showed a normal karyotype in 45 cases and an abnormal karyotype in 56 cases; in the remaining cases, CCA either failed to yield sufficient metaphase cells (19/26) or was not done (7/26). Abnormal CGH profiles were identified in 39 patients (30.7%). DNA copy number losses (61%) were high compared to gains (39%), whereas partial chromosome changes (76%) were more common than whole chromosomes changes (24%). Recurrent losses were detected on chromosomes 7, 5q (comprising bands 5q15 to 5q33), 7q (7q32∼q36), 16q (16q13∼q21), and 17p, and gains were detected on chromosomes 8, 22, and 3q (comprising bands 3q26.1∼q27). Furthermore, distinct amplifications were identified in chromosome regions 21q, 13q12∼q13, and 13q21.1. No cryptic recurrent chromosomal imbalances were identified by CGH in cases with normal karyotypes. The concordance between CGH results and CCA was 72.5%. In the remaining cases, CGH gave additional information compared to CCA (20%) and partially failed to identify the alterations previously detected by CCA (7.5%). The majority of discrepancies arose from the limitations of the CGH technique, such as insensitivity to detect unbalanced chromosomal changes when occurring in a low proportion of cells. CGH increased the detection of unbalanced chromosomal alterations and allowed precise defining of partial or uncharacterized cytogenetical abnormalities. Application of the CGH technique is thus a useful complementary diagnostic tool for CCA in de novo AML cases with abnormal karyotypes or with unsuccessful cytogenetics.

Genomic Profiling of Peripheral T-Cell Lymphoma, Unspecified, and Anaplastic Large T-Cell Lymphoma Delineates Novel Recurrent Chromosomal Alterations

To characterize genetic alterations in peripheral T-cell lymphoma, not otherwise specified (PTCL NOS), and anaplastic large T-cell lymphoma (ALCL), 42 PTCL NOS and 37 ALCL [17 anaplastic large cell kinase (ALK)-negative ALCL, 9 ALK-positive ALCL, 11 cutaneous ALCL] were analyzed by comparative genomic hybridization. Among 36 de novo PTCL NOS, recurrent chromosomal losses were found on chromosomes 13q (minimally overlapping region 13q21, 36% of cases), 6q and 9p (6q21 and 9p21-pter, in 31% of cases each), 10q and 12q (10q23-24 and 12q21-q22, in 28% of cases each), and 5q (5q21, 25% of cases). Recurrent gains were found on chromosome 7q22-qter (31% of cases). In 11 PTCL NOS, high-level amplifications were observed, among them 3 cases with amplification of 12p13 that was restricted to cytotoxic PTCL NOS. Whereas cutaneous ALCL and ALK-positive ALCL showed few recurrent chromosomal imbalances, ALK-negative ALCL displayed recurrent chromosomal gains of 1q (1q41-qter, 46%), and losses of 6q (6q21, 31%) and 13q (13q21-q22, 23%). Losses of chromosomes 5q, 10q, and 12q characterized a group of noncytotoxic nodal CD5+ peripheral T-cell lymphomas. The genetics of PTCL NOS and ALK-negative ALCL differ from other T-NHLs characterized genetically so far, among them enteropathy-type T-cell lymphoma, T-cell prolymphocytic leukemia, and adult T-cell lymphoma/leukemia.

Automated array-based genomic profiling in chronic lymphocytic leukemia: development of a clinical tool and discovery of recurrent genomic alterations.

B cell chronic lymphocytic leukemia (B-CLL) is characterized by a highly variable clinical course. Recurrent chromosomal imbalances provide significant prognostic markers. Risk-adapted therapy based on genomic alterations has become an option that is currently being tested in clinical trials. To supply a robust tool for such large scale studies, we developed a comprehensive DNA microarray dedicated to the automated analysis of recurrent genomic imbalances in B-CLL by array-based comparative genomic hybridization (matrix-CGH). Validation of this chip in a series of 106 B-CLL cases revealed a high specificity and sensitivity that fulfils the criteria for application in clinical oncology. This chip is immediately applicable within clinical B-CLL treatment trials that evaluate whether B-CLL cases with distinct chromosomal abnormalities should be treated with chemotherapy of different intensities and/or stem cell transplantation. Through the control set of DNA fragments equally distributed over the genome, recurrent genomic imbalances were discovered: trisomy of chromosome 19 and gain of the MYCN oncogene correlating with an elevation of MYCN mRNA expression.

Dissecting karyotypic patterns in malignant melanomas: temporal clustering of losses and gains in melanoma karyotypic evolution.

Malignant melanomas can be divided into two major subtypes, involving either the skin or eye melanomas. Both tumor forms exhibit highly complex karyotypes with nonrandom recurrent chromosomal imbalances. Loss of chromosome 3, the short arm of chromosome 1, and gain of 8q have been suggested to be associated with eye melanomas, whereas gain of 6p and loss of 6q have been more often seen in skin melanomas. Imbalances implicated in tumor progression include among others, -10 and +7. In spite of the abundance of cytogenetic information, with more than 300 published karyotypes, very little is known about the mode of karyotypic evolution or of the presence of possible cytogenetic pathways. In our investigation, we have used 362 melanoma karyotypes, including both the skin and eye subtypes, to identify the most frequently occurring imbalances. Tumor cases were then classified with respect to the presence or absence of these imbalances and statistically analyzed in order to assess the order of appearance of chromosomal imbalances, the presence of karyotypic pathways, as well as possible cytogenetic subtypes. We show that the melanomas develop through one mode of karyotypic evolution, common to both low and high complexity karyotypes, and we establish the temporal order by which the different imbalances occur. By applying several statistical methods, we show that at least two cytogenetic pathways of clonal evolution exist in malignant melanomas, one initiated with -3 and one with +6p, and that these pathways operate in both skin and eye melanomas.

Anomalies génétiques des leucémies lymphoides chroniques

Chronic B–cell leukemias (CLL) are characterised by a striking cytogenetic signature composed of multiple recurrent chromosomal imbalances involving specific chromosomal regions i.e. 13q, 11q, 12q, 17p et 6q (decreasing order of frequency). These chromosomal aberrations may be found in up to 80% of the cases either as isolated or associated anomalies. They can also appear during the course of the disease suggesting their secondary nature. Furthermore, and at variance with other B–cell proliferations like lymphomas or myelomas, balanced translocations involving imunoglobulin (Ig) gene locus are rare. In addition to their interest in patient diagnosis and follow-up, these tumour-specific genetic markers also harbor important prognostic significance : isolated 13q deletions correlate with prolonged survival whereas both 17p and 11q partial deletions are independant predictors of rapid disease progression and short survival times in multivariate analyses. Genetic analyses as well as the first transcriptome studies of CLL reveal 1) a common mechanism of transformation and/or cell of origin, 2) the existence of at least two prognostic subgroups based on Ig mutational status.

Distinct chromosomal imbalances in pleomorphic and in high‐grade dedifferentiated liposarcomas

Using comparative genomic hybridization, DNA copy number changes were studied in 14 pleomorphic liposarcomas and compared to those detected in high-grade areas of 9 dedifferentiated liposarcomas. A total of 251 gains and 84 losses were detected. The most frequent gains involved subregions of chromosomal arms 12q and 20q (70% each), 5p (57%), 6q and 9q (52% each), 1q, 7p and 17p (48% each), 1p (43%), 6p and 17q (39% each), 20p and 22q (35% each) as well as 7q and 12p (30% each). The same subregions were also affected by 30 high level amplifications. The most frequent losses were found in subregions of chromosomal arms 13q (35%) as well as 11q and 12p (30% each). Overall, gains of chromosomal material were more frequent than losses (p < 0.001). There were significant differences in the frequency and distribution of recurrent chromosomal imbalances between pleomorphic liposarcomas and the dedifferentiated areas of dedifferentiated liposarcomas. Gains of chromosomal material detected predominantly in pleomorphic liposarcomas involved subbands 5p13-p15 (p < 0.010), 1p21 (p < 0.019), 1q21-q22 (p < 0.040) and 7q22 (p < 0.049). Conversely, high level amplifications within chromosomal subregion 12q13-q21 were only found in the dedifferentiated components of dedifferentiated liposarcomas (p < 0.001). Overall, both gains and the less pronounced losses of chromosomal material were more frequent in pleomorphic than in dedifferentiated liposarcomas (p < 0.001 and p < 0.025, respectively). These results show that pleomorphic liposarcomas display a considerable number of recurrent chromosomal imbalances that are essentially different from those present in high-grade areas of dedifferentiated liposarcomas. Therefore, genetic data are considered as a helpful diagnostic adjunct for the discrimination between these 2 types of liposarcoma. The overall higher frequency of chromosomal imbalances in pleomorphic as compared to dedifferentiated liposarcomas could account for the more aggressive biological behavior of pleomorphic relative to dedifferentiated liposarcoma types.

Genetic Imbalances in Precursor Lesions of Endometrial Cancer Detected by Comparative Genomic Hybridization

Endometrial hyperplasia is regarded as a precursor lesion of endometrioid adenocarcinomas of the endometrium. The genetic events involved in the multistep process from normal endometrial glandular tissue to invasive endometrial carcinomas are primarily unknown. We chose endometrial hyperplasia as a model for identifying chromosomal aberrations occurring during carcinogenesis. Comparative genomic hybridization (CGH) was performed on 47 formalin-fixed, paraffin-embedded specimens of endometrial hyperplasia using the microdissection technique to increase the number of tumor cells in the samples and reduce contamination from normal cells. CGH analysis revealed that 24 out of 47 (51%) samples had detectable chromosomal imbalances, whereas 23 (49%) were in a genetically balanced state. The incidence of aberrant CGH profiles tended to parallel dysplasia grade, ranging from 22% aberrant profiles in simple hyperplasia to 67% in complex hyperplasia with atypia. The most frequent imbalances were 1p, 16p, and 20q underrepresentations and 4q overrepresentations. Copy number changes in 1p were more frequent in atypical complex hyperplasia than in complex lesions without atypical cells or simple lesions (42% versus 20% and 0%). Our results show that endometrial hyperplasia reveals recurrent chromosomal imbalances which tend to increase with the presence of atypical cells. The most frequent aberrations in endometrial cancer, 1q and 8q overrepresentations, are not present or are rare in its precursor lesions. This analysis provides evidence that tumorigenesis proceeds through the accumulation of a series of genetic alterations and suggests a stepwise mode of tumorigenesis.

Among numerous DNA copy number changes, losses of chromosome 13 are highly recurrent in plasmacytoma

Chromosomal imbalances were studied by comparative genomic hybridization (CGH) on 27 specimens from 24 patients with plasmacytoma. All the specimens exhibited DNA copy number changes (mean, 7.7 aberrations/tumor; range, 2-15). The most recurrent change involved losses at 13q, found in 19 out of 24 patients. Other frequent losses were at 1p (42%), 14q (33%), X (33%), 8p (25%), and 6q (25%). Gains were frequent at 19p (58%), 9q (58%), 1q (58%), 7p (42%), 11q (38%), 15 (33%), 6p (25%), 8q (25%), and 5p (21%). High-level copy number increases were found at 1q, 5, 7, 8q, 9q, 11q, 15, and 19. The findings of highly recurrent chromosomal imbalances in plasmacytomas confirm the analytical power of CGH to detect chromosomal abnormalities in malignancies characterized by low mitotic activity. Our most striking finding, the losses in chromosome 13, provides a basis to investigate the role of the 13q loss in the tumorigenesis and progression of plasmacytoma and to evaluate the prognostic significance of this loss.

Mapping of chromosomal imbalances in gastric adenocarcinoma revealed amplified protooncogenesMYCN,MET,WNT2, andERBB2

Gastric adenocarcinoma is a malignant tumor with a high incidence and a low survival rate. In order to identify genetic alterations associated with this tumor, we screened 23 gastric adenocarcinomas for recurrent chromosomal imbalances by using comparative genomic hybridization (CGH). The most common gains of chromosomal material were found on chromosome arms 20q (10 cases), 16p (7 cases), and 1q (4 cases) and on chromosome 11 (4 cases). Losses were observed on chromosome arms 4q, 5q, 9p, and 21q (3 cases each). Four tumors exhibited high-level amplifications localized on chromosome regions 2p23-p24, 7q31-q32, 8p21-p22, 10q25-q26, 11q13, 17q11-q21, and 20q. Based on the position of these amplifications, candidate (onco)genes were selected and subsequently tested by Southern blot analysis of the respective tumors. Of the seven tested candidates, MYCN, MET, WNT2, and ERBB2 were found to participate in the amplicons of the respective tumor samples. Of these four presumably activated oncogenes, two, MYCN and WNT2, were previously not assumed to play a pathogenic role in stomach cancer. Among the other regions of imbalance, gain of 20q seems particularly interesting, because it is found in almost half of the analyzed cases and is highly amplified. Our data allowed us to narrow the relevant region down to the commonly gained bands 20q12-q13.1. This and other imbalanced regions provide a basis for searching new putative oncogenes and tumor suppressor genes involved in the development or progression of gastric adenocarcinoma.

Mapping of chromosomal imbalances in gastric adenocarcinoma revealed amplified protooncogenes MYCN , MET , WNT2 , and ERBB2

Gastric adenocarcinoma is a malignant tumor with a high incidence and a low survival rate. In order to identify genetic alterations associated with this tumor, we screened 23 gastric adenocarcinomas for recurrent chromosomal imbalances by using comparative genomic hybridization (CGH). The most common gains of chromosomal material were found on chromosome arms 20q (10 cases), 16p (7 cases), and 1q (4 cases) and on chromosome 11 (4 cases). Losses were observed on chromosome arms 4q, 5q, 9p, and 21q (3 cases each). Four tumors exhibited high-level amplifications localized on chromosome regions 2p23-p24, 7q31-q32, 8p21-p22, 10q25-q26, 11q13, 17q11-q21, and 20q. Based on the position of these amplifications, candidate (onco)genes were selected and subsequently tested by Southern blot analysis of the respective tumors. Of the seven tested candidates, MYCN, MET, WNT2, and ERBB2 were found to participate in the amplicons of the respective tumor samples. Of these four presumably activated oncogenes, two, MYCN and WNT2, were previously not assumed to play a pathogenic role in stomach cancer. Among the other regions of imbalance, gain of 20q seems particularly interesting, because it is found in almost half of the analyzed cases and is highly amplified. Our data allowed us to narrow the relevant region down to the commonly gained bands 20q12-q13.1. This and other imbalanced regions provide a basis for searching new putative oncogenes and tumor suppressor genes involved in the development or progression of gastric adenocarcinoma.

Amplification of DNA Sequences from Chromosome 19q13.1 in Human Pancreatic Cell Lines

Conventional cytogenetics and comparative genomic hybridization (CGH) were utilized to identify recurrent chromosomal imbalances in 12 pancreatic adenocarcinoma cell lines. Multiple deletions and gains were observed in all cell lines. Losses affecting chromosomes or chromosome arms 9p, 13, 18q, 8p, 4, and 10p and gains involving chromosome arms or bands 19q13.1, 20q, 5p, 7p, 11q, 3q25–qter, 8q24, and 10q were commonly observed. Interestingly, 19 distinct sites of high-level amplification were found by CGH. Recurrent sites involved 19q13.1 (6 cases), 5p (3 cases), and 12p and 16p (2 cases). Amplification ofKRAS2was demonstrated in 2 cell lines and that ofERBB2in another. To define the occurrence of chromosome 19 amplification further, two-dimensional analysis ofNotI genomic restriction digests and fluorescencein situhybridization using probes from band 19q13.1 were utilized. High-level amplification of overlapping sets of chromosome 19NotI fragments was exhibited in 3 cell lines of which 2 showed amplification of bothOZFandAKT2genes and 1 that ofAKT2alone. In these 3 cell lines, amplification of chromosome 19 sequences was associated with the presence of a homogeneously staining region. Our results provide evidence of heterogeneity in the extent of chromosome 19 amplification and suggest the existence of yet unknown amplified genes that may play a role in pancreatic carcinogenesis.

Recurrent Chromosomal Imbalances Detected in Biopsy Material from Oral Premalignant and Malignant Lesions by Combined Tissue Microdissection, Universal DNA Amplification, and Comparative Genomic Hybridization

Biopsies routinely performed for the histopathological diagnosis of oral epithelial lesions before treatment were screened for chromosomal imbalances by comparative genomic hybridization. Comparative genomic hybridization was performed on 12 oral premalignant lesions (OPLs; dysplasias and carcinomas in situ) and 14 oral squamous cell carcinomas (OSCCs). Eight biopsies displayed areas of different histopathological appearance, so that OPLs and OSCCs from the same patient were analyzed. To avoid contamination with nonneoplastic cells, defined cell populations were isolated by micromanipulation with a glass needle. Before comparative genomic hybridization analysis, universal DNA amplification was performed using the DOP-polymerase chain reaction protocol. In the 14 OSCCs examined, the average number of chromosomal imbalances was significantly higher than in the 12 OPLs (mean +/- SEM: 11.9 +/- 1.9 versus 3.2 +/- 1.2; P = 0.003). The DNA copy number changes identified in more than one OPL were gains on 8q (3 of 12) and 16p (2 of 12), as well as losses on 3p (5 of 12); 5q (4 of 12); 13q (3 of 12); and 4q, 8p, and 9p (2 of 12 each). In more than 30% of OSCCs, gains of chromosomal material were identified on 20q (8 of 14); 8q, 11q, 22q (7 of 14 each); 3q, 15q, and 17p (6 of 14 each); and 14q, 17q, and 20p (5 of 14 each), and losses were identified on 3p and 4q (9 of 14 each), 5q (7 of 14), 13q (6 of 14), and 2q and 9p (5 of 14 each). These results were validated by positive and negative control comparative genomic hybridization experiments and microsatellite analysis for the detection of allelic loss. The vast majority of genomic alterations found in OPLs were again identified in OSCCs from the same biopsy, supporting the hypothesis that multiple lesions in the same patient are clonally related. In summary, we show that comprehensive information on the genomic alterations in oral epithelial lesions can be obtained from small biopsies. Such data may identify prognostic indicators that could eventually assist in designing therapeutic strategies.

Comparative genomic hybridization detects frequent overrepresentation of chromosomal material from 3q26, 8q24, and 20q13 in human ovarian carcinomas

We used comparative genomic hybridization (CGH) to identify recurrent chromosomal imbalances in tumor DNA from 25 malignant ovarian carcinomas and two ovarian tumors of low malignant potential (LMP). Many of the carcinoma specimens displayed numerous imbalances. The most common sites of copy number increases, in order of frequency, were 8q24.1, 20q13.2-qter, 3q26.3-qter, 1q32, 20p, 9p21-pter, and 12p. DNA amplification was identified in 12 carcinomas (48%). The most frequent sites of amplification were 8q24.1-24.2, 3q26.3, and 20q13.2-qter. Other recurrent sites of amplification included 7q36, 17q25, and 19q13.1-13.2. The most frequent sites of copy number decreases were 5q21, 9q, 17p, 17q12-21, 4q26-31, 16q, and 22q. Underrepresentation of 17p was observed in six of 16 stage III/IV tumors, but in none of seven stage I/II tumors, suggesting that this change may be a late event associated with the transition of ovarian carcinomas to a more metastatic disease. Overrepresentation of 3q26.3-qter, 5p14-pter, 8q24.1, 9p21-pter, 20p, and 20q13.2-qter and underrepresentation of 4q26-31 and 17q12-21 also tended to be more common in advanced-stage tumors. All ten grade 3 tumors had copy number increases involving 8q24.1, compared to only three of nine grade 2 tumors. Overrepresentation of 3q26.3-qter and 20q13.2-qter was also observed at a higher frequency in high-grade tumors. One of the two LMP tumors displayed chromosomal alterations, which consisted of overrepresentation of 5p and 9p only. Taken collectively, these findings and data from other CGH studies of ovarian cancers define a set of small chromosome segments that are consistently over- or underrepresented and, thus, highlight sites of putative oncogenes and tumor suppressor genes that contribute to the pathogenesis of these highly malignant neoplasms.

Comparative genomic hybridization detects frequent overrepresentation of chromosomal material from 3q26, 8q24, and 20q13 in human ovarian carcinomas

We used comparative genomic hybridization (CGH) to identify recurrent chromosomal imbalances in tumor DNA from 25 malignant ovarian carcinomas and two ovarian tumors of low malignant potential (LMP). Many of the carcinoma specimens displayed numerous imbalances. The most common sites of copy number increases, in order of frequency, were 8q24.1, 20q13.2-qter, 3q26.3-qter, 1q32, 20p, 9p21-pter, and 12p. DNA amplification was identified in 12 carcinomas (48%). The most frequent sites of amplification were 8q24.1-24.2, 3q26.3, and 20q13.2-qter. Other recurrent sites of amplification included 7q36, 17q25, and 19q13.1-13.2. The most frequent sites of copy number decreases were 5q21, 9q, 17p, 17q12-21, 4q26-31, 16q, and 22q. Underrepresentation of 17p was observed in six of 16 stage III/IV tumors, but in none of seven stage I/II tumors, suggesting that this change may be a late event associated with the transition of ovarian carcinomas to a more metastatic disease. Overrepresentation of 3q26.3-qter, 5p14-pter, 8q24.1, 9p21-pter, 20p, and 20q13.2-qter and underrepresentation of 4q26-31 and 17q12-21 also tended to be more common in advanced-stage tumors. All ten grade 3 tumors had copy number increases involving 8q24.1, compared to only three of nine grade 2 tumors. Overrepresentation of 3q26.3-qter and 20q13.2-qter was also observed at a higher frequency in high-grade tumors. One of the two LMP tumors displayed chromosomal alterations, which consisted of overrepresentation of 5p and 9p only. Taken collectively, these findings and data from other CGH studies of ovarian cancers define a set of small chromosome segments that are consistently over- or underrepresented and, thus, highlight sites of putative oncogenes and tumor suppressor genes that contribute to the pathogenesis of these highly malignant neoplasms. Genes Chromosomes Cancer 20:320–328, 1997. © 1997 Wiley-Liss, Inc.

Characteristic chromosomal imbalances in 18 near-diploid colorectal tumors

The cytogenetic study of 18 near-diploid colorectal tumors shows that the observed numerical and structural abnormalities resulted in recurrent chromosomal losses and gains. By order of decreasing frequencies, they are: monosomy 17p ( 16 18 ), partial or more frequently complete monosomy 18 ( 14 18 ), trisomy 20q ( 11 18 ), trisomy or tetrasomy 13 ( 10 18 ), monosomy lp and trisomies X and 8q ( 9 18 ). The absence of recurrent breakpoints in euchromatin contrasts with the high preponderance of breakage at various places of heterochromatic region. Because these tumors are characterized by very recurrent chromosomal imbalances, it is assumed that the observed chromosomal changes may be related to a recessive genetic determinism and to gene dosage imbalances.