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Johansson, Bertil; Mertens, Fredrik; Mitelman, Felix
doi: 10.1002/gcc.2870080402pmid: 7512363
Research in oncogenetics has led to the identification of two major classes of tumor‐associated genes, oncogenes and tumor suppressor genes. In a wide variety of solid tumor types, mutations of both groups of genes have been implicated in the tumorigenic process. In hematologic neoplasms, on the other hand, most attention has focused on illegitimate activation of oncogenes, e.g., deregulation leading to disturbed transcriptional activity and structural rearrangements resulting in hybrid genes. Whether loss or mutational inactivation of tumor suppressor genes also plays an essential role in the genesis of tumors of the hematopoietic system has received less attention. Because such inactivation can be the result of karyotypically detectable loss of chromosomal material, cytogenetic studies may prove helpful in pinpointing genomic sites that harbor tumor suppressor genes. The present study is based on a total of 12,473 cytogenetically abnormal hematologic neoplasms reported in the literature to date. Among these, we selected the 6,422 cases with sole clonal chromosomal abnormalities in order to include only aberrations of importance in the genesis, rather than in the progression, of these neoplasms. All tumors with monosomies or structural abnormalities resulting in loss of chromosomal material were compiled, and for every such structural aberration, i.e., deletion, unbalanced translocation, isochromosome, and ring chromosome, the chromosome bands lost were ascertained. This cytogenetic deletion mapping revealed that the most commonly lost chromosomes were Y and 7 in acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), and chronic myeloproliferative disorders (MPD); X, Y, 7, 20, and 21 in acute lymphocytic leukemia (ALL); X, Y, and 17 in chronic lymphoproliferative disorders (LPD); and X and Y in non‐Hodgkin's lymphoma (NHL). Chromosome segments/bands lost due to unbalanced structural abnormalities in at least 5% of the cases were 5q13ndash;33. 7q22ndash;36, 9q13ndash;31, 11q23ndash;25, 12p12ndash;13, 17p11ndash;13, and 20q11ndash;13 in AML; 5q13ndash;35 and 20q11ndash;13 in MDS; 5q22ndash;23, 7q22, 13q12ndash;22, 17p11ndash;13, and 20q11ndash;13 in MPD; 6q15ndash;27, 9p11ndash;24, 12p12ndash;13, and 19p13 in ALL; 6q16ndash;27, 11q21ndash;25, 13q13ndash;14, and 14q32 in LPD; and 6q21ndash;27, 11q13ndash;25, and 14q24ndash;32 in NHL. Based on these findings, three conclusions can be drawn. First, there is no good correspondence between total and partial monosomies, the only exception being ndash;7 and 7qndash;, both of which are common in myeloid neoplasms. This indicates different pathogenetic effects of total and partial losses. Second, clinically and biologically related hematologic malignancies display similarities in chromosomal material lost. Third, molecular studies on genetic loss have, to date, focused on deletions involving the long arms of chromosomes 5, 6, 7, 13, and 20 and the short arms of chromosomes 9 and 17. The cytogenetic deletion maps presented herein indicate that there are also other genomic sites of interest for further molecular analyses. © 1993 Wiley‐Liss, Inc.
Knuutila, Sakari; Alitalo, Riitta; Ruutu, Tapani
doi: 10.1002/gcc.2870080403pmid: 7512364
We present a patient with acute lymphatic leukemia, eosinophilia, and a 5;14‐translocation, a rare but well‐documented condition. In order to clarify whether granulocytes were involved in the disease, we applied the MAC (Morphology‐Antibody‐Chromosomes) technique to samples of the bone marrow and, during a central nervous system relapse, to those of the cerebrospinal fluid. The karyotype of the blast cells was 47,XY,+X,t(5;14)(q31;q32),i(7)(q10). Interphase cytogenetic study by in situ hybridization with an X‐specific alphoid probe revealed the abnormality in CD10, CD19, and TdT (terminal deoxynucleotidyl transferase) positive lymphoid cells, whereas CD13 positive, Sudan black B positive, eosinophilic, and basophilic granulocytes as well as monocytes and small lymphocytes did not have the abnormality. Our results show that the eosinophilic and basophilic granulocytes in this subtype of acute leukemia do not belong to the malignant clone but are reactive. This study also confirmed the usefulness of the MAC technique in distinguishing neoplastic and reactive cells in malignancy.© 1993 Wiley‐Liss, Inc.
Wlodarska, Iwona; Schoenmakers, Eric; Kas, Koen; Merregaert, Jozef; Lemahieu, Vanessa; Weier, Ulli; Berghe, Herman Van Den; Van De Ven, Wim J. M.
doi: 10.1002/gcc.2870080404pmid: 7512365
The FAU gene is the cellular homologue of the viral FOX sequences in the genome of the Finkel‐Biskis‐Reilly murine sarcoma virus (FBR‐MuSV); the viral FOX sequences have been shown to increase the transforming capacity of FBR‐MuSV in vitro. The human FAU gene has recently been isolated, characterized, and mapped to chromosome band 11q13. Here, we report results of fluorescence in situ hybridization (FISH) analysis which indicate that the FAU gene maps proximally to the putative oncogene BCL1 at 11q13. Furthermore, we identified a t(11;17)(q13;q21) translocation in tumor cells of a t(11;14)(q13;q32)‐positive B‐cell non‐Hodgkin's lymphoma patient by FISH analysis using a FAU containing cosmid clone as molecular probe and by double‐colour chromosome painting analysis using chromosome 11‐ and chromosome 17‐specific painting probes. The position of the chromosome 11 breakpoint of the t(11;17) translocation was pinpointed to a human DNA region around the FAU gene of about 40 kbp. © 1993 Wiley‐Liss, Inc.
Rodriguez, Eduardo; Houldsworth, Jane; Reuter, Victor E.; Meltzer, Paul; Zhang, Ji; Trent, Jeffrey M.; Bosl, George J.; Chaganti, R. S. K.
doi: 10.1002/gcc.2870080405pmid: 7512366
The i(12p) chromosome has been shown to characterize more than 80% of male germ cell tumors (GCTs) and is an important diagnostic marker. Although recent cytogenetic analyses of GCTs have defined nonrandom chromosome abnormalities in these tumors, no attempt has so far been made to compare i(12p)‐positive and ‐negative tumors in terms of their cytogenetic, histologic, and clinical features. During a 5‐year period, we have ascertained 202 GCTs, of which 117 had clonally abnormal karyotypes. Among the latter, 91 had one or more copies of i(12p), whereas 26 lacked an i(12p). We report here the karyotypic analysis of these 26 i(12p)‐negative GCTs. In this group, nonrandom sites of chromosomal rearrangements included 12p13 (9/26) and 1p11‐q11 (5/26). Comparison of the cytogenetic features of i(12p)‐negative tumors with i(12p)‐positive tumors revealed the only significant difference to be rearrangements affecting 12p 13 in the former (35%) as compared to their absence in the latter (3%). Hybridization of metaphase preparations of 9 i(12p)‐negative tumors with a chromosome 12 painting probe and with a microdissected 12p painting probe revealed extra copies of chromosome 12 segments incorporated into marker chromosomes whose composition could not otherwise be resolved by banding analysis; all were shown to be derived from 12p. These data demonstrate that both i(12p)‐negative and ‐positive groups are characterized by an increased copy number of 12p, which is consistent with a lack of significant clinical or biological difference between them. An increased 12p copy number thus is a specific aberration of significance to the development of germ cell tumors. © 1993 Wiley‐Liss, Inc.
Hagemeijer, Anne; Buijs, Arjan; Smit, Elizabeth; Janssen, Bart; Creemers, Geert‐Jan; Plas, Dorien Van Der; Grosveld, Gerard
doi: 10.1002/gcc.2870080406pmid: 7512367
Leukemic cells from two patients with Philadelphia‐negative chronic myeloid leukemia (CML) were investigated: I) Cytogenetics showed a normal 46.XY karyotype in both cases, 2) molecular studies revealed rearrangement of the M‐BCR region and formation of BCR‐ABL fusion mRNA with b2a2 (patient I) or b3a2 (patient 2) configuration, and 3) fluorescence in situ hybridization (FISH) demonstrated relocation of the 5′ BCR sequences from one chromosome 22 to one chromosome 9. The ABL probe hybridized to both chromosomes 9 at band q34, while two other probes which map centromeric and telomeric of BCR on 22q 11 hybridized solely with chromosome 22. For the first time, a BCR‐ABL rearrangement is shown to take place on 9q34 instead of in the usual location on 22q 11. A rearrangement in the latter site is found in all Ph‐positive CML and in almost all investigated CML with variant Ph or Ph‐negative, BCR‐positive cases. The few aberrant chromosomal localizations of BCR‐ABL recombinant genes found previously were apparently the result of complex and successive changes. Furthermore in patient 2, both chromosomes 9 showed positive FISH signals with both ABL and BCR probes. Restriction fragment length polymorphism (RFLP) analysis indicated that mitotic recombination had occurred on the long arm of chromosome 9 and that the rearranged chromosome 9 was of paternal origin. The leukemic cells of this patient showed a duplication of the BCR‐ABL gene, analogous to duplication of the Ph chromosome in classic CML. In addition they had lost the maternal alleles of the 9q34 chromosomal region. The lymphocytes of patient 2 carried the maternal chromosome 9 alleles and were Ph‐negative as evidenced by RFLP and FISH analyses, respectively. © 1993 Wiley‐Liss, Inc.
Kobayashi, Hirofumi; Espinosa, Rafael; Fernald, Anthony A.; Begy, Catherine; Diaz, Manuel O.; Beau, Michelle M. Le; Rowley, Janet D.
doi: 10.1002/gcc.2870080407pmid: 7512368
We studied samples containing deletions of the long arm of chromosome 11 (11 q) from patients with hematologic malignancies by using cytogenetic and fluorescence in situ hybridization (FISH) techniques. Cytogenetic analysis of 28 patients and of a cell line showed that all deletions included band 11q23. FISH analysis demonstrated that the proximal part of 11q23, including NCAM, was deleted in 13 of 15 patients and the cell line. Recurring chromosomal losses in human tumors have been regarded as evidence that the affected regions contain tumor‐suppressor genes. These results suggest that the putative tumor‐suppressor gene is proximal to the MLL gene which is also located in 11q23. © 1993 Wiley‐Liss, Inc.
Adra, Chaker N.; Ko, Jon; Leonard, David; Wirth, Lori J.; Cerione, Richard A.; Lim, Bing
doi: 10.1002/gcc.2870080408pmid: 7512369
We have recently cloned the human cDNA for a gene, denoted D4, that encodes a protein 67% identical to the bovine rhoGDI protein, a GDP dissociation inhibitor (GDI) for the ras‐related rho‐subtype proteins. We now present data on the cloning and structural analysis of the murine D4 cDNA and confirm its preferential expression in hematopoietic tissues. The predicted murine and human D4 proteins are almost 90% identical, indicating that D4 and rhoGDI are different genes and that they are probably members of a related family of genes. Functional studies with the human D4 protein demonstrate that D4 has GDI activity against the CDC42Hs and rac I proteins, but binds to these proteins with a significantly weaker affinity than does the rho‐subtype GDI. These data suggest that D4, which will in subsequent communications be denoted as GDI.D4, might be a GDI for other known or as yet unidentified ras‐like GTP‐binding proteins. Alternatively, D4 could have other biochemical functions. During murine embryogenesis, D4 transcripts are detected in yolk‐sac cells, where the earliest hematopoietic precursors are found. When these precursors undergo proliferation and differentiation in vitro, a dramatic increase in D4 expression is seen. D4 probably has a significant function during the growth and development of hematopoietic precursors. © 1993 Wiley‐Liss, Inc.
Lukeis, Robyn; Ball, David; Irving, Louis; Garson, O. Margaret; Hasthorpe, Suzanne
doi: 10.1002/gcc.2870080409pmid: 7512370
A cytogenetic study of pleural effusions (PE) containing metastatic or invasive tumor cells from 11 patients with non‐small cell lung cancer (NSCLC) (3 squamous cell carcinomas (SQC) and 8 adenocarcinomas (ADC) including 1 giant cell variant) was performed to identify non‐random chromosome abnormalities. Numerical abnormalities seen in ≥ 30% of cases included gain of chromosomes 7 and 20, and loss of chromosomes 4, 9, 10, 13, 15, 16, 18, 19, 21, and 22. The most frequent structural abnormality involved rearrangement in 1p with breakpoints clustering at 1p10‐p13. Other recurrent breakpoint regions, seen in ≥ 30% of cases, occurred in chromosome regions 3p10‐p21, 3q11‐q25, 6p11‐p25, 6q13‐q23, 7q11‐q36, 9q32‐q34, 11p11‐p13, 11q13‐q24, 13p/14p and/or 15p, 17p and 19p, with, in particular, apparent loss of 6q21‐q27, 3p21‐p26, 7q21‐q22, 9p22‐p24 (shortest regions of common overlap) and 17p. There was also recurrent gain of 1q23‐q44, 8q13‐q24, and 11q13‐q23. These abnormalities were not restricted to a particular histological subtype, with the exception of + 8 and a breakpoint in 9q32‐q34, which were seen only in ADC. The 9q32‐q34 breakpoint observed in 4 ADC PE (including 1 giant cell variant) represents a new observation in NSCLC. These findings, when compared to those reported for primary NSCLC indicate cytogenetic differences between the two which may be associated with pleural invasion of NSCLC. © 1993 Wiley‐Liss, Inc.
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