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Chromosome 20 Deletions in Myeloid Malignancies: Reduction of the Common Deleted Region, Generation of a PAC/BAC Contig and Identi®Cation of Candidate Genes

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Chromosome 20 Deletions in Myeloid Malignancies: Reduction of the Common Deleted Region, Generation of a PAC/BAC Contig and Identi®Cation of Candidate Genes Oncogene (2000) 19, 3902 ± 3913 ã 2000 Macmillan Publishers Ltd All rights reserved 0950 ± 9232/00 $15.00 www.nature.com/onc Chromosome 20 deletions in myeloid malignancies: reduction of the common deleted region, generation of a PAC/BAC contig and identi®cation of candidate genes Anthony J Bench1,4, Elisabeth P Nacheva1,4, Tracey L Hood1, Jane L Holden2, Lisa French2, Soheila Swanton1, Kim M Champion1, Juan Li1, Pamela Whittaker2, George Stavrides2, Adrienne R Hunt2, Brian JP Huntly1, Lynda J Campbell3, David R Bentley2, Panos Deloukas2 and Anthony R Green,*,1 together with the UK Cancer Cytogenetics Group (UKCCG) 1University of Cambridge, Department of Haematology, Cambridge Institute for Medical Research, Hills Road, Cambridge, CB2 2XY, UK; 2The Sanger Centre, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, CB10 1SA, UK; 3Victorian Cancer Cytogenetics Service, St Vincent's Hospital, Fitzroy, Victoria, Australia 3065 Deletion of the long arm of chromosome 20 represents deletion of the long arm of chromosome 20 was found the most common chromosomal abnormality associated in 5% of these samples and represented the second with the myeloproliferative disorders (MPDs) and is also most common structural abnormality after the Phila- found in other myeloid malignancies including myelodys- delphia chromosome. plastic syndromes (MDS) and acute myeloid leukaemia Deletion of the long arm of chromosome 20 is (AML). Previous studies have identi®ed a common observed in 10% of patients with polycythaemia vera deleted region (CDR) spanning approximately 8 Mb. (PV) as well as in other myeloproliferative disorders We have now used G-banding, FISH or microsatellite (MPD) (Bench et al., 1998b). It is also seen in PCR to analyse 113 patients with a 20q deletion approximately 4% of patients with myelodysplastic associated with a myeloid malignancy. Our results de®ne syndromes (MDS) (Fenaux et al., 1996) and 1 ± 2% of a new MPD CDR of 2.7 Mb, an MDS/AML CDR of patients with acute myeloid leukaemia (AML) (Heim 2.6 Mb and a combined `myeloid' CDR of 1.7 Mb. We and Mitelman, 1992). These malignancies are thought have also constructed the most detailed physical map of to result from acquired mutations aecting a plur- this region to date ± a bacterial clone map spanning ipotent haematopoietic progenitor cell. By contrast, 5 Mb of the chromosome which contains 456 bacterial 20q deletions are rarely seen in lymphoid malignancies clones and 202 DNA markers. Fifty-one expressed (Mitelman, 1995) although the 20q deletion has been sequences were localized within this contig of which 37 shown to arise in a progenitor cell which is capable of lie within the MPD CDR and 20 within the MDS/AML giving rise to both myeloid cells and B cells (White et CDR. Of the 16 expressed sequences (six genes and 10 al., 1994). Taken together, these observations suggest unique ESTs) within the `myeloid' CDR, ®ve were that 20q deletions mark the site of one or more tumour expressed in both normal bone marrow and puri®ed suppressor genes, the loss of which perturbs the CD34 positive cells. These data identify a set of genes behaviour of multipotent haematopoietic progenitors. which are both positional and expression candidates for Initial studies by isotopic in situ hybridization the target gene(s) on 20q. Oncogene (2000) 19, 3902 ± demonstrated retention of the c-src gene in three 3913. patients with a 20q deletion (Le Beau et al., 1985) but loss of c-src in two other patients (Morris et al., Keywords: chromosome 20; tumour suppressor genes; 1989). These results may have been complicated by myeloproliferative disorders; myelodysplastic syn- cross-hybridization of the probe to additional se- dromes quences on 20q, but did suggest that deletions were interstitial rather than terminal. Investigations using high resolution G-banding and reverse chromosome Introduction painting identi®ed two groups of deletions (Nacheva et al., 1995b). Large deletions resulted in loss of both Acquired chromosomal deletions are frequently de- Giemsa dark bands on 20q whilst small deletions tected in both solid tumours and haematological resulted in loss of 20q12 but retention of the more malignancies (Mitelman et al., 1997). Such deletions distal Giemsa dark band at 20q13.2. FISH mapping by are believed to harbour tumour suppressor genes, loss Le Beau and colleagues (Roulston et al., 1993) or inactivation of which contributes to the pathogen- provided the ®rst molecular identi®cation of a common esis of the tumour. In a large study of patients with deleted region (CDR) between RPN2 and D20S17, a haematological malignancies, Dewald et al. (1993) region of approximately 13 Mb. Molecular analysis analysed almost 3000 consecutive bone marrow using microsatellite PCR and Southern blotting re®ned samples with a sole chromosomal abnormality. A the proximal boundary to D20S174 and demonstrated that both the centromeric and telomeric breakpoints were heterogeneous (Asimakopoulos et al., 1994; Hollings, 1994). *Correspondence: AR Green 4The ®rst two authors contributed equally to this work Patients with an MPD or MDS have distinct Received 8 March 2000; revised 5 June 2000; accepted 6 June 2000 biological and clinical characteristics and it is not Chromosome 20 deletions in myeloid malignancies AJ Bench et al 3903 known whether the same 20q target genes will prove to variable chromosome partners (Figure 1c). In all ®ve be involved in the two groups of myeloid disorders. It cases, the der(20) marker was the only translocation is therefore prudent to consider the two categories of product retained in the genome. Furthermore, FISH patients separately. On the basis of published data, the mapping showed that the breakpoint on chromosome CDR in MPD patients is ¯anked by D20S206 and 20 had occurred in a region proximal to D20S107 and D20S481 and the CDR in MDS/AML patients is con®rmed loss of the remainder of the long arm of ¯anked by D20S465 and D20S481 (Bench et al., 1998a; chromosome 20 (data not shown). These results will be Wang et al., 1998). Two yeast arti®cial chromosome reported in detail elsewhere. (YAC) contigs which span these CDRs have been In the remaining 42 cases, chromosome painting was constructed (Bench et al., 1998a; Stoel et al., 1996). consistent with a small interstitial deletion of 20q These have allowed the physical size of the MPD CDR (Figure 1d). The majority (33 cases) carried a 20q to be estimated as 8 ± 9 Mb and the MDS/AML CDR deletion as the sole karyotypic abnormality. In the as 7 ± 8 Mb (Bench et al., 1998a; Stoel et al., 1996). remaining nine cases, the 20q deletion was accompa- However, the large size of the CDRs makes the task of nied by various additional chromosomal aberrations target gene identi®cation an arduous one. (Table 1). All 42 cases with a small 20q deletion were The discovery of small submicroscopic deletions subjected to further FISH mapping with locus speci®c would greatly aid identi®cation of putative target probes. genes. Unfortunately systematic microsatellite PCR analysis of an 11 Mb region spanning the CDRs did Deletion mapping analysis not reveal any small deletions in patients with PV and a normal karyotype (Asimakopoulos et al., 1996a). The 42 patients with small 20q deletions were analysed Similarly, in patients with a visible 20q deletion, no by FISH using a centromeric PAC (CEP20), a PAC small deletions have been detected on the normal hybridizing to a distal region of 20q (LSI 20q13) and a chromosome 20 homologue (Bench et al., 1998a). In PAC hybridizing within the CDR (LSI D20S108). In both these studies, the microsatellite markers were each patient, signals from both LSI 20q13 and CEP20 separated by an average of 500 ± 1000 kb and so it is but not LSI D20S108 were observed on the deleted possible that deletions smaller than this may have been chromosome 20 con®rming the presence of an missed. interstitial deletion (summarized in Figure 3). Meta- In order to re®ne the CDR further we have now phases from each patient were then hybridized with examined 113 patients with a myeloid malignancy PACs mapping at the boundaries of the known MPD associated with a 20q deletion. Both the MDS/AML and MDS/AML CDRs ± D20S107 which lies at the CDR and MPD CDR have been considerably reduced proximal boundary of the CDRs and D20S176 which in size. The generation of a detailed PAC and BAC lies telomeric of the distal boundary of the CDRs based physical map spanning the CDR allowed the (Bench et al., 1998a; Wang et al., 1998). positioning of 51 unique expressed sequences. RT ± In 37 patients (25 with MDS or AML, 12 with PCR analysis of bone marrow and puri®ed CD34 MPD) both probes failed to produce a signal on the positive cells has allowed the identi®cation of a set of deleted chromosome 20 demonstrating the presence of genes which are both positional and expression extensive deletions which would not help re®ne the candidates for the target gene(s) on 20q. CDRs. Such samples were not investigated further. However, in four patients with MDS (DB53, MH40, DB122 and DB214) and one with MPD (JH41) one of the two probes gave a signal on the deleted Results chromosome 20 and these samples were analysed in more detail. Chromosome banding and painting In addition to the 42 patients with small 20q Bone marrow chromosome preparations of 107 cases deletions which were analysed by FISH using locus with myeloid disorders were analysed by G banding to speci®c probes, a further six patients with a 20q assess the size of the deletion of the long arm of deletion (four with MDS, two with MPD), from whom chromosome 20. As previously described (Nacheva et bone marrow metaphases were not available, were al., 1995b), two categories of 20q deletion were analysed using microsatellite PCR.
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