Confirmation of Centromeric Fusion in 7p/lq Translocation Associated with Myelodysplastic Syndrome J. J. Hoo, K. Szego, and B. Jones
ABSTRACT: Fluorescence in situ hybridization (FISH) using chromosome 1- and chromosome 7-specific centromeric u-satellite probes was performed on the bone marrow (BM) cells of a patient with myelodysplastic syndrome (MDS) who had been treated for l y m p h o m a and whose BM karyotype was initially considered to be 46,XY, -7, + der(1)t(1;7)(p11;p11). FISH results suggested the presence of both chromosome I and chrom o s o m e 7 centromeres in the rearranged chromosome. Thus, the correct karyotype should be written as 46,XY, -7, + der(1;7)(qlO;plO).
INTRODUCTION
CASE REPORT, METHODS AND RESULTS
Translocation between chromosome I and 7 at juxtacentromeric regions resulting in a rearranged chromosome, which consists of 7p and lq and replaces a normal chromosome 7, apparently was first described by Geraedts et al. [1]. Scheres et al. [2, 3], Pedersen-Bjergaard et al. [4], Mecucci et al. [5], Sandberg et al. [6], Morrison-Delap et al. [7], and Lai et al. [8] reported further cases. Frequently, patients show a myelodysplastic syndrome (MDS) secondary to radiation therapy or chemotherapy of another malignancy. In all these studies [1-8], the breakpoints were interpreted as being at l p l l and 71011; thus, the centromere of the rearranged chromosome is considered to derive entirely from chromosome 1. Consequently, 46,XX or X'Y,- 7, + der(1)t(1;7)(p11;p11) has been generally accepted as the karyotype for the above aberration. Using high-resolution preparation, Yunis et al. [9] designated the breakpoints as lp11.2 and 7p11.2, respectively. The presumed breakpoint at 7pll prompted Woloschak et al. [10] to investigate the dosage of erb B gene in the bone marrow (BM) of patients with the above karyotype, because the erb B gene has been assigned to 7p11. More recently, using chromosome-specific centromeric 7-satellite probes, Nederlof et al. [11], Alitalo et al. [12], and Speleman et al. [13] demonstrated that the centromeric material from chromosome I and chromosome 7 were present in the translocated chromosome. Their results imply that the breakpoints leading to the 7p/lq translocation are not at l p l l and 7pll as previously suggested, but rather at the centromeres of respective chromosomes.
Our patient was a 39-year-old man who showed MDS in his BM after chemotherapy and radiation therapy for lymphoma. Chromosome analysis was performed on 25 BM metaphase cells; all showed loss of a chromosome 7 and the presence of a rearranged chromosome comprising the short arm of chromosome 7 and the long arm of chromosome 1 (Fig. 1). Fluorescence in situ hybridization (FISH) was subsequently performed on two slides using ONCOR's chromosome 7-specific (DTZ1) or chromosome I (DIZS)-specific centromeric u-satellite DNA probes. On the slide hybridized to DIZ5 probe, as expected, three signals were indeed observed in about 80% (54 of 72) of the interphase nuclei (Fig. 2); the remaining nuclei showed either two signals, one signal, or no signal. Surprisingly, on the slide hybridized to D7Z1 probe, more than 80% of the interphase nuclei (84 of 103) showed two signals (Fig. 3); the remaining nuclei contained only one signal or no signal. If the centromere of the rearranged chromosome originated entirely from chromosome 1, we should have noticed only one signal of D7Z1 in most interphase nuclei. Thus, we can conclude that D7Z1 is also present in the centromere of the rearranged chromosome. Unfortunately, no appropriate metaphase spread was available for the above observation. Repeat BM preparation 6 weeks later no longer showed any aberrant clone.
From the Office of Consolidated Laboratory Services and Department of Pediatrics, Rush-Presbyterian-St. Lake's Medical Center, Chicago, Illinois. Address reprint requests to: J. J. Hoo, M.D., Rush-PresbyterianSt. Luke's Medical Center, 1750 W. Harrison St., Chicago, IL 60612 Received November 20, 1991; accepted July 22, 1992.
186 Cancer Genet Cytogenet 64:186-188 (1992) 0165-4608/92/$05.00
DISCUSSION Although three DIZ5 signals and two D7Z1 signals were not demonstrated on metaphase chromosome spreads, the interphase results justify the conclusion that the 7p/lq translocation described above is the product of centromeric fusion; i.e., the breakpoints are not on the proximal short arms of chromosome I and chromosome 7, but are at the centromeres of both chromosomes. The above result does confirm
© 1992 Elsevier Science Publishing Co., Inc. 655 Avenue of the Americas. New York, NY 10010
7 p / l q Translocation and MDS
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Karyogram of bone marrow cells shewing the 7p/lq translocation chromosome replacing one chromosome 7.
the previous results of Nederlof et al. [11], Alitalo et al. [12], and S p e l e m a n et al. [13]. We consider that the C-band preparation of Lai et al. (1987) is in accord with the above conclusion, because the C-band on the rearranged c h r o m o s o m e a p p e a r e d to consist of a smaller top part originating from chromosome 7 and a much larger bottom part deriving from chromosome 1. Furthermore, Woloschak et al. [10] d i d not find a decrease in erb B gene in BM cells, as may be expected in the event of deletion. Because this particular translocation probably results from centromeric fusion between c h r o m o s o m e I and chro-
Figure 2 Three signals were evident in both interphase nuclei after hybridization with chromosome 1-specific centromeric a-satellite probe (DIZ5).
mosome 7, the karyotype of the above rearrangement should be written as 46,XX,- 7, + der(1;7)(ql0;pl0). REFERENCES 1. Geraedts JPM, Ottolander GJ, den Ploem JE, Muntinghe OG (1980): An identical translocation between chromosome I and 7 in three patients with myelofibrosis and myeloid metaplasia. Br J Haematol 44:569-575. 2. Scheres JMJC, Hustinx TWJ, Holdrinet RSG, Gemedts JPM, Hagemeijer A, Van der Blij-Philipsen M [1984): Tmnslocation 1;7 in dyshematopoiesis: Possibly induced with a nonrandom geographic distribution. Cancer Genet Cytogenet 12:283-294. 3. Scheres JMJC, Hustinx TWJ, C-eraedtsJPM, Leeksma CHW, Meltzer PS (1985): Tmnslocation 1;7 in hematologic disorders: A brief review of 22 cases. Cancer Genet Cytogenet 18:207-213. 4. Pedersen-Bjergaard J, Philip P, Pedersen NT, Hou-Jansen K, Svejgaard A, Jensen G, Nissen NI (1984): Acute non-lymphocytic leukemia, preleukemia, and acute myeloproliferativesyndrome secondary to treatment of other malignant diseases. Cancer 54:452-462. 5. Mecucci C, Ghione F, Tricot G, Louwagie A, Van den Berghe H (1985): Combined trisomy lq and monosomy 7p due to translocation 1;7 in myelodysplastic syndromes. Cancer Genet Cytogent 18:193-19Z 6. Sandberg AA, Morgan R, Hecht BK, Hecht F (1985): Tmnslocation (1;7)(pll;p11): A new myeloproliferativehematologic entity. Cancer Genet Cytogenet 18:199-206.
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Figure 3 Two signals were evident in all three interphase nuclei after hybridization with chromosome 7-specific centromeric a-satellite probe (DTZ1).
7. Morrison-DeLap SJ, Kuffel DG, Dewald GW, Letendre L (1986): Unbalanced 1;7 translocation and themw-induced hematologic disorder: A possible relationship. Am J Hematol 21:39-47. 8. Lai JL, Fenaux P, Savary JB, Jouet JP, Le Pelly P, Bautras F, Deminatti M {1967}:Translocation [1;7}in a case of secondary chronic myelomonocytic leukemia. Cancer Genet Cytogenet 24:355-35Z 9. Yunis JJ, Rydell RE, Oken MM, Arnesen MA, Mayer MG, Lobell M (1986): Refined chromosome analysis as an independent prognostic indicator in de novo myelodysplastic syndromes. Blood 67:1721-1730. 10. Woloschak GE, Dewald GW, Bahn RS, Kyle RA, Greipp PR, Ash RC (1986}: Amplification of RNA and DNA specific for erb B in unbalanced 1;7 chromosomal translocation associated with myelodysplastic syndrome. J Cell Biochem 32:23-34.
11. Nederlof PM, van der Flier S, Raap AK, Tanke HJ, van der Ploeg M, Kornips F, Geraedts JPM (1989): Detection of chromosome aberrations in interphase tumor nuclei by nonradioactive in situ hybridization. Cancer Genet Cytogenet 42:87-98. 12. Alitalo T, Willard HF, de la Chapelle A (1989): Determination of the breakpoints of 1;7 translocations in myelodysplastic syndrome by in situ hybridization using chromosome-specific alpha satellite DNA from human chromosome I and 7. Cytogenet Cell Genet 50:49-53. 13. Speleman F, Mangelshots K, Vercruyssen M, Dal Cin P, Avantin A, Offner F, Laureys G, Van Den Berghe H, Leroy J (1991): Analysis of whole-arm translocations in malignant blood ceils by nonisotopic in situ hybridization. Cytogenet Cell Ganet 56:14-17.
ABSTRACT: Fluorescence in situ hybridization (FISH) using chromosome 1- and chromosome 7-specific centromeric u-satellite probes was performed on the bone marrow (BM) cells of a patient with myelodysplastic syndrome (MDS) who had been treated for l y m p h o m a and whose BM karyotype was initially considered to be 46,XY, -7, + der(1)t(1;7)(p11;p11). FISH results suggested the presence of both chromosome I and chrom o s o m e 7 centromeres in the rearranged chromosome. Thus, the correct karyotype should be written as 46,XY, -7, + der(1;7)(qlO;plO).
INTRODUCTION
CASE REPORT, METHODS AND RESULTS
Translocation between chromosome I and 7 at juxtacentromeric regions resulting in a rearranged chromosome, which consists of 7p and lq and replaces a normal chromosome 7, apparently was first described by Geraedts et al. [1]. Scheres et al. [2, 3], Pedersen-Bjergaard et al. [4], Mecucci et al. [5], Sandberg et al. [6], Morrison-Delap et al. [7], and Lai et al. [8] reported further cases. Frequently, patients show a myelodysplastic syndrome (MDS) secondary to radiation therapy or chemotherapy of another malignancy. In all these studies [1-8], the breakpoints were interpreted as being at l p l l and 71011; thus, the centromere of the rearranged chromosome is considered to derive entirely from chromosome 1. Consequently, 46,XX or X'Y,- 7, + der(1)t(1;7)(p11;p11) has been generally accepted as the karyotype for the above aberration. Using high-resolution preparation, Yunis et al. [9] designated the breakpoints as lp11.2 and 7p11.2, respectively. The presumed breakpoint at 7pll prompted Woloschak et al. [10] to investigate the dosage of erb B gene in the bone marrow (BM) of patients with the above karyotype, because the erb B gene has been assigned to 7p11. More recently, using chromosome-specific centromeric 7-satellite probes, Nederlof et al. [11], Alitalo et al. [12], and Speleman et al. [13] demonstrated that the centromeric material from chromosome I and chromosome 7 were present in the translocated chromosome. Their results imply that the breakpoints leading to the 7p/lq translocation are not at l p l l and 7pll as previously suggested, but rather at the centromeres of respective chromosomes.
Our patient was a 39-year-old man who showed MDS in his BM after chemotherapy and radiation therapy for lymphoma. Chromosome analysis was performed on 25 BM metaphase cells; all showed loss of a chromosome 7 and the presence of a rearranged chromosome comprising the short arm of chromosome 7 and the long arm of chromosome 1 (Fig. 1). Fluorescence in situ hybridization (FISH) was subsequently performed on two slides using ONCOR's chromosome 7-specific (DTZ1) or chromosome I (DIZS)-specific centromeric u-satellite DNA probes. On the slide hybridized to DIZ5 probe, as expected, three signals were indeed observed in about 80% (54 of 72) of the interphase nuclei (Fig. 2); the remaining nuclei showed either two signals, one signal, or no signal. Surprisingly, on the slide hybridized to D7Z1 probe, more than 80% of the interphase nuclei (84 of 103) showed two signals (Fig. 3); the remaining nuclei contained only one signal or no signal. If the centromere of the rearranged chromosome originated entirely from chromosome 1, we should have noticed only one signal of D7Z1 in most interphase nuclei. Thus, we can conclude that D7Z1 is also present in the centromere of the rearranged chromosome. Unfortunately, no appropriate metaphase spread was available for the above observation. Repeat BM preparation 6 weeks later no longer showed any aberrant clone.
From the Office of Consolidated Laboratory Services and Department of Pediatrics, Rush-Presbyterian-St. Lake's Medical Center, Chicago, Illinois. Address reprint requests to: J. J. Hoo, M.D., Rush-PresbyterianSt. Luke's Medical Center, 1750 W. Harrison St., Chicago, IL 60612 Received November 20, 1991; accepted July 22, 1992.
186 Cancer Genet Cytogenet 64:186-188 (1992) 0165-4608/92/$05.00
DISCUSSION Although three DIZ5 signals and two D7Z1 signals were not demonstrated on metaphase chromosome spreads, the interphase results justify the conclusion that the 7p/lq translocation described above is the product of centromeric fusion; i.e., the breakpoints are not on the proximal short arms of chromosome I and chromosome 7, but are at the centromeres of both chromosomes. The above result does confirm
© 1992 Elsevier Science Publishing Co., Inc. 655 Avenue of the Americas. New York, NY 10010
7 p / l q Translocation and MDS
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Karyogram of bone marrow cells shewing the 7p/lq translocation chromosome replacing one chromosome 7.
the previous results of Nederlof et al. [11], Alitalo et al. [12], and S p e l e m a n et al. [13]. We consider that the C-band preparation of Lai et al. (1987) is in accord with the above conclusion, because the C-band on the rearranged c h r o m o s o m e a p p e a r e d to consist of a smaller top part originating from chromosome 7 and a much larger bottom part deriving from chromosome 1. Furthermore, Woloschak et al. [10] d i d not find a decrease in erb B gene in BM cells, as may be expected in the event of deletion. Because this particular translocation probably results from centromeric fusion between c h r o m o s o m e I and chro-
Figure 2 Three signals were evident in both interphase nuclei after hybridization with chromosome 1-specific centromeric a-satellite probe (DIZ5).
mosome 7, the karyotype of the above rearrangement should be written as 46,XX,- 7, + der(1;7)(ql0;pl0). REFERENCES 1. Geraedts JPM, Ottolander GJ, den Ploem JE, Muntinghe OG (1980): An identical translocation between chromosome I and 7 in three patients with myelofibrosis and myeloid metaplasia. Br J Haematol 44:569-575. 2. Scheres JMJC, Hustinx TWJ, Holdrinet RSG, Gemedts JPM, Hagemeijer A, Van der Blij-Philipsen M [1984): Tmnslocation 1;7 in dyshematopoiesis: Possibly induced with a nonrandom geographic distribution. Cancer Genet Cytogenet 12:283-294. 3. Scheres JMJC, Hustinx TWJ, C-eraedtsJPM, Leeksma CHW, Meltzer PS (1985): Tmnslocation 1;7 in hematologic disorders: A brief review of 22 cases. Cancer Genet Cytogenet 18:207-213. 4. Pedersen-Bjergaard J, Philip P, Pedersen NT, Hou-Jansen K, Svejgaard A, Jensen G, Nissen NI (1984): Acute non-lymphocytic leukemia, preleukemia, and acute myeloproliferativesyndrome secondary to treatment of other malignant diseases. Cancer 54:452-462. 5. Mecucci C, Ghione F, Tricot G, Louwagie A, Van den Berghe H (1985): Combined trisomy lq and monosomy 7p due to translocation 1;7 in myelodysplastic syndromes. Cancer Genet Cytogent 18:193-19Z 6. Sandberg AA, Morgan R, Hecht BK, Hecht F (1985): Tmnslocation (1;7)(pll;p11): A new myeloproliferativehematologic entity. Cancer Genet Cytogenet 18:199-206.
188
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Figure 3 Two signals were evident in all three interphase nuclei after hybridization with chromosome 7-specific centromeric a-satellite probe (DTZ1).
7. Morrison-DeLap SJ, Kuffel DG, Dewald GW, Letendre L (1986): Unbalanced 1;7 translocation and themw-induced hematologic disorder: A possible relationship. Am J Hematol 21:39-47. 8. Lai JL, Fenaux P, Savary JB, Jouet JP, Le Pelly P, Bautras F, Deminatti M {1967}:Translocation [1;7}in a case of secondary chronic myelomonocytic leukemia. Cancer Genet Cytogenet 24:355-35Z 9. Yunis JJ, Rydell RE, Oken MM, Arnesen MA, Mayer MG, Lobell M (1986): Refined chromosome analysis as an independent prognostic indicator in de novo myelodysplastic syndromes. Blood 67:1721-1730. 10. Woloschak GE, Dewald GW, Bahn RS, Kyle RA, Greipp PR, Ash RC (1986}: Amplification of RNA and DNA specific for erb B in unbalanced 1;7 chromosomal translocation associated with myelodysplastic syndrome. J Cell Biochem 32:23-34.
11. Nederlof PM, van der Flier S, Raap AK, Tanke HJ, van der Ploeg M, Kornips F, Geraedts JPM (1989): Detection of chromosome aberrations in interphase tumor nuclei by nonradioactive in situ hybridization. Cancer Genet Cytogenet 42:87-98. 12. Alitalo T, Willard HF, de la Chapelle A (1989): Determination of the breakpoints of 1;7 translocations in myelodysplastic syndrome by in situ hybridization using chromosome-specific alpha satellite DNA from human chromosome I and 7. Cytogenet Cell Genet 50:49-53. 13. Speleman F, Mangelshots K, Vercruyssen M, Dal Cin P, Avantin A, Offner F, Laureys G, Van Den Berghe H, Leroy J (1991): Analysis of whole-arm translocations in malignant blood ceils by nonisotopic in situ hybridization. Cytogenet Cell Ganet 56:14-17.
