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Prevalence, breakpoint distribution, and clinical correlates of t(5;12)
Cancer Genetics and Cytogenetics 153 (2004) 170–172
Short communication
Prevalence, breakpoint distribution, and clinical correlates of t(5;12) Patricia T. Greippa, Gordon W. Dewaldb, Ayalew Tefferia,* a
Division of Hematology and Internal Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN 55905 b Division of Laboratory Genetics, Mayo Clinic, Rochester, MN 55905 Received 11 August 2003; received in revised form 6 January 2004; accepted 13 January 2004
Abstract
Among 56,709 cytogenetic studies performed during a 15-year period at the Mayo Clinic, 25 cases of t(5;12) were identified. Among 11 patients with available clinical information, 4 had myelodysplastic syndrome, 2 had acute myelocytic leukemia, 2 had myelofibrosis with myeloid metaplasia (MMM), 2 had atypical chronic myelocytic disorder (ACMD), and 1 had chronic myelomonocytic leukemia (CMMoL). The 5q arm was involved in all patients and the 12p arm in only two patients [ACMD,t(5;12)(q33;p13) and MMM,t(5;12)(q11.2;p11.2)], both of whom had eosinophilia and monocytosis. These two features were present in only two other patients [CMMoL, t(5;12)(q35;q24.1) and ACMD,t(5;12)(q31;q24.1)]. The t(5;12) is a rare, myelocytic-exclusive cytogenetic abnormality with a breakpoint-specific association with eosinophilia or monocytosis. 쑖 2004 Elsevier Inc. All rights reserved.
1. Introduction There has been a recent surge of interest in the chromosome abnormality t(5;12)(q33;p13) because of its characteristic association with eosinophilia and monocytosis and its responsiveness to treatment with imatinib [1,2]. These features are believed to be due to activating rearrangements of the platelet-derived growth factor receptor β (PDGFRB) gene located at chromosome band 5q31⬃q33. In the t(5;12)(q33;p13), PDGFRB is activated by fusion with the ETV6 gene (previously TEL) located at chromosome band 12p13 (Fig. 1) [3]. Other PDGFRB-activating chromosome partners include 7q11.2 (HIP1), 10q21 (H4), 14q13 (TRIP11; alias CEV14), and 17p11 (RAB5C) [4]. In the present study, we describe the general prevalence of all t(5;12) lesions in a large, unselected series of cytogenetic studies performed at one institution over a 15-year period. Details regarding precise chromosome breakpoints, diagnosis, and laboratory and clinical features are provided.
2. Methods We retrospectively reviewed all cytogenetic studies performed in the cytogenetics laboratory at the Mayo Clinic between January 1987 and December 2001 and identified all patients who had a t(5;12), either alone or in combination * Corresponding author. Tel.: (507) 284-3159; fax: (507) 266-4972. E-mail address: [email protected] (A. Tefferi). 0165-4608/04/$ – see front matter 쑖 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.cancergencyto.2004.01.013
with other karyotype abnormalities. The prevalence of this translocation was determined in both patients seen (internal cases) and those not seen (external cases) at the Mayo Clinic. Clinical and laboratory information was reviewed for internal cases. Conventional criteria were used to define disease categories [5,6]. Disproportionate eosinophilia was defined as a peripheral blood eosinophil percentage greater than 5% (normal being less than 5%) and an absolute eosinophil count of more than 1500/µL (normal, less than 600/µL). Disproportionate monocytosis was defined as a peripheral blood monocyte percentage greater than 5% (normal, less than 5%) and an absolute monocyte count of more than 1000/µL (normal, less than 500/µL). 3. Results and discussion In all, 56,709 specimens (38,918 external; 17,791 internal) were referred for chromosome analysis over a 15year period. The number of cases in which t(5;12) was cytogenetically identified was 14 among the 38,918 external cases (prevalence, 0.04%) and 11 among the 17,791 internal cases (prevalence, 0.06%). The prevalence of the classic t(5;12)(q33;p13) was even less; only 4 such cases were identified from both the internal and the external study populations. These data are assertive of the rarity of t(5;12) in general and of the classic variant, t(5;12)(q33;p13), in particular. The clinical and laboratory information for the 11 patients from our institution is outlined in Tables 1 and 2. All 11
P.T. Greipp et al. / Cancer Genetics and Cytogenetics 153 (2004) 170–172
171
Fig 1. Ideogram showing breakpoints on chromosome 5 at q33 platelet-derived growth factor receptor 3 (PDGFRB) and chromosome 12 at p13 (ETV6/ TEL), as well as a representative t(5;12)(q33;p13) translocation.
patients had an associated underlying myeloid malignancy: 4 patients had myelodysplastic syndrome (MDS) (2 with therapy-related MDS, 1 with MDS with fibrosis, 1 with refractory anemia), 2 had acute myelocytic leukemia (AML) (M2), 2 had myelofibrosis with myeloid metaplasia (MMM), 2 had atypical chronic myelocytic disorder (ACMD), and 1 had chronic myelomonocytic leukemia (CMMoL). This observation not only implies an exclusive
association of t(5;12) with a myelocytic disorder but also suggests the lack of subclass specificity, in the absence of additional information regarding the precise breakpoint regions on both chromosomes 5 and 12. The classic t(5;12)(q33;p13) was found in only one patient (ACMD), who had both eosinophilia and monocytosis, but only the eosinophilia was disproportionate (case 2 in Table 1). Only one other patient (MMM) had a chromosome
Table 1 Specific diagnosis and peripheral blood findings in 11 patients with t(5;12) Chromosome breakpoint 5
12
Metaphase involved
1
q11.2
p11.2
20/20
del(7)(q22)
2
q33
p13
16/20
None
3
q13
q13
3/20
Complex
4
q13
q15
5/20
Complex
5
q15
q22
15/20
Complex
6
q22
q22
16/20
idem, +8
7
q35
q11
5/6
Complex
8
q31
q13
9/20
Complex
9
q31
q24.1
20/20
Complex
10
q33
q13
11
q35
q24.1
Case no.
2/17 20/20
Additional abnormality
Clinical diagnosis, date MMM (6/16/95) ACMD (11/18/92) MDS-t (2/16/01) AML-M2 (11/10/89) AML-M2 (4/30/92) RA (9/14/95) MDS-f (1/29/91) Myeloma/MDS-t (3/10/99) ACMD (7/27/98) MMM (6/28/00) CMMoL (1/6/97)
None 3-way translocation
Associated peripheral eosinophilia
Leukocyte/ µL
Eosinophil/ µL
Monocyte/ µL
Previous chemotherapy
Yes
170,000
1700
16,150
No
Yes
22,400
5600
1232
No
No
1000
20
3
No
1700
0
85
Yes
No
1000
20
30
Yes
No
4500
50
780
No
No
2200
0
110
No
1100
22
176
Isotretinoin (2 mo) Yes
No
37,000
0
1100
No
No
5700
57
57
No
Yes
181,000
7240
50,680
Radiation
Hydroxyurea
Abbreviations: ACMD, atypical chronic myelocytic disorder; AML, acute myelocytic leukemia; CMMoL, chronic myelomonocytic leukemia; MDS-f, myelodysplastic syndrome with myelofibrosis; MDS-t, therapy-related MDS; MMM, myelofibrosis with myelocytic metaplasia; RA, refractory anemia.
172
P.T. Greipp et al. / Cancer Genetics and Cytogenetics 153 (2004) 170–172
Table 2 Clinical findings in 11 patients with t(5;12) Chromosome breakpoint Case no.
Age/sex
5
12
Enlarged liver
Enlarged spleen
Marrow eosinophilia
Reticulin fibrosis
1 2 3 4 5 6 7 8 9 10
67/M 64/M 63/F 5/F 74/M 82/M 67/M 74/M 65/M 67/F
q11.2 q33 q13 q13 q15 q22 q35 q31 q31 q33
p11.2 p13 q13 q15 q22 q22 q11 q13 q24.1 q13
Yes No No No No No No No No Yes
Yes No No No No No No No No Yes
Yes Yes No No No No No No No No
11
57/M
q35
q24.1
No
Yes
No
Present Not done Absent Not done Not done Not done Present Not done Absent Markedly increased Present
Clinical course (date)
Months to death (date)
Progression at last FU (4/8/00) Stable at last FU (10/17/97) Progression to M4; failed imatinib Relapsed after BMT Treatment toxicity Indolent Unknown Relapse MMM/MDS 8 mo after BMT Positive neurologic involvement; ACMD Stable counts (July 2002)
58⫹ (unknown) 59⫹ (unknown) 10 (12/16/01) 18 (5/6/91) 4 (8/25/92) 18 (3/21/97) Unknown (unknown) Alive at 48⫹ 7 (2/19/99) Alive at 24⫹
Progression to M4
7 (8/5/97)
Abbreviations: ACMD, atypical chronic myelocytic disorder; BMT, bone marrow transplantation; FU, follow-up; MDS, myelodysplastic syndrome; MMM, myelofibrosis with myeloid metaplasia.
breakpoint involving 12p (i.e., p11.2), as opposed to 12q, and this patient also had displayed both eosinophilia and monocytosis, but not to a disproportionate degree (case 1 in Table 1). The remaining nine patients had a chromosome 12 breakpoint involving the q arm. We note that one of these patients (CMMoL,t(5;12)q35;q24.1) had both disproportionate monocytosis and nondisproportionate eosinophilia, suggesting the presence of a PDGFRB-activating fusion partner gene in the vicinity of 12q24.1 (case 11 in Table 1). The documentation of nondisproportionate monocytosis in the only other patient (ACMD) with a similar breakpoint profile, t(5;12)(q31;q24.1), is supportive of this possibility (case 9 in Table 1). Neither eosinophilia nor monocytosis was apparent in 7 of the 11 study cases. The chromosome 12q arm was involved in all 7 cases; 5 had complex cytogenetic abnormalities and 4 had either AML or therapy-related MDS. This suggests that the t(5;12) in this instance represents a nonspecific event that is probably not indicative of PDGFRB activation. The observation underscores the breakpoint specificity of the association between t(5;12) and either eosinophilia or monocytosis, information that is relevant to consideration of treatment with imatinib.
References [1] Steer EJ, Cross NC. Myeloproliferative disorders with translocations of chromosome 5q31–35: role of the platelet-derived growth factor receptor Beta. Acta Haematol 2002;107:113–22. [2] Apperley JF, Gardembas M, Melo JV, Russell-Jones R, Bain BJ, Baxter EJ, Chase A, Chessells JM, Colombat M, Dearden CE, Dimitrijevic S, Mahon FX, Marin D, Nikolova Z, Olavarria E, Silberman S, Schultheis B, Cross NC, Goldman JM. Response to imatinib mesylate in patients with chronic myeloproliferative diseases with rearrangements of the platelet-derived growth factor receptor beta. N Engl J Med 2002; 347:481–7. [3] Golub TR, Barker GF, Lovett M, Gilliland DG. Fusion of PDGF receptor beta to a novel ETS-like gene, TEL, in chronic myelomonocytic leukemia with t(5;12) chromosomal translocation. Cell 1994; 77:307–16. [4] Baxter EJ, Kulkarni S, Vizmanos JL, Jaju R, Martinelli G, Testoni N, Hughes G, Salamanchuk Z, Calasanz MJ, Lahortiga I, Pocock CF, Dang R, Fidler C, Wainscoat JS, Boultwood J, Cross NC. Novel translocations that disrupt the platelet-derived growth factor receptor beta (PDGFRB) gene in BCR-ABL-negative chronic myeloproliferative disorders. Br J Haematol 2003;120:251–6. [5] Bennett JM. World Health Organization classification of the acute leukemias and myelodysplastic syndrome. Int J Hematol 2000;72: 131–3. [6] Steensma DP, Hanson CA, Letendre L, Tefferi A. Myelodysplasia with fibrosis: a distinct entity? Leuk Res 2001;25:829–38.
Short communication
Prevalence, breakpoint distribution, and clinical correlates of t(5;12) Patricia T. Greippa, Gordon W. Dewaldb, Ayalew Tefferia,* a
Division of Hematology and Internal Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN 55905 b Division of Laboratory Genetics, Mayo Clinic, Rochester, MN 55905 Received 11 August 2003; received in revised form 6 January 2004; accepted 13 January 2004
Abstract
Among 56,709 cytogenetic studies performed during a 15-year period at the Mayo Clinic, 25 cases of t(5;12) were identified. Among 11 patients with available clinical information, 4 had myelodysplastic syndrome, 2 had acute myelocytic leukemia, 2 had myelofibrosis with myeloid metaplasia (MMM), 2 had atypical chronic myelocytic disorder (ACMD), and 1 had chronic myelomonocytic leukemia (CMMoL). The 5q arm was involved in all patients and the 12p arm in only two patients [ACMD,t(5;12)(q33;p13) and MMM,t(5;12)(q11.2;p11.2)], both of whom had eosinophilia and monocytosis. These two features were present in only two other patients [CMMoL, t(5;12)(q35;q24.1) and ACMD,t(5;12)(q31;q24.1)]. The t(5;12) is a rare, myelocytic-exclusive cytogenetic abnormality with a breakpoint-specific association with eosinophilia or monocytosis. 쑖 2004 Elsevier Inc. All rights reserved.
1. Introduction There has been a recent surge of interest in the chromosome abnormality t(5;12)(q33;p13) because of its characteristic association with eosinophilia and monocytosis and its responsiveness to treatment with imatinib [1,2]. These features are believed to be due to activating rearrangements of the platelet-derived growth factor receptor β (PDGFRB) gene located at chromosome band 5q31⬃q33. In the t(5;12)(q33;p13), PDGFRB is activated by fusion with the ETV6 gene (previously TEL) located at chromosome band 12p13 (Fig. 1) [3]. Other PDGFRB-activating chromosome partners include 7q11.2 (HIP1), 10q21 (H4), 14q13 (TRIP11; alias CEV14), and 17p11 (RAB5C) [4]. In the present study, we describe the general prevalence of all t(5;12) lesions in a large, unselected series of cytogenetic studies performed at one institution over a 15-year period. Details regarding precise chromosome breakpoints, diagnosis, and laboratory and clinical features are provided.
2. Methods We retrospectively reviewed all cytogenetic studies performed in the cytogenetics laboratory at the Mayo Clinic between January 1987 and December 2001 and identified all patients who had a t(5;12), either alone or in combination * Corresponding author. Tel.: (507) 284-3159; fax: (507) 266-4972. E-mail address: [email protected] (A. Tefferi). 0165-4608/04/$ – see front matter 쑖 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.cancergencyto.2004.01.013
with other karyotype abnormalities. The prevalence of this translocation was determined in both patients seen (internal cases) and those not seen (external cases) at the Mayo Clinic. Clinical and laboratory information was reviewed for internal cases. Conventional criteria were used to define disease categories [5,6]. Disproportionate eosinophilia was defined as a peripheral blood eosinophil percentage greater than 5% (normal being less than 5%) and an absolute eosinophil count of more than 1500/µL (normal, less than 600/µL). Disproportionate monocytosis was defined as a peripheral blood monocyte percentage greater than 5% (normal, less than 5%) and an absolute monocyte count of more than 1000/µL (normal, less than 500/µL). 3. Results and discussion In all, 56,709 specimens (38,918 external; 17,791 internal) were referred for chromosome analysis over a 15year period. The number of cases in which t(5;12) was cytogenetically identified was 14 among the 38,918 external cases (prevalence, 0.04%) and 11 among the 17,791 internal cases (prevalence, 0.06%). The prevalence of the classic t(5;12)(q33;p13) was even less; only 4 such cases were identified from both the internal and the external study populations. These data are assertive of the rarity of t(5;12) in general and of the classic variant, t(5;12)(q33;p13), in particular. The clinical and laboratory information for the 11 patients from our institution is outlined in Tables 1 and 2. All 11
P.T. Greipp et al. / Cancer Genetics and Cytogenetics 153 (2004) 170–172
171
Fig 1. Ideogram showing breakpoints on chromosome 5 at q33 platelet-derived growth factor receptor 3 (PDGFRB) and chromosome 12 at p13 (ETV6/ TEL), as well as a representative t(5;12)(q33;p13) translocation.
patients had an associated underlying myeloid malignancy: 4 patients had myelodysplastic syndrome (MDS) (2 with therapy-related MDS, 1 with MDS with fibrosis, 1 with refractory anemia), 2 had acute myelocytic leukemia (AML) (M2), 2 had myelofibrosis with myeloid metaplasia (MMM), 2 had atypical chronic myelocytic disorder (ACMD), and 1 had chronic myelomonocytic leukemia (CMMoL). This observation not only implies an exclusive
association of t(5;12) with a myelocytic disorder but also suggests the lack of subclass specificity, in the absence of additional information regarding the precise breakpoint regions on both chromosomes 5 and 12. The classic t(5;12)(q33;p13) was found in only one patient (ACMD), who had both eosinophilia and monocytosis, but only the eosinophilia was disproportionate (case 2 in Table 1). Only one other patient (MMM) had a chromosome
Table 1 Specific diagnosis and peripheral blood findings in 11 patients with t(5;12) Chromosome breakpoint 5
12
Metaphase involved
1
q11.2
p11.2
20/20
del(7)(q22)
2
q33
p13
16/20
None
3
q13
q13
3/20
Complex
4
q13
q15
5/20
Complex
5
q15
q22
15/20
Complex
6
q22
q22
16/20
idem, +8
7
q35
q11
5/6
Complex
8
q31
q13
9/20
Complex
9
q31
q24.1
20/20
Complex
10
q33
q13
11
q35
q24.1
Case no.
2/17 20/20
Additional abnormality
Clinical diagnosis, date MMM (6/16/95) ACMD (11/18/92) MDS-t (2/16/01) AML-M2 (11/10/89) AML-M2 (4/30/92) RA (9/14/95) MDS-f (1/29/91) Myeloma/MDS-t (3/10/99) ACMD (7/27/98) MMM (6/28/00) CMMoL (1/6/97)
None 3-way translocation
Associated peripheral eosinophilia
Leukocyte/ µL
Eosinophil/ µL
Monocyte/ µL
Previous chemotherapy
Yes
170,000
1700
16,150
No
Yes
22,400
5600
1232
No
No
1000
20
3
No
1700
0
85
Yes
No
1000
20
30
Yes
No
4500
50
780
No
No
2200
0
110
No
1100
22
176
Isotretinoin (2 mo) Yes
No
37,000
0
1100
No
No
5700
57
57
No
Yes
181,000
7240
50,680
Radiation
Hydroxyurea
Abbreviations: ACMD, atypical chronic myelocytic disorder; AML, acute myelocytic leukemia; CMMoL, chronic myelomonocytic leukemia; MDS-f, myelodysplastic syndrome with myelofibrosis; MDS-t, therapy-related MDS; MMM, myelofibrosis with myelocytic metaplasia; RA, refractory anemia.
172
P.T. Greipp et al. / Cancer Genetics and Cytogenetics 153 (2004) 170–172
Table 2 Clinical findings in 11 patients with t(5;12) Chromosome breakpoint Case no.
Age/sex
5
12
Enlarged liver
Enlarged spleen
Marrow eosinophilia
Reticulin fibrosis
1 2 3 4 5 6 7 8 9 10
67/M 64/M 63/F 5/F 74/M 82/M 67/M 74/M 65/M 67/F
q11.2 q33 q13 q13 q15 q22 q35 q31 q31 q33
p11.2 p13 q13 q15 q22 q22 q11 q13 q24.1 q13
Yes No No No No No No No No Yes
Yes No No No No No No No No Yes
Yes Yes No No No No No No No No
11
57/M
q35
q24.1
No
Yes
No
Present Not done Absent Not done Not done Not done Present Not done Absent Markedly increased Present
Clinical course (date)
Months to death (date)
Progression at last FU (4/8/00) Stable at last FU (10/17/97) Progression to M4; failed imatinib Relapsed after BMT Treatment toxicity Indolent Unknown Relapse MMM/MDS 8 mo after BMT Positive neurologic involvement; ACMD Stable counts (July 2002)
58⫹ (unknown) 59⫹ (unknown) 10 (12/16/01) 18 (5/6/91) 4 (8/25/92) 18 (3/21/97) Unknown (unknown) Alive at 48⫹ 7 (2/19/99) Alive at 24⫹
Progression to M4
7 (8/5/97)
Abbreviations: ACMD, atypical chronic myelocytic disorder; BMT, bone marrow transplantation; FU, follow-up; MDS, myelodysplastic syndrome; MMM, myelofibrosis with myeloid metaplasia.
breakpoint involving 12p (i.e., p11.2), as opposed to 12q, and this patient also had displayed both eosinophilia and monocytosis, but not to a disproportionate degree (case 1 in Table 1). The remaining nine patients had a chromosome 12 breakpoint involving the q arm. We note that one of these patients (CMMoL,t(5;12)q35;q24.1) had both disproportionate monocytosis and nondisproportionate eosinophilia, suggesting the presence of a PDGFRB-activating fusion partner gene in the vicinity of 12q24.1 (case 11 in Table 1). The documentation of nondisproportionate monocytosis in the only other patient (ACMD) with a similar breakpoint profile, t(5;12)(q31;q24.1), is supportive of this possibility (case 9 in Table 1). Neither eosinophilia nor monocytosis was apparent in 7 of the 11 study cases. The chromosome 12q arm was involved in all 7 cases; 5 had complex cytogenetic abnormalities and 4 had either AML or therapy-related MDS. This suggests that the t(5;12) in this instance represents a nonspecific event that is probably not indicative of PDGFRB activation. The observation underscores the breakpoint specificity of the association between t(5;12) and either eosinophilia or monocytosis, information that is relevant to consideration of treatment with imatinib.
References [1] Steer EJ, Cross NC. Myeloproliferative disorders with translocations of chromosome 5q31–35: role of the platelet-derived growth factor receptor Beta. Acta Haematol 2002;107:113–22. [2] Apperley JF, Gardembas M, Melo JV, Russell-Jones R, Bain BJ, Baxter EJ, Chase A, Chessells JM, Colombat M, Dearden CE, Dimitrijevic S, Mahon FX, Marin D, Nikolova Z, Olavarria E, Silberman S, Schultheis B, Cross NC, Goldman JM. Response to imatinib mesylate in patients with chronic myeloproliferative diseases with rearrangements of the platelet-derived growth factor receptor beta. N Engl J Med 2002; 347:481–7. [3] Golub TR, Barker GF, Lovett M, Gilliland DG. Fusion of PDGF receptor beta to a novel ETS-like gene, TEL, in chronic myelomonocytic leukemia with t(5;12) chromosomal translocation. Cell 1994; 77:307–16. [4] Baxter EJ, Kulkarni S, Vizmanos JL, Jaju R, Martinelli G, Testoni N, Hughes G, Salamanchuk Z, Calasanz MJ, Lahortiga I, Pocock CF, Dang R, Fidler C, Wainscoat JS, Boultwood J, Cross NC. Novel translocations that disrupt the platelet-derived growth factor receptor beta (PDGFRB) gene in BCR-ABL-negative chronic myeloproliferative disorders. Br J Haematol 2003;120:251–6. [5] Bennett JM. World Health Organization classification of the acute leukemias and myelodysplastic syndrome. Int J Hematol 2000;72: 131–3. [6] Steensma DP, Hanson CA, Letendre L, Tefferi A. Myelodysplasia with fibrosis: a distinct entity? Leuk Res 2001;25:829–38.