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Involvement of chromosome 13 in myelodysplastic syndromes
Involvement of Chromosome 13 in Myelodysplastic Syndromes Anna D. Panani, Angeliki Ferti-Passantonopoulou, Vasiliki Pappa, J. Dervenoulas, and S. Raptis
ABSTRACT: We report 2 of 80 cases of myelodysplastic syndromes (MDS) cytogenetically studied, with involvement of chromosome 13. The first case had a t(6;13), and the second had a t(1;13). Abnormalities of chromosome 13 mainly involving loss of band 13q14 have been described in hematologic malignancies. In both our cases band 13q14 did not participate in the deleted segment.
INTRODUCTION
Chromosomal abnormalities are e v i d e n t in one third to one half of all cytogenetically studied cases with myelodysplastic syndromes (MDS). Certain c h r o m o s o m e s are i n v o l v e d n o n r a n d o m l y , and the c h r o m o s o m a l changes are important in evaluating the patient's clinical course [1]. A m o n g c h r o m o s o m a l changes observed in MDS, a deletion of 13q, mainly i n v o l v i n g loss of band 13q14, has been described [2]. In 2 of 80 cases of MDS studied cytogenetically, we found two cases with c h r o m o s o m e 13 abnormalities. In both cases, c h r o m o s o m e 13 participated in translocations with c h r o m o s o m e s 6 and 1, respectively.
CASE REPORTS
Case 1
A 76-year-old w o m a n was first admitted to the hospital in December 1986 because of a lobular infiltrative carcinoma of the left breast; a mastectomy was performed. She was started on treatment with tamoxifen until September 1987, w h e n bleeding manifestations from the skin were noted for the first time. At that time, the hematocrit was 34%, the white blood cell (WBC) count 3,700/txl with 23% neutrophils, 73% lymphocytes, 2% monocytes, 1% eosinophils, and 1% myelocytes. The platelet count was normal. She c o n ti n u e d treatment with tamoxifen until January 1988. A bone marrow aspirate was then performed and the diagnosis of MDS refractory anemia with excess blasts (RAEB) was made. The patient received transfusions and was followed for 1 year. In February 1989, a second bone marrow aspirate was performed,
From the Second Department of Internal Medicine Propaedeutic of Athens University, Evangelismos Hospital, Athens, Greece. Address reprint requests to: A n n a D. Panani, M.D., Second Department of Internal Medicine. Propaedeutic of Athens University, Evangelismos Hospital, Athens 106 76, Greece. Received June 28, 1990; accepted September 6, 1990.
149 :© 1991 Elsevier Science Publishing Co., Inc. 655 Avenue of the Americas, New York, NY 10010
Cancer Genet Cytogenet 55:149 152 (19911 0165-4608,'91/$03.50
150
A.D. Panani et al.
a
b
Figure I Partialkaryotypes showing t(6;13) (case 1). C
d
i 6
t(6;13)
13
and a diagnosis of RAEB in transformation (RAEBT) MDS was made. The patient was started on treatment with cytocine arabinoside subcutaneously with no response. In May 1989, the patient became seriously ill; she died of cerebral hemorrhage 1 m o n t h later.
Cytogenetic findings. The first cytogenetic study was performed in January 1988 on a bone marrow aspirate using direct culture and a G-banding technique. Thirty-four metaphases were studied: 27 had 46 chromosomes with a translocation between chromosomes 6 and 13, t(6;13)(q11;p12) {Figs. 1 and 2). The remaining metaphases had 47 chromosomes with the same t(6;13) and an extra chromosome 8. Peripheral blood lymphocyte (PBL) culture stimulated with phytohemagglutinin (PHA) showed a normal karyotype. A second cytogenetic study was performed on bone marrow aspirate in February 1989, when a diagnosis of RAEBT was made. Ten metaphases were studied, and the chromosomal findings were the same as in the first study. Case 2
A 67-year-old w o m a n was admitted to the hospital in April 1989 because she had had fever for 2 weeks. She had felt u n w e l l for 2 months and had been pale. On examination at admission she was pale; her liver and spleen were palpable; she had
Chromosome 13 Involvement in MDS
15 1
- - P12-13 -iq11 "~~i" •
~-
-,p12
' ! q12-13 - ;qter
' "qter
- - ' q ter
,- - q t e r
13 Figure 2
6
13
Segments of chromosomes 1, 6, and 13 participating in t(1;13) and t(6;13).
no peripheral l y m p h a d e n o p a t h y . The hematocrit was 25%, the WBC count was 1,500/ /zl with 25% blast cells. The platelet count was 450,000//x1. A bone marrow aspirate was performed, and a diagnosis of MDS (RAEBT) was made. Of interest was the increased n u m b e r of megakaryocytes with dysplastic morphology. The patient received blood transfusions and a 5-day course of c h e m o t h e r a p y with aracytine and daunorubicin. She did not r e s p o n d to c h e m o t h e r a p y and died 1 month later of septicemia.
Cytogenetic findings. T w e n t y metaphases were studied by direct culture of bone marrow aspirate and a G-banding technique. All metaphases had 46 c h r o m o s o m e s and an interstitial deletion of 5q, del(5)(q15-21q31-32), and a translocation between c h r o m o s o m e s 1 and 13, der(1)t(1;13)(1qter--*1p12-13::13q12-13--*13qter) (Figs. 2 and 3). One c h r o m o s o m e 13 was lost, and two normal c h r o m o s o m e s 1 were present.
Figure 3
Partial karyotypes showing t(1;13) (case 2).
!;
t(1;13)
13
5
5q-
152
A . D . Panani et al.
DISCUSSION Cytogenetic studies show that in MDS the ch r o m o so m es most c o m m o n l y i n v o l v e d are 5, 7, 8, 11-13, and 20. The n u m b e r and type of ch r o m o so m al abnormalities are considered of prognostic significance. A m o n g the ch r o m o so m al changes, deletion of the long arm of c h r o m o s o m e 13 has been reported in some cases [1-7]. We describe two cases of MDS with i n v o l v e m e n t of c h r o m o s o m e 13. The first patient had breast cancer and had received only tamoxifen. She d ev el o p ed an MDS, a second malignant disease, and died 17 months later. In all metaphases studied, a t(6;13)(q11;p12) was found; in some, trisomy 8 was also observed. The karyotype remained stable w h e n the RAEB type of MDS progressed to RAEBT. Gain of chromosome 8 is one of the most c o m m o n numerical changes in MDS, whereas a t(6;13) seldom has been described in hematologic disorders of myeloid type [8]. The second patient had a RAEBT type of MDS with a very poor clinical course. All metaphases studied had 46 c h r o m o s o m e s with a t(l:13)(p12-13;q12-13) and a deletion of 5q. Rarely has t(1;13) been reported in MDS [8], whereas deletion of 5q is one of the most c o m m o n ch ro m o s o m a l findings in MDS. Chromosomal changes are considered significant in neoplastic transformation; among them, deletions have been correlated to loss of oncogene suppressor genes. Deletion of band 13q14 has been detected in hematologic malignancies [2, 7] and has also been described as a primary karyotypic change in preleukemia and leukemia [9]. This band 13q14 is k n o w n to be of considerable importance in cancer genetics because it contains a gene for retinoblastoma. In both our patients band 13q14 did not participate in the deleted segments. The authors gratefully acknowledge the technical assistance of France Kousouri-Stamatelli.
REFERENCES 1. Helm S, Mitelman F (1987)'. Cancer Cytogenetics. Alan R. Liss, New York, pp. 111-128. 2. Third MIC Cooperative Study Group, 1987 {1988): Recommendation for a morphologic, immunologic, and cytogenetic (MIC) working classification of the primary and therapyrelated myelodysplastic disorders. Cancer Genet Cytogenet 32:1-10. 3. Suciu S, Kuse R, Web HI, Hossfeld DK (1990): Results of chromosome studies and their relation to morphology, course, and prognosis in 120 patients with de novo myelodysplastic syndrome. Cancer Genet Cytogenet 44:] 5-26. 4. Jacobs RH, Cornbleet MA, Vardiman JW, Larson RA, Le Beau MM. Rowley ID (1986): Prognostic implications of morphology and karyotype in primary myelodysplastic syndromes. Blood 67:1765-1772. 5. Borgstr6m GH (1986): Cytogem-ti~ s of tim myelodysplastic syndromes. Stand J Haematol 36 (suppl 45):74-77. 6. Horiike S, Taniwaki M, Misawa S. Abe T (1988): Chromosome abnormalities and karyotypic evolution in 83 patients with myelodysplastic syndrome and predictive value for prognosis. Cancer 62:1129-1138. 7. Johnson DD, Dewald GW, Pierre RV, Letendre L, Silverstein MN (1985): Deletions of chromosome 13 in malignant hematologic disorders. Cancer Genet Cytogenet 18:235 241. 8. Mitehnan F (1988): Catalog of Chromosome Aberrations in Cancer, 3rd Ed. Alan R. Liss, New York. 9. Morgan R, Hecht F (1985): Deletion of chromosome band 13q14: A primary event in preleukemia and leukemia. Cancer Genet Cytogenet 18:243-249.
ABSTRACT: We report 2 of 80 cases of myelodysplastic syndromes (MDS) cytogenetically studied, with involvement of chromosome 13. The first case had a t(6;13), and the second had a t(1;13). Abnormalities of chromosome 13 mainly involving loss of band 13q14 have been described in hematologic malignancies. In both our cases band 13q14 did not participate in the deleted segment.
INTRODUCTION
Chromosomal abnormalities are e v i d e n t in one third to one half of all cytogenetically studied cases with myelodysplastic syndromes (MDS). Certain c h r o m o s o m e s are i n v o l v e d n o n r a n d o m l y , and the c h r o m o s o m a l changes are important in evaluating the patient's clinical course [1]. A m o n g c h r o m o s o m a l changes observed in MDS, a deletion of 13q, mainly i n v o l v i n g loss of band 13q14, has been described [2]. In 2 of 80 cases of MDS studied cytogenetically, we found two cases with c h r o m o s o m e 13 abnormalities. In both cases, c h r o m o s o m e 13 participated in translocations with c h r o m o s o m e s 6 and 1, respectively.
CASE REPORTS
Case 1
A 76-year-old w o m a n was first admitted to the hospital in December 1986 because of a lobular infiltrative carcinoma of the left breast; a mastectomy was performed. She was started on treatment with tamoxifen until September 1987, w h e n bleeding manifestations from the skin were noted for the first time. At that time, the hematocrit was 34%, the white blood cell (WBC) count 3,700/txl with 23% neutrophils, 73% lymphocytes, 2% monocytes, 1% eosinophils, and 1% myelocytes. The platelet count was normal. She c o n ti n u e d treatment with tamoxifen until January 1988. A bone marrow aspirate was then performed and the diagnosis of MDS refractory anemia with excess blasts (RAEB) was made. The patient received transfusions and was followed for 1 year. In February 1989, a second bone marrow aspirate was performed,
From the Second Department of Internal Medicine Propaedeutic of Athens University, Evangelismos Hospital, Athens, Greece. Address reprint requests to: A n n a D. Panani, M.D., Second Department of Internal Medicine. Propaedeutic of Athens University, Evangelismos Hospital, Athens 106 76, Greece. Received June 28, 1990; accepted September 6, 1990.
149 :© 1991 Elsevier Science Publishing Co., Inc. 655 Avenue of the Americas, New York, NY 10010
Cancer Genet Cytogenet 55:149 152 (19911 0165-4608,'91/$03.50
150
A.D. Panani et al.
a
b
Figure I Partialkaryotypes showing t(6;13) (case 1). C
d
i 6
t(6;13)
13
and a diagnosis of RAEB in transformation (RAEBT) MDS was made. The patient was started on treatment with cytocine arabinoside subcutaneously with no response. In May 1989, the patient became seriously ill; she died of cerebral hemorrhage 1 m o n t h later.
Cytogenetic findings. The first cytogenetic study was performed in January 1988 on a bone marrow aspirate using direct culture and a G-banding technique. Thirty-four metaphases were studied: 27 had 46 chromosomes with a translocation between chromosomes 6 and 13, t(6;13)(q11;p12) {Figs. 1 and 2). The remaining metaphases had 47 chromosomes with the same t(6;13) and an extra chromosome 8. Peripheral blood lymphocyte (PBL) culture stimulated with phytohemagglutinin (PHA) showed a normal karyotype. A second cytogenetic study was performed on bone marrow aspirate in February 1989, when a diagnosis of RAEBT was made. Ten metaphases were studied, and the chromosomal findings were the same as in the first study. Case 2
A 67-year-old w o m a n was admitted to the hospital in April 1989 because she had had fever for 2 weeks. She had felt u n w e l l for 2 months and had been pale. On examination at admission she was pale; her liver and spleen were palpable; she had
Chromosome 13 Involvement in MDS
15 1
- - P12-13 -iq11 "~~i" •
~-
-,p12
' ! q12-13 - ;qter
' "qter
- - ' q ter
,- - q t e r
13 Figure 2
6
13
Segments of chromosomes 1, 6, and 13 participating in t(1;13) and t(6;13).
no peripheral l y m p h a d e n o p a t h y . The hematocrit was 25%, the WBC count was 1,500/ /zl with 25% blast cells. The platelet count was 450,000//x1. A bone marrow aspirate was performed, and a diagnosis of MDS (RAEBT) was made. Of interest was the increased n u m b e r of megakaryocytes with dysplastic morphology. The patient received blood transfusions and a 5-day course of c h e m o t h e r a p y with aracytine and daunorubicin. She did not r e s p o n d to c h e m o t h e r a p y and died 1 month later of septicemia.
Cytogenetic findings. T w e n t y metaphases were studied by direct culture of bone marrow aspirate and a G-banding technique. All metaphases had 46 c h r o m o s o m e s and an interstitial deletion of 5q, del(5)(q15-21q31-32), and a translocation between c h r o m o s o m e s 1 and 13, der(1)t(1;13)(1qter--*1p12-13::13q12-13--*13qter) (Figs. 2 and 3). One c h r o m o s o m e 13 was lost, and two normal c h r o m o s o m e s 1 were present.
Figure 3
Partial karyotypes showing t(1;13) (case 2).
!;
t(1;13)
13
5
5q-
152
A . D . Panani et al.
DISCUSSION Cytogenetic studies show that in MDS the ch r o m o so m es most c o m m o n l y i n v o l v e d are 5, 7, 8, 11-13, and 20. The n u m b e r and type of ch r o m o so m al abnormalities are considered of prognostic significance. A m o n g the ch r o m o so m al changes, deletion of the long arm of c h r o m o s o m e 13 has been reported in some cases [1-7]. We describe two cases of MDS with i n v o l v e m e n t of c h r o m o s o m e 13. The first patient had breast cancer and had received only tamoxifen. She d ev el o p ed an MDS, a second malignant disease, and died 17 months later. In all metaphases studied, a t(6;13)(q11;p12) was found; in some, trisomy 8 was also observed. The karyotype remained stable w h e n the RAEB type of MDS progressed to RAEBT. Gain of chromosome 8 is one of the most c o m m o n numerical changes in MDS, whereas a t(6;13) seldom has been described in hematologic disorders of myeloid type [8]. The second patient had a RAEBT type of MDS with a very poor clinical course. All metaphases studied had 46 c h r o m o s o m e s with a t(l:13)(p12-13;q12-13) and a deletion of 5q. Rarely has t(1;13) been reported in MDS [8], whereas deletion of 5q is one of the most c o m m o n ch ro m o s o m a l findings in MDS. Chromosomal changes are considered significant in neoplastic transformation; among them, deletions have been correlated to loss of oncogene suppressor genes. Deletion of band 13q14 has been detected in hematologic malignancies [2, 7] and has also been described as a primary karyotypic change in preleukemia and leukemia [9]. This band 13q14 is k n o w n to be of considerable importance in cancer genetics because it contains a gene for retinoblastoma. In both our patients band 13q14 did not participate in the deleted segments. The authors gratefully acknowledge the technical assistance of France Kousouri-Stamatelli.
REFERENCES 1. Helm S, Mitelman F (1987)'. Cancer Cytogenetics. Alan R. Liss, New York, pp. 111-128. 2. Third MIC Cooperative Study Group, 1987 {1988): Recommendation for a morphologic, immunologic, and cytogenetic (MIC) working classification of the primary and therapyrelated myelodysplastic disorders. Cancer Genet Cytogenet 32:1-10. 3. Suciu S, Kuse R, Web HI, Hossfeld DK (1990): Results of chromosome studies and their relation to morphology, course, and prognosis in 120 patients with de novo myelodysplastic syndrome. Cancer Genet Cytogenet 44:] 5-26. 4. Jacobs RH, Cornbleet MA, Vardiman JW, Larson RA, Le Beau MM. Rowley ID (1986): Prognostic implications of morphology and karyotype in primary myelodysplastic syndromes. Blood 67:1765-1772. 5. Borgstr6m GH (1986): Cytogem-ti~ s of tim myelodysplastic syndromes. Stand J Haematol 36 (suppl 45):74-77. 6. Horiike S, Taniwaki M, Misawa S. Abe T (1988): Chromosome abnormalities and karyotypic evolution in 83 patients with myelodysplastic syndrome and predictive value for prognosis. Cancer 62:1129-1138. 7. Johnson DD, Dewald GW, Pierre RV, Letendre L, Silverstein MN (1985): Deletions of chromosome 13 in malignant hematologic disorders. Cancer Genet Cytogenet 18:235 241. 8. Mitehnan F (1988): Catalog of Chromosome Aberrations in Cancer, 3rd Ed. Alan R. Liss, New York. 9. Morgan R, Hecht F (1985): Deletion of chromosome band 13q14: A primary event in preleukemia and leukemia. Cancer Genet Cytogenet 18:243-249.