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Rearrangements involving 12p12 in two cases of cardiac myxoma
ELSEVIER
Rearrangements Involving 12p12 in Two Cases of Cardiac Myxoma Trijnie Dijkhuizen, Eva van den Berg, Willemina M. Molenaar, Jacobus J. Meuzelaar, and Bauke de Jong
ABSTRACT: Recently, we reported on the cytogenetic analysis of a case of cardiac m y x o m a , revealing a 46,XY, der(7)t(7;17)(p21;p11), add (10) (q22), add (12) (p12), del(17)(p11) chromosomal pattern. In this article we p r e s e n t the cytogenetic analysis of a n o t h e r case of cardiac myxoma, in which we found several clonal and nonclonal abnormalities including dicentric c h r o m o s o m e s and telomeric associations (tas). One of the clonal aberrations was a translocation between chromosomes I and 12, involving a b r e a k p o i n t at 12p12, as observed in the case described earlier. This finding suggest that 12p12 might play an important role in the histogenesis of cardiac myxomas.
INTRODUCTION
CASE HISTORY
Cardiac myxoma is the most frequent p r i m a r y t u m o r of the heart [1, 2]. It arises from the e n d o c a r d i u m as a p o l y p o i d , often p e d u n c u l a t e d t u m o r mass, extending into a cardiac chamber. In most of the cases the left atrium is involved. Cardiac myxomas are derived from mesenchymal cells of the subendocardial layer and imitate primitive mesenchyme. Surgical removal of the t u m o r is usual curative, although sometimes the n e o p l a s m recurs months to years later. There is limited data on cytogenetics of cardiac myxoma. Thus far, 10 cases have b e e n p u b l i s h e d [3-5]. Cytogenetic analysis revealed a 46,XY, der(7)t(7;17)(p21;pal),add(10)(q22), add(12)(p12),del(17)(p11) chromosomal pattern in one case [3], clonal loss of the Y-chromosome in two cases [4], and a clonal tas(13;15) in one case [5]. Nonclonal aberrations, m a i n l y dicentrics and tas, were also frequently observed. In two cases the short arm of c h r o m o s o m e 12 was involved in different translocations and tas [4, 5]. In this article we describe the chromosomal pattern of another case of cardiac myxoma, revealing clonal structural rearrangements, one of them involving breakpoint 12p12. A clonal a b n o r m a l i t y involving the same b r e a k p o i n t was also found in our first case of cardiac myxoma p u b l i s h e d in 1992 [3].
The patient was a 74-year-old male, d i a g n o s e d as having cardiac myxoma in the left atrium. The t u m o r was excised and the resected s p e c i m e n consisted of soft, myxoid tissue fragments, of w h i c h the largest m e a s u r e d 4 x 2 x 1.5 cm. Microscopic e x a m i n a t i o n revealed a proliferation of fibroblasts a n d small vessels in a myxoid stroma.
From the Departments of Medical Genetics (T. D., E. v. d. B., B. d. J.), and Pathology (W. M. M.), of the University of Groningen and the Department of Cardiothoracic Surgery (J. J. M.), University Hospital of Groningen, The Netherlands. Address reprint requests to: T. Dijkhuizen, Department of Medical Genetics, University of Groningen, Antonius Deusinglaan 4, 9713 AW Groningen, The Netherlands. Received September Z 1994; accepted November 16, 1994. Cancer Genet Cytogenet 8 2 : 1 6 1 - 1 6 2 (1995) © Elsevier Science Inc., 1995 655 A v e n u e of the Americas, N e w York, NY 10010
RESULTS A N D DISCUSSION
It has long been questioned w h e t h e r cardiac myxomas are hamartomatous or organized t h m m b i , or benign n e o p l a s i a [2]. However, cytogenetic analysis of these n e o p l a s m s have revealed clonal c h r o m o s o m e changes, supporting the contention that cardiac myxomas are indeed benign tumors. Thus far no specific rearrangements are associated with these neoplasms, but there is limited data available. We describe the cytogenetic analysis of another case of cardiac myxoma. Twenty-three GTG-banded metaphases were analyzed. Ten cells were (near) diploid, whereas 11 had chromosome counts in the tetraploid range (74-92 chromosomes, m o d e 88). The remaining cells had 138 and 131 chromosomes, respectively. The DNA profile showed a d i p l o i d and a tetraploid peak in agreement w i t h the cytogenetic findings. All cells e x a m i n e d revealed a b a l a n c e d translocation involving c h r o m o s o m e s 1 a n d 12 (t[1;12][p31;p12]). Since no peripheral b l o o d l y m p h o c y t e s were available, the possibility that this translocation is constitutional could not be excluded. Other clonal abnormalities were t(4;9)(q35;q12), dic(13;21)(p12;p11), idic(21)(p12), and loss of the Y chromosome in four, two, four, and seven cells, respectively. In the tetraploid cells these abnormalities were found twice except for the idic(21)(p12) w h i c h was o n l y found once in d i p l o i d as well as in tetraploid cells. A karyotype of one of the
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F i g u r e 1 A karyotype of one of the analyzed cardiac myxoma cells with a 92,XXYY, t(1;12)(p31;p12)x2, t(4;9)(q35;q12)tas(4;21)(p16;p13) x 2 chromosomal pattern.
m e t a p h a s e s of t h e t u m o r is g i v e n in F i g u r e 1. F u r t h e r m o r e t h e t u m o r cells r e v e a l e d several n o n c l o n a l structural abnormalities, n a m e l y tas a n d d i c e n t r i c c h r o m o s o m e s . C h r o m o s o m e s m o s t f r e q u e n t l y i n v o l v e d w e r e 19 (qter), 20, and 21. Tas are also c o m m o n l y o b s e r v e d in m a l i g n a n t fibrous h i s t i o c y t o m a s [6] a n d g i a n t cell t u m o r s [7, 8], a n d rarely r e p o r t e d in o t h e r n e o p l a s t i c [9-11], a n d n o n - n e o p l a s t i c [12] c o n d i t i o n s . T h e o n c o g e n e t i c role of tas in cardiac m y x o m a s is not clear, b u t it is c o n c e i v a b l e that t h e y m a y facilitate the e m e r g e n c e of stable c h r o m o s o m a l a b n o r m a l i t i e s [9, 13]. T h e i n v o l v e m e n t of 12p12 in c l o n a l structural a b n o r m a l i ties in two u n r e l a t e d cases of cardiac m y x o m a ([3] and the p r e s e n t case) and the f i n d i n g of 12p aberrations in t h e s e neop l a s m s by others [4, 5], suggests that g e n e s h a r b o r e d in that c h r o m o s o m a l r e g i o n may play a role in the d e v e l o p m e n t of t h e s e tumors. REFERENCES 1. McAllister HA, Fenoglio JJ (1978) : Tumors of the cardiovascular system. In: Atlas of tumor pathology, 2nd Ed., Hartmann WH, Cowan WR, (eds.). Armed Forces Institute of Pathology, Washington D.C., pp. 5-20. 2. Cotran RS, Kumar V, Robbins SL (1989): The Heart. In: Pathologic basis of disease, 4th Ed., WB Saunders, ed. W.B. Saunders Company, Philadelphia, pp. 652-653. 3. Dijkhuizen T, Van Den Berg E, Molenaar WM, Meuzelaar JJ, De long B (1992): Cytogenetics of a case of cardiac myxoma. Cancer Genet Cytogenet 63:73-75.
4. Dewald GW, Dahl RJ, Spurbeck BS, Carney JA, Gordon H (1987): Chromosomally abnormal clones and nonrandom telomeric translocations in cardiac myxomas. Mayo Clin Proc 62:558-567. 5. Richkind KE, Wason D, Vidaillet HJ (1994): Cardiac myxoma characterized by clonal telomeric associations. Genes Chrom Cancer 9:68-71. 6. Mandahl N, Heim S, Arheden K, Rydholm A, Will6n H, Mitelman F (1988): Rings, dicentrics, and telomeric associations in histiocytomas. Cancer Genet Cytogenet 30:23-33. 7. Bridge JA, Neff JR, Bhatia PS, Sanger WG, Murphey MD (1990): Cytogenetic findings and biologic behavior of giant cell tumors of bone. Cancer 65:2697-2703. 8. Molenaar WM, Van Den Berg E, Veth RPH, Dijkhuizen T, De Vries EGE (1994): Tumor progression in a giant cell type malignant fibrous histiocytoma of bone: Clinical, radiologic, histologic, and cytogenetic evidence. Genes Chrom Cancer 10:66-70. 9. Holzmann K, Blin N, Welter C, Zang KD, Seitz G, Helm W (1993): Telomeric associations and loss of telomeric DNA repeats in renal tumors. Genes Chrom Cancer 6:178-181. 10. Sandberg AA (1990): Some facets of the cell cycle and unique aspects of chromosome structure. In: The Chromosomes in Human Cancer and Leukemia, 2nd Ed., Sandberg AA (ed.). Elsevier Science Publishing Co., New York, pp 68-99. 11. Seruca R, Carneiro F, Soares P, Fonseca E, Castedo SMMJ (1992): Clonal cytogenetic abnormalities and telomeric associations in a fibroxanthoma of the stomach. Genes Chrom Cancer 5:407-409. 12. Fitzgerald PH, Morris CM (1984): Telomeric association of chromosomes in B-cell lymphoid leukemia. Hum Genet 67:385-390. 13. Haste ND, Allshire RC (1989): Human telomeres: fusion and interstitial sites. TIG 5:326-331.
Rearrangements Involving 12p12 in Two Cases of Cardiac Myxoma Trijnie Dijkhuizen, Eva van den Berg, Willemina M. Molenaar, Jacobus J. Meuzelaar, and Bauke de Jong
ABSTRACT: Recently, we reported on the cytogenetic analysis of a case of cardiac m y x o m a , revealing a 46,XY, der(7)t(7;17)(p21;p11), add (10) (q22), add (12) (p12), del(17)(p11) chromosomal pattern. In this article we p r e s e n t the cytogenetic analysis of a n o t h e r case of cardiac myxoma, in which we found several clonal and nonclonal abnormalities including dicentric c h r o m o s o m e s and telomeric associations (tas). One of the clonal aberrations was a translocation between chromosomes I and 12, involving a b r e a k p o i n t at 12p12, as observed in the case described earlier. This finding suggest that 12p12 might play an important role in the histogenesis of cardiac myxomas.
INTRODUCTION
CASE HISTORY
Cardiac myxoma is the most frequent p r i m a r y t u m o r of the heart [1, 2]. It arises from the e n d o c a r d i u m as a p o l y p o i d , often p e d u n c u l a t e d t u m o r mass, extending into a cardiac chamber. In most of the cases the left atrium is involved. Cardiac myxomas are derived from mesenchymal cells of the subendocardial layer and imitate primitive mesenchyme. Surgical removal of the t u m o r is usual curative, although sometimes the n e o p l a s m recurs months to years later. There is limited data on cytogenetics of cardiac myxoma. Thus far, 10 cases have b e e n p u b l i s h e d [3-5]. Cytogenetic analysis revealed a 46,XY, der(7)t(7;17)(p21;pal),add(10)(q22), add(12)(p12),del(17)(p11) chromosomal pattern in one case [3], clonal loss of the Y-chromosome in two cases [4], and a clonal tas(13;15) in one case [5]. Nonclonal aberrations, m a i n l y dicentrics and tas, were also frequently observed. In two cases the short arm of c h r o m o s o m e 12 was involved in different translocations and tas [4, 5]. In this article we describe the chromosomal pattern of another case of cardiac myxoma, revealing clonal structural rearrangements, one of them involving breakpoint 12p12. A clonal a b n o r m a l i t y involving the same b r e a k p o i n t was also found in our first case of cardiac myxoma p u b l i s h e d in 1992 [3].
The patient was a 74-year-old male, d i a g n o s e d as having cardiac myxoma in the left atrium. The t u m o r was excised and the resected s p e c i m e n consisted of soft, myxoid tissue fragments, of w h i c h the largest m e a s u r e d 4 x 2 x 1.5 cm. Microscopic e x a m i n a t i o n revealed a proliferation of fibroblasts a n d small vessels in a myxoid stroma.
From the Departments of Medical Genetics (T. D., E. v. d. B., B. d. J.), and Pathology (W. M. M.), of the University of Groningen and the Department of Cardiothoracic Surgery (J. J. M.), University Hospital of Groningen, The Netherlands. Address reprint requests to: T. Dijkhuizen, Department of Medical Genetics, University of Groningen, Antonius Deusinglaan 4, 9713 AW Groningen, The Netherlands. Received September Z 1994; accepted November 16, 1994. Cancer Genet Cytogenet 8 2 : 1 6 1 - 1 6 2 (1995) © Elsevier Science Inc., 1995 655 A v e n u e of the Americas, N e w York, NY 10010
RESULTS A N D DISCUSSION
It has long been questioned w h e t h e r cardiac myxomas are hamartomatous or organized t h m m b i , or benign n e o p l a s i a [2]. However, cytogenetic analysis of these n e o p l a s m s have revealed clonal c h r o m o s o m e changes, supporting the contention that cardiac myxomas are indeed benign tumors. Thus far no specific rearrangements are associated with these neoplasms, but there is limited data available. We describe the cytogenetic analysis of another case of cardiac myxoma. Twenty-three GTG-banded metaphases were analyzed. Ten cells were (near) diploid, whereas 11 had chromosome counts in the tetraploid range (74-92 chromosomes, m o d e 88). The remaining cells had 138 and 131 chromosomes, respectively. The DNA profile showed a d i p l o i d and a tetraploid peak in agreement w i t h the cytogenetic findings. All cells e x a m i n e d revealed a b a l a n c e d translocation involving c h r o m o s o m e s 1 a n d 12 (t[1;12][p31;p12]). Since no peripheral b l o o d l y m p h o c y t e s were available, the possibility that this translocation is constitutional could not be excluded. Other clonal abnormalities were t(4;9)(q35;q12), dic(13;21)(p12;p11), idic(21)(p12), and loss of the Y chromosome in four, two, four, and seven cells, respectively. In the tetraploid cells these abnormalities were found twice except for the idic(21)(p12) w h i c h was o n l y found once in d i p l o i d as well as in tetraploid cells. A karyotype of one of the
0165-4608/95/$9.50 SSDI 0165-4608(94)00268-G
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F i g u r e 1 A karyotype of one of the analyzed cardiac myxoma cells with a 92,XXYY, t(1;12)(p31;p12)x2, t(4;9)(q35;q12)tas(4;21)(p16;p13) x 2 chromosomal pattern.
m e t a p h a s e s of t h e t u m o r is g i v e n in F i g u r e 1. F u r t h e r m o r e t h e t u m o r cells r e v e a l e d several n o n c l o n a l structural abnormalities, n a m e l y tas a n d d i c e n t r i c c h r o m o s o m e s . C h r o m o s o m e s m o s t f r e q u e n t l y i n v o l v e d w e r e 19 (qter), 20, and 21. Tas are also c o m m o n l y o b s e r v e d in m a l i g n a n t fibrous h i s t i o c y t o m a s [6] a n d g i a n t cell t u m o r s [7, 8], a n d rarely r e p o r t e d in o t h e r n e o p l a s t i c [9-11], a n d n o n - n e o p l a s t i c [12] c o n d i t i o n s . T h e o n c o g e n e t i c role of tas in cardiac m y x o m a s is not clear, b u t it is c o n c e i v a b l e that t h e y m a y facilitate the e m e r g e n c e of stable c h r o m o s o m a l a b n o r m a l i t i e s [9, 13]. T h e i n v o l v e m e n t of 12p12 in c l o n a l structural a b n o r m a l i ties in two u n r e l a t e d cases of cardiac m y x o m a ([3] and the p r e s e n t case) and the f i n d i n g of 12p aberrations in t h e s e neop l a s m s by others [4, 5], suggests that g e n e s h a r b o r e d in that c h r o m o s o m a l r e g i o n may play a role in the d e v e l o p m e n t of t h e s e tumors. REFERENCES 1. McAllister HA, Fenoglio JJ (1978) : Tumors of the cardiovascular system. In: Atlas of tumor pathology, 2nd Ed., Hartmann WH, Cowan WR, (eds.). Armed Forces Institute of Pathology, Washington D.C., pp. 5-20. 2. Cotran RS, Kumar V, Robbins SL (1989): The Heart. In: Pathologic basis of disease, 4th Ed., WB Saunders, ed. W.B. Saunders Company, Philadelphia, pp. 652-653. 3. Dijkhuizen T, Van Den Berg E, Molenaar WM, Meuzelaar JJ, De long B (1992): Cytogenetics of a case of cardiac myxoma. Cancer Genet Cytogenet 63:73-75.
4. Dewald GW, Dahl RJ, Spurbeck BS, Carney JA, Gordon H (1987): Chromosomally abnormal clones and nonrandom telomeric translocations in cardiac myxomas. Mayo Clin Proc 62:558-567. 5. Richkind KE, Wason D, Vidaillet HJ (1994): Cardiac myxoma characterized by clonal telomeric associations. Genes Chrom Cancer 9:68-71. 6. Mandahl N, Heim S, Arheden K, Rydholm A, Will6n H, Mitelman F (1988): Rings, dicentrics, and telomeric associations in histiocytomas. Cancer Genet Cytogenet 30:23-33. 7. Bridge JA, Neff JR, Bhatia PS, Sanger WG, Murphey MD (1990): Cytogenetic findings and biologic behavior of giant cell tumors of bone. Cancer 65:2697-2703. 8. Molenaar WM, Van Den Berg E, Veth RPH, Dijkhuizen T, De Vries EGE (1994): Tumor progression in a giant cell type malignant fibrous histiocytoma of bone: Clinical, radiologic, histologic, and cytogenetic evidence. Genes Chrom Cancer 10:66-70. 9. Holzmann K, Blin N, Welter C, Zang KD, Seitz G, Helm W (1993): Telomeric associations and loss of telomeric DNA repeats in renal tumors. Genes Chrom Cancer 6:178-181. 10. Sandberg AA (1990): Some facets of the cell cycle and unique aspects of chromosome structure. In: The Chromosomes in Human Cancer and Leukemia, 2nd Ed., Sandberg AA (ed.). Elsevier Science Publishing Co., New York, pp 68-99. 11. Seruca R, Carneiro F, Soares P, Fonseca E, Castedo SMMJ (1992): Clonal cytogenetic abnormalities and telomeric associations in a fibroxanthoma of the stomach. Genes Chrom Cancer 5:407-409. 12. Fitzgerald PH, Morris CM (1984): Telomeric association of chromosomes in B-cell lymphoid leukemia. Hum Genet 67:385-390. 13. Haste ND, Allshire RC (1989): Human telomeres: fusion and interstitial sites. TIG 5:326-331.