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Cytogenetic findings in a pleomorphic xanthoastrocytoma
Cytogenetic Findings in a Pleomorphic Xanthoastrocytoma Jeffrey R. Sawyer, Gary J. Roloson, William M. Chadduck, and Frederick A. Boop
ABSTRACT: We report a pleomarphic xanthoastrocytoma with an abnormal clonal cell line of 48,XY, + 3, + 5, - 2 0 , - 22, + der(7)t(7;?)(p22;?), + der(20)t(15;20)(ql 1 ;q13).
INTRODUCTION Pleomorphic xanthoastrocytomas are low-grade gliomas usually found in young patients, most c o m m o n l y during the second decade of life. They are superficially located and are typically primary in the temporal lobe, but also occur in the frontal and parietal lobe. The p l e o m o r p h i s m of the astrocytes includes b u n d l e s of fusiform cells, large gemistocytic-like astrocytes with eccentric nuclei, and multinucleate giant cells, with variable atypia and hyperchromatism. Xanthomatous change w i t h i n these same cells can range from scant to a b u n d a n t [1]. In spite of the o m i n o u s histologic appearance of xanthoastrocytomas, they are reported to generally have a favorable postoperative course [2]. However, this tumor has been described to have the potential for malignant transformation [3]. Cytogenetic reports of low-grade astrocytomas are not well defined, as m a n y early studies did not utilize G-banding, or did not provide information on histologic subtypes. In this report, we present the results from a pleomorphic xanthoastrocytoma grown in short-term cultures with a karyotype of 48,XY, + 3, + 5 , - 20, - 22, + der(7)t(7;?) (p2 2;?), + der(20)t(15;20)(q11 ;ql 3).
Case Report C. D. (ACH #942727), a 15-year-old boy, had a 4-month history of episodic aphasia followed by severe headaches. One week prior to admission he had a generalized tonic-clonic seizure initiated with focal twitching of the right side of the face and the right arm. Computerized tomographic s c a n n i n g of the brain (Fig. 1) showed a cystic tumor in the left frontal suprasylvian region. At surgery the cystic portion of the tumor contained straw-colored fluid; the nodule was firm and very vascular. Gross total resection of the tumor was accomplished, and there was no residual tumor on postoperative CT scanning. The patient remained without neurologic deficit, but had From the Departmentsof Pathology (J. R. S., G. J. R.) and Neurosurgery(W. M. C.. IC A. B.). Universityof Arkansas for Medical Sciences, Little Rock. Arkansas. Address reprint requests to: Jeffrey R. Sawyer, Ph.D., Cytogenetics Laboratory, Arkansas Children's Hospital, 800 Marshall Street, Little Rock, AR 72202. Received December 10, 1990; accepted January 31, 1991.
225 © 1991 Elsevier SciencePublishingCo.. Inc. 655 Avenueof the Americas.New York. NY 10010
Cancer Genet Cytogenet55:225-230 (1991) 0165-4608/91/$03.50
226
J.R. Sawyer et al.
Figure 1 Axial section of the contrast-enhanced CT scan of the patient, shows the cystic lesion in the left fronto-temporal region with enhancement of the nodular portion of the tumor, laterally. Considerable vasogenic edema is present medially. occasional breakthrough of c o m p l e x partial seizures, requiring c o n t i n u e d use of anticonvulsants. Pathology received m u l t i p l e (0.2-0.8 cm) pieces of moderately firm tissue which was pale yellow and tan. The histology was that of a p l e o m o r p h i c xanthoastrocytoma. The p r e d o m i n a n t pattern was a fusiform cell in a partially storiform (fibrous histocytoma-like) pattern. Cellular atypia was present, and enlarged, hyperchromatic, and occasionally multinucleate giant cells were seen (Fig. 2). Occasional i n d i v i d u a l and scattered clusters of cells had m i n i m a l xanthomatous change. L y m p h o c y t e s were
Chromosomal Findings in a Xanthoastrocytoma
227
Figure 2
Pleomorphic xanthoastrocytoma. The tumor was cellular with predominantly fusiform cells, focal storiform pattern, scattered lymphocytes, and both individual and clustered cells with minimal xanthomatous change. Cellular typia and occasional enlarged, hyperchromatic, and multinucleate giant cells are present. (H&E, x 235). present perivascularly, and i n d i v i d u a l l y throughout the tumor. Microscopically, a discrete interface with the pial surface was evident in several sections. A reticulin stain had a b u n d a n t reticulin around most i n d i v i d u a l cells. Mitoses were rare, and necrosis was not identified.
MATERIALS AND METHODS Fresh tumor was transported to the laboratory in tissue culture m e d i u m and treated in the following manner. The tumor biopsy specimen was immediately minced and enzymatically treated with a solution of collagenase (0.125 mg/ml) for 2 hours. The biopsy was then washed with u n s u p p l e m e n t e d RPMI-1640 m e d i u m and was set up in Chang M e d i u m s u p p l e m e n t e d with 2% glutamine/pen-strep solution on Lab-Tech 2 chamber slides (Miles Laboratories) for in-situ culture and harvest. Cells were harvested in 5 - 1 4 days (when mitotic cells were considered adequate for analysis) by adding 10/xl of colcemid (2 mg/ml) to each chamber for 2 hours. The slides were harvested using standard in-situ techniques.
Cytogenetic Findings Twenty i n d e p e n d e n t colonies were studied for chromosome aberrations. Five colonies from 3 different culture chambers showed a karyotype of 48,XY,+3, + 5 , - 20, - 22, + der(7)t(7;?)(p22;?), + der(20)t(15;20)(q11;q13) (Figs. 3 and 4) and 15 colonies showed a normal karyotype of 46,XY.
228
J.R. Sawyer et al.
o
il
1
2
4
5
mN
mm
10
11
12
16
17
18
21
22
XY
3
¢ w; i-i; ;° 6
7
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i,
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X~_
19 20
Figure 3 Representative G-banded karyotype showing 48,XY,+ 3, + 5 , - 20, 22, + der(7)t[7:?)(p22;?), + der(20)t(15:20)(ql I ;q13). (Arrows indicate chromosome breakpoJnts). DISCUSSION The majority of low-grade astrocytomas reported contain a normal stem line and small abnormal clones as sidelines [4]. The chromosome findings in most cases indicate numerical aberrations predominate in low-grade astrocytomas, rather than structural rearrangements. Polysomy 7, m o n o s o m y 10 and 22, and loss of a sex chromosome are the most characteristic findings in low-grade gliomas [5, 6]. Interestingly, the same numerical aberrations found in low-grade astrocytomas have also been found in highgrade astrocytomas [7-9]. The numerical chromosome aberrations found in the present case include trisomies for chromosomes 3, 5, 7, and 15, and m o n o s o m y for chromosome 22. Trisomy 7 and m o n o s o m y 22 are the only numerical aberrations seen in this case that have frequently
229
Chromosomal Findings in a Xanthoastrocytoma
t 3
5
7
20
3
5
7
20
Figure 4 Partial karyotypes of two ceils showing the consistent numerical and structural aberrations. (Arrows indicate chromosome breakpoints). been reported in gliomas (4-6; 9-13). Recently, however, some question as to the association between malignancy and trisomy 7 has been raised. Heim et al. [14] have shown in a limited study that trisomy 7 can occur in short-term cultures of nonneoplastic brain tissue. Presumably this p h e n o m e n o n may be generated in vitro or is present in vivo as normal organ mosaicism. Trisomies for chromosomes 3, 5, and 15 as seen in this tumor have been reported in other low-grade gliomas, but too few tumors have been reported to indicate any consistent pattern [6]. M o n o s o m y for c h r o m o s o m e 22 was first reported associated with m e n i n g i o m a by Zang and Singer [15], and has subsequently been c o m m o n l y associated with astrocytomas. The loss or inactivation of tumor suppressor genes, which may reside on c h r o m o s o m e 22, has been suggested in the genesis of a variety of tumors, i n c l u d i n g meningioma, acoustic neuroma, p h e o c h r o m o c y t o m a , and gliomas [4, 16, 17]. The significance of the loss of heterozygosity for c h r o m o s o m e regions in astrocytomas, such as the losses of c h r o m o s o m e 10 or 22, have recently been correlated with malignancy grade [18, 19]. These studies have corroborated cytogenetic findings and demonstrate the ability to sublocalize regions that may be responsible for the progression to more malignant histologic stages. The structural c h r o m o s o m e aberrations observed in this tumor do not involve any of the c o m m o n l y reported structural aberrations in gliomas, such as those reported by Bigner et al. [10] involving 9p, 1, 6, 13, 7, and 11. However, the translocation of an extra copy of c h r o m o s o m e 15 onto the distal long arm of c h r o m o s o m e 20 shows the same breakpoint on the c h r o m o s o m e 15 as reported by Jenkins et al. [5[ in a grade 4 astrocytoma arising from a xanthoastrocytoma. They describe a 28-year-old female with a complex, near tetraploid clone, and a der(15)t(15;?)(p11;?). The other structural aberration in this tumor is a trans[ocation of a small c h r o m o s o m a l segment onto the distal short arm of c h r o m o s o m e 7. We h y p o t h e s i z e that this may represent part of the stalk or satellite region from the extra c h r o m o s o m e 15 or the missing 22.
230
J.R.
S a w y e r et al.
T h e f i n d i n g s in t h i s case of t r i s o m y 7 a n d m o n o s o m y 22 are c o n s i s t e n t w i t h p r e v i o u s l y p u b l i s h e d c y t o g e n e t i c s t u d i e s of l o w - g r a d e g l i o m a s . A l t h o u g h t h e signific a n c e of t h e k a r y o t y p i c a b e r r a t i o n s i n t h i s p a t i e n t are u n c l e a r , t h e c o r r e l a t i o n of f i n d i n g s in a large n u m b e r of l o w - g r a d e a s t r o c y t o m a s m a y s o m e d a y p r o v i d e a c l u e to i d e n t i f y i n g w h i c h c h r o m o s o m e s c a r r y g e n e s i m p o r t a n t for t h e m a l i g n a n t p r o g r e s s i o n a n d e v o l u t i o n of t h e s e t u m o r s . This work was supported in part by a grant from the University of Arkansas for Medical Sciences, Foundation Fund: Medical Research Endowment, Whitbeck Research Award. The authors thank Dr. John I. Kepes for review of pathology sections, and Glenda Probus for help in manuscript preparation.
REFERENCES 1. Kepes Jl, Rubinstein LJ, Eng LF (1979): Pleomorphic xanthoastrocytoma: A distinctive meningocerebral glioma of young subjects with relatively favorable prognosis. Cancer 44:1839-1852. 2. Russell DS, Rubinstein LJ (1989): Pathology of Tumors of the Nervous System. Williams & Wilkins, Baltimore, pp. 120-125. 3. Gaskill SJ, Marlin AE, Saldivar V (1988): Glioblastoma multiforme masquerading as a pleomorphic xanthoastrocytoma. Child's Nerv Syst 4:237-240. 4. Bigner SH, Mark J, Bigner DD (1990): Cytogenetics of h u m a n brain tumors. Cancer Genet Cytogenet47:141 154. 5. Rey JA, Bello MJ. de Campos JM, Kusak ME, Moreno S {1987a): Chromosomal composition of a series of 22 h u m a n low-grade gliomas. Cancer Genet Cytogenet 29:223-237. 6. Jenkins RB, Kimmel DW, Moertel CA. Schultz CG, Scheithauer BW, Kelly PJ, Dewald GW (1989): A cytogenetic study of 53 h u m a n gliomas. Cancer Genet Cytogenet 39:253-279. 7. Shapiro JR, Mohamed AN, Pu P-Y, Shapiro WR (1985}: Identical n o n r a n d o m karyotypic changes seen in the primary cytogenetic analysis of low grade and high grade gliomas. Proc 75th Ann Meet Am Assoc Cancer Res 26:32. 8. Rey JA, Bello MJ, de Campos JM, Kusak ME. Ramos C. Benitez J (1987b): Chromosomal patterns in h u m a n malignant astrocytomas. Cancer Genet Cytogenet 29:201-221. 9. Bigner SH, Mark J, Burger PC, Mahaley Jr. MS, Bullard DE, Huhlbaier LH, Bigner DD (1988): Specific Chromosomal Abnormalities in Malignant Human Gliomas. Cancer Res 88:405-411. 10. Rey JA, Bello MJ, de Campos JM, Kusak ME, Moreno S (1987c): On trisomy of chromosome 7 in h u m a n gliomas. Cancer Genet Cytogenet 29:323-326. 11. Bigner SH, Mark J, Mahaley MS, Bigner DD (1984): Patterns of early, gross chromosomal changes in malignant h u m a n gliomas. Hereditas 101:103-113. 12. Bigner SH, Mark J, Bullard DE, Mahaley MS, Bigner DD (1986): Chromosomal evolution in malignant h u m a n gliomas starts with specific and usually numerical deviations. Cancer Genet Cytogenet 22:121-135. 13. Griffin CA, Hawkins AL, Packer RJ, Rocke LB, Emanuel BS (1988): Chromosome abnormalities in pediatric brain tumors. Cancer Res 48:175-180. 14. Helm S, Mandahl N, Jin Y, Stromblad S, Lindstrom E, Salford LG, Mitelman F (1989): Trisomy 7 and sex chromosome loss in h u m a n brain tissue. Cytogenet Cell Genet 52:136-138. 15. Zang KD, Singer H (1967): Chromosomal constitution of nreningiomas. Nature 216:84-85. 16. Ponder B (1988): Gene losses in h u m a n tumors. Nature 335:400-402. 17. Sager R (1989): Tumor suppressor genes: The puzzle and the promise. Science 246:1406 1412. 18. James CD, Carlbom E, Duinandki JP, Hansen M, Nordenskjold M, Collins VP, Cavenee WK (19881: Clonal genomic alterations in glioma malignancy stages. Cancer Res 48:5546-5551. 19. James CD, Carlbom E, Nordenskjold M, Collins VP, Cavenee WK (19891: Mitotic recombination of chromosome 17 in astrocytomas. Proc Natl Acad Sci USA 86:2858-2862.
ABSTRACT: We report a pleomarphic xanthoastrocytoma with an abnormal clonal cell line of 48,XY, + 3, + 5, - 2 0 , - 22, + der(7)t(7;?)(p22;?), + der(20)t(15;20)(ql 1 ;q13).
INTRODUCTION Pleomorphic xanthoastrocytomas are low-grade gliomas usually found in young patients, most c o m m o n l y during the second decade of life. They are superficially located and are typically primary in the temporal lobe, but also occur in the frontal and parietal lobe. The p l e o m o r p h i s m of the astrocytes includes b u n d l e s of fusiform cells, large gemistocytic-like astrocytes with eccentric nuclei, and multinucleate giant cells, with variable atypia and hyperchromatism. Xanthomatous change w i t h i n these same cells can range from scant to a b u n d a n t [1]. In spite of the o m i n o u s histologic appearance of xanthoastrocytomas, they are reported to generally have a favorable postoperative course [2]. However, this tumor has been described to have the potential for malignant transformation [3]. Cytogenetic reports of low-grade astrocytomas are not well defined, as m a n y early studies did not utilize G-banding, or did not provide information on histologic subtypes. In this report, we present the results from a pleomorphic xanthoastrocytoma grown in short-term cultures with a karyotype of 48,XY, + 3, + 5 , - 20, - 22, + der(7)t(7;?) (p2 2;?), + der(20)t(15;20)(q11 ;ql 3).
Case Report C. D. (ACH #942727), a 15-year-old boy, had a 4-month history of episodic aphasia followed by severe headaches. One week prior to admission he had a generalized tonic-clonic seizure initiated with focal twitching of the right side of the face and the right arm. Computerized tomographic s c a n n i n g of the brain (Fig. 1) showed a cystic tumor in the left frontal suprasylvian region. At surgery the cystic portion of the tumor contained straw-colored fluid; the nodule was firm and very vascular. Gross total resection of the tumor was accomplished, and there was no residual tumor on postoperative CT scanning. The patient remained without neurologic deficit, but had From the Departmentsof Pathology (J. R. S., G. J. R.) and Neurosurgery(W. M. C.. IC A. B.). Universityof Arkansas for Medical Sciences, Little Rock. Arkansas. Address reprint requests to: Jeffrey R. Sawyer, Ph.D., Cytogenetics Laboratory, Arkansas Children's Hospital, 800 Marshall Street, Little Rock, AR 72202. Received December 10, 1990; accepted January 31, 1991.
225 © 1991 Elsevier SciencePublishingCo.. Inc. 655 Avenueof the Americas.New York. NY 10010
Cancer Genet Cytogenet55:225-230 (1991) 0165-4608/91/$03.50
226
J.R. Sawyer et al.
Figure 1 Axial section of the contrast-enhanced CT scan of the patient, shows the cystic lesion in the left fronto-temporal region with enhancement of the nodular portion of the tumor, laterally. Considerable vasogenic edema is present medially. occasional breakthrough of c o m p l e x partial seizures, requiring c o n t i n u e d use of anticonvulsants. Pathology received m u l t i p l e (0.2-0.8 cm) pieces of moderately firm tissue which was pale yellow and tan. The histology was that of a p l e o m o r p h i c xanthoastrocytoma. The p r e d o m i n a n t pattern was a fusiform cell in a partially storiform (fibrous histocytoma-like) pattern. Cellular atypia was present, and enlarged, hyperchromatic, and occasionally multinucleate giant cells were seen (Fig. 2). Occasional i n d i v i d u a l and scattered clusters of cells had m i n i m a l xanthomatous change. L y m p h o c y t e s were
Chromosomal Findings in a Xanthoastrocytoma
227
Figure 2
Pleomorphic xanthoastrocytoma. The tumor was cellular with predominantly fusiform cells, focal storiform pattern, scattered lymphocytes, and both individual and clustered cells with minimal xanthomatous change. Cellular typia and occasional enlarged, hyperchromatic, and multinucleate giant cells are present. (H&E, x 235). present perivascularly, and i n d i v i d u a l l y throughout the tumor. Microscopically, a discrete interface with the pial surface was evident in several sections. A reticulin stain had a b u n d a n t reticulin around most i n d i v i d u a l cells. Mitoses were rare, and necrosis was not identified.
MATERIALS AND METHODS Fresh tumor was transported to the laboratory in tissue culture m e d i u m and treated in the following manner. The tumor biopsy specimen was immediately minced and enzymatically treated with a solution of collagenase (0.125 mg/ml) for 2 hours. The biopsy was then washed with u n s u p p l e m e n t e d RPMI-1640 m e d i u m and was set up in Chang M e d i u m s u p p l e m e n t e d with 2% glutamine/pen-strep solution on Lab-Tech 2 chamber slides (Miles Laboratories) for in-situ culture and harvest. Cells were harvested in 5 - 1 4 days (when mitotic cells were considered adequate for analysis) by adding 10/xl of colcemid (2 mg/ml) to each chamber for 2 hours. The slides were harvested using standard in-situ techniques.
Cytogenetic Findings Twenty i n d e p e n d e n t colonies were studied for chromosome aberrations. Five colonies from 3 different culture chambers showed a karyotype of 48,XY,+3, + 5 , - 20, - 22, + der(7)t(7;?)(p22;?), + der(20)t(15;20)(q11;q13) (Figs. 3 and 4) and 15 colonies showed a normal karyotype of 46,XY.
228
J.R. Sawyer et al.
o
il
1
2
4
5
mN
mm
10
11
12
16
17
18
21
22
XY
3
¢ w; i-i; ;° 6
7
8
13
14
15
i,
9
X~_
19 20
Figure 3 Representative G-banded karyotype showing 48,XY,+ 3, + 5 , - 20, 22, + der(7)t[7:?)(p22;?), + der(20)t(15:20)(ql I ;q13). (Arrows indicate chromosome breakpoJnts). DISCUSSION The majority of low-grade astrocytomas reported contain a normal stem line and small abnormal clones as sidelines [4]. The chromosome findings in most cases indicate numerical aberrations predominate in low-grade astrocytomas, rather than structural rearrangements. Polysomy 7, m o n o s o m y 10 and 22, and loss of a sex chromosome are the most characteristic findings in low-grade gliomas [5, 6]. Interestingly, the same numerical aberrations found in low-grade astrocytomas have also been found in highgrade astrocytomas [7-9]. The numerical chromosome aberrations found in the present case include trisomies for chromosomes 3, 5, 7, and 15, and m o n o s o m y for chromosome 22. Trisomy 7 and m o n o s o m y 22 are the only numerical aberrations seen in this case that have frequently
229
Chromosomal Findings in a Xanthoastrocytoma
t 3
5
7
20
3
5
7
20
Figure 4 Partial karyotypes of two ceils showing the consistent numerical and structural aberrations. (Arrows indicate chromosome breakpoints). been reported in gliomas (4-6; 9-13). Recently, however, some question as to the association between malignancy and trisomy 7 has been raised. Heim et al. [14] have shown in a limited study that trisomy 7 can occur in short-term cultures of nonneoplastic brain tissue. Presumably this p h e n o m e n o n may be generated in vitro or is present in vivo as normal organ mosaicism. Trisomies for chromosomes 3, 5, and 15 as seen in this tumor have been reported in other low-grade gliomas, but too few tumors have been reported to indicate any consistent pattern [6]. M o n o s o m y for c h r o m o s o m e 22 was first reported associated with m e n i n g i o m a by Zang and Singer [15], and has subsequently been c o m m o n l y associated with astrocytomas. The loss or inactivation of tumor suppressor genes, which may reside on c h r o m o s o m e 22, has been suggested in the genesis of a variety of tumors, i n c l u d i n g meningioma, acoustic neuroma, p h e o c h r o m o c y t o m a , and gliomas [4, 16, 17]. The significance of the loss of heterozygosity for c h r o m o s o m e regions in astrocytomas, such as the losses of c h r o m o s o m e 10 or 22, have recently been correlated with malignancy grade [18, 19]. These studies have corroborated cytogenetic findings and demonstrate the ability to sublocalize regions that may be responsible for the progression to more malignant histologic stages. The structural c h r o m o s o m e aberrations observed in this tumor do not involve any of the c o m m o n l y reported structural aberrations in gliomas, such as those reported by Bigner et al. [10] involving 9p, 1, 6, 13, 7, and 11. However, the translocation of an extra copy of c h r o m o s o m e 15 onto the distal long arm of c h r o m o s o m e 20 shows the same breakpoint on the c h r o m o s o m e 15 as reported by Jenkins et al. [5[ in a grade 4 astrocytoma arising from a xanthoastrocytoma. They describe a 28-year-old female with a complex, near tetraploid clone, and a der(15)t(15;?)(p11;?). The other structural aberration in this tumor is a trans[ocation of a small c h r o m o s o m a l segment onto the distal short arm of c h r o m o s o m e 7. We h y p o t h e s i z e that this may represent part of the stalk or satellite region from the extra c h r o m o s o m e 15 or the missing 22.
230
J.R.
S a w y e r et al.
T h e f i n d i n g s in t h i s case of t r i s o m y 7 a n d m o n o s o m y 22 are c o n s i s t e n t w i t h p r e v i o u s l y p u b l i s h e d c y t o g e n e t i c s t u d i e s of l o w - g r a d e g l i o m a s . A l t h o u g h t h e signific a n c e of t h e k a r y o t y p i c a b e r r a t i o n s i n t h i s p a t i e n t are u n c l e a r , t h e c o r r e l a t i o n of f i n d i n g s in a large n u m b e r of l o w - g r a d e a s t r o c y t o m a s m a y s o m e d a y p r o v i d e a c l u e to i d e n t i f y i n g w h i c h c h r o m o s o m e s c a r r y g e n e s i m p o r t a n t for t h e m a l i g n a n t p r o g r e s s i o n a n d e v o l u t i o n of t h e s e t u m o r s . This work was supported in part by a grant from the University of Arkansas for Medical Sciences, Foundation Fund: Medical Research Endowment, Whitbeck Research Award. The authors thank Dr. John I. Kepes for review of pathology sections, and Glenda Probus for help in manuscript preparation.
REFERENCES 1. Kepes Jl, Rubinstein LJ, Eng LF (1979): Pleomorphic xanthoastrocytoma: A distinctive meningocerebral glioma of young subjects with relatively favorable prognosis. Cancer 44:1839-1852. 2. Russell DS, Rubinstein LJ (1989): Pathology of Tumors of the Nervous System. Williams & Wilkins, Baltimore, pp. 120-125. 3. Gaskill SJ, Marlin AE, Saldivar V (1988): Glioblastoma multiforme masquerading as a pleomorphic xanthoastrocytoma. Child's Nerv Syst 4:237-240. 4. Bigner SH, Mark J, Bigner DD (1990): Cytogenetics of h u m a n brain tumors. Cancer Genet Cytogenet47:141 154. 5. Rey JA, Bello MJ. de Campos JM, Kusak ME, Moreno S {1987a): Chromosomal composition of a series of 22 h u m a n low-grade gliomas. Cancer Genet Cytogenet 29:223-237. 6. Jenkins RB, Kimmel DW, Moertel CA. Schultz CG, Scheithauer BW, Kelly PJ, Dewald GW (1989): A cytogenetic study of 53 h u m a n gliomas. Cancer Genet Cytogenet 39:253-279. 7. Shapiro JR, Mohamed AN, Pu P-Y, Shapiro WR (1985}: Identical n o n r a n d o m karyotypic changes seen in the primary cytogenetic analysis of low grade and high grade gliomas. Proc 75th Ann Meet Am Assoc Cancer Res 26:32. 8. Rey JA, Bello MJ, de Campos JM, Kusak ME. Ramos C. Benitez J (1987b): Chromosomal patterns in h u m a n malignant astrocytomas. Cancer Genet Cytogenet 29:201-221. 9. Bigner SH, Mark J, Burger PC, Mahaley Jr. MS, Bullard DE, Huhlbaier LH, Bigner DD (1988): Specific Chromosomal Abnormalities in Malignant Human Gliomas. Cancer Res 88:405-411. 10. Rey JA, Bello MJ, de Campos JM, Kusak ME, Moreno S (1987c): On trisomy of chromosome 7 in h u m a n gliomas. Cancer Genet Cytogenet 29:323-326. 11. Bigner SH, Mark J, Mahaley MS, Bigner DD (1984): Patterns of early, gross chromosomal changes in malignant h u m a n gliomas. Hereditas 101:103-113. 12. Bigner SH, Mark J, Bullard DE, Mahaley MS, Bigner DD (1986): Chromosomal evolution in malignant h u m a n gliomas starts with specific and usually numerical deviations. Cancer Genet Cytogenet 22:121-135. 13. Griffin CA, Hawkins AL, Packer RJ, Rocke LB, Emanuel BS (1988): Chromosome abnormalities in pediatric brain tumors. Cancer Res 48:175-180. 14. Helm S, Mandahl N, Jin Y, Stromblad S, Lindstrom E, Salford LG, Mitelman F (1989): Trisomy 7 and sex chromosome loss in h u m a n brain tissue. Cytogenet Cell Genet 52:136-138. 15. Zang KD, Singer H (1967): Chromosomal constitution of nreningiomas. Nature 216:84-85. 16. Ponder B (1988): Gene losses in h u m a n tumors. Nature 335:400-402. 17. Sager R (1989): Tumor suppressor genes: The puzzle and the promise. Science 246:1406 1412. 18. James CD, Carlbom E, Duinandki JP, Hansen M, Nordenskjold M, Collins VP, Cavenee WK (19881: Clonal genomic alterations in glioma malignancy stages. Cancer Res 48:5546-5551. 19. James CD, Carlbom E, Nordenskjold M, Collins VP, Cavenee WK (19891: Mitotic recombination of chromosome 17 in astrocytomas. Proc Natl Acad Sci USA 86:2858-2862.