LETTERS TO THE EDITOR Clonal Evolution of a Wilms' Tumor We report the cytogenetic findings in a case of unilateral W i l m s ' t u m o r arising in the left k i d n e y of a 3-year-old girl without a family history of cancer. The tumor d i s p l a y e d the classic triphasic histologic pattern but was not anaplastic: however, necrosis, vascular invasion, and multiple perilobular n e p h r o g e n i c rests (a finding frequently associated with bilateral disease) were present [1]. No evidence of metastatic or contralateral disease has been detected after 12 m o n t h s of follow-up. Figure 1
Tissue from the m a i n t u m o r mass (nephrogenic rests were not present in the region sampled) was either minced or treated with collagenase and seeded into T-25 culture flasks. Cells were harvested using standard synchronization procedures at 48 and 96 hours. Slides were stained with quinacrine and standard karyotypes prepared. All 12 cells available for analysis were abnormal, each containing an extra c h r o m o s o m e 12. None contained a cytogenetically detectable alteration of chromosome 11. Two
A representative karyotype for the cell line showing only trisomy 12 (Quinacrine staining).
102 Cancer Genet Cytogenet 60:102-104 (1992) 0165-4608/92/$05.00
co 1992 Elsevier Science Publishing Co., Inc. 655 Avenue of the Americas, New York, NY 10010
Clonal Evolution in W i l m s ' T u m o r
cells had trisomy 12 as the only detectable abnormality (Fig. 1) w h i l e 10 cells also contained a c h r o m o s o m e derived from an u n b a l a n c e d translocation of chromosomes 1 and 18, der(18)t(1;18) (p12;q11). These cells had one normal c h r o m o s o m e 18, and two normal c h r o m o s o m e l s in a d d i t i o n to the der(18). These cells were thus trisomic for c h r o m o s o m e 12 and lq, as well as m o n o s o m i c for 18p (Fig. 2). The presence of these two related but distinct cell lines suggests clonal e v o l u t i o n occurred w i t h i n this tumor. Molecular and cytogenetic studies of sporadic Wilms' tumor have confirmed the i n v o l v e m e n t of the chromosome 11p13 and 11p15 regions [2]; however, linkage studies have e x c l u d e d c h r o m o s o m e 11 as the site involved in fa-
103 milial cases [3]. W h i l e no abnormalities of chromosome 11 were detected cytogenetically in this case, it is possible that alterations are present at the molecular level. Cytogenetics studies have demonstrated n o n r a n d o m secondary abnormalities that m a y be associated with progression of W i l m s ' t u m o r [4]. A m o n g the most c o m m o n are the structural rearrangements of c h r o m o s o m e 1 (resulting in trisomy lq) and 16 and trisomy of chromosomes 12 and 18 [4-6]. Our case d e m o n s t r a t e d these c o m m o n structural findings and suggests the sequence of clonal evolution of this tumor to be trisomy 12 followed by the der(18)t(1;18), resulting in trisomy lq. The significance of the abnormalities of c h r o m o s o m e 18
Figure 2 A representative karyotype of the more common cell line containing trisomy 12, and the der(18)t(1;18) is shown (Quinacrine staining).
104
W. Golden
in this case [involvement in the translocation and the previously unreported monosomy 18~) remain to be determined. To date, two genes, DCC and BCLB, which are associated with colorectal cancer and B cell lymphoma, respectively, have been assigned to chromosome 18q and no proto-oncogenes or tumor suppressor genes have been detected on 18p [7]. Partial or complete chromosomal losses are often associated with loss of tumor suppressor genes. In Wilms’ tumor, other than the abnormalities on chromosome 11, none of five other possible tumor suppressor gene loci examined, including 3p, 5p, 13p, and 22p, has shown loss of heterozygosity [8]. Continued documentation of cytogenetic abnormalities in Wilms’ tumor focuses attention on areas of the genome which may be involved in the initiation or progression of this neoplasm, for further characterization at the molecular level.
WENDY L. GOLDEN KATHRYNW.SUDDUTH MARK A. LOVELL University
Department
of Pediatrics
Department of Pathology of Virginia Health Sciences Center 300 Park Place Charlottesville, Virginia 22908
et al.
REFERENCES 1.
Beckwith JB, Kiviat NB, Bonadio
2.
Kondo K, Chilote RR, Maurer HS, Rowley JD (1984): Chromosome abnormalities in tumor cells from patients with sporadic Wilms’ tumors. Cancer Res 44:5376-5381.
3.
Grundy P, Koufos A, Morgan K, Li FP, Meadows AT, Cavenee WK (1988): Familial predisposition to Wilms’ tumor does not map to short arm of chromosome 11. Nature (Lond) 336:374-
JF (1990): Nephrogenic rests, nephroblastomatosis, and the pathogenesis of Wilms’ tumor. Pediatr Path01 lO:l-36.
376. 4.
Wang-Wuu S, Soukup S, Bove K, Gotwals B, Lampkin B (1990): Chromosome analysis of 31 Wilms’ tumors. Cancer Res 50:2786-2793.
5.
McDowell H, Howard P, Martin J, Hart C, Cramptom J (1989): Chromosome 1 studies in Wilms’ tumor. Cancer Genet Cytogenet 43:203-209.
6.
Solis V, Pritchard J, Cowell JK (1988): Cytogenetic changes in Wilms’ Tumors. Cancer Genet Cytogenet 34:223-234.
7.
Le Beau MM, Geurts van Kessel AHM (1990): Report of the committee on the genetic constitution of chromosome 18. Cytogenet Cell Genet 55:216-217.
8.
Mannens M, Devilee P, Bliek J, Mandjes I, deKraker J, Heyting C, Slater RM, Westerveld A (1990): Loss of heterozygosity in Wilms’ tumors, studied for six putative tumor suppressor regions, is limited to chromosome 11. Cancer Res 50:32793283.
Tissue from the m a i n t u m o r mass (nephrogenic rests were not present in the region sampled) was either minced or treated with collagenase and seeded into T-25 culture flasks. Cells were harvested using standard synchronization procedures at 48 and 96 hours. Slides were stained with quinacrine and standard karyotypes prepared. All 12 cells available for analysis were abnormal, each containing an extra c h r o m o s o m e 12. None contained a cytogenetically detectable alteration of chromosome 11. Two
A representative karyotype for the cell line showing only trisomy 12 (Quinacrine staining).
102 Cancer Genet Cytogenet 60:102-104 (1992) 0165-4608/92/$05.00
co 1992 Elsevier Science Publishing Co., Inc. 655 Avenue of the Americas, New York, NY 10010
Clonal Evolution in W i l m s ' T u m o r
cells had trisomy 12 as the only detectable abnormality (Fig. 1) w h i l e 10 cells also contained a c h r o m o s o m e derived from an u n b a l a n c e d translocation of chromosomes 1 and 18, der(18)t(1;18) (p12;q11). These cells had one normal c h r o m o s o m e 18, and two normal c h r o m o s o m e l s in a d d i t i o n to the der(18). These cells were thus trisomic for c h r o m o s o m e 12 and lq, as well as m o n o s o m i c for 18p (Fig. 2). The presence of these two related but distinct cell lines suggests clonal e v o l u t i o n occurred w i t h i n this tumor. Molecular and cytogenetic studies of sporadic Wilms' tumor have confirmed the i n v o l v e m e n t of the chromosome 11p13 and 11p15 regions [2]; however, linkage studies have e x c l u d e d c h r o m o s o m e 11 as the site involved in fa-
103 milial cases [3]. W h i l e no abnormalities of chromosome 11 were detected cytogenetically in this case, it is possible that alterations are present at the molecular level. Cytogenetics studies have demonstrated n o n r a n d o m secondary abnormalities that m a y be associated with progression of W i l m s ' t u m o r [4]. A m o n g the most c o m m o n are the structural rearrangements of c h r o m o s o m e 1 (resulting in trisomy lq) and 16 and trisomy of chromosomes 12 and 18 [4-6]. Our case d e m o n s t r a t e d these c o m m o n structural findings and suggests the sequence of clonal evolution of this tumor to be trisomy 12 followed by the der(18)t(1;18), resulting in trisomy lq. The significance of the abnormalities of c h r o m o s o m e 18
Figure 2 A representative karyotype of the more common cell line containing trisomy 12, and the der(18)t(1;18) is shown (Quinacrine staining).
104
W. Golden
in this case [involvement in the translocation and the previously unreported monosomy 18~) remain to be determined. To date, two genes, DCC and BCLB, which are associated with colorectal cancer and B cell lymphoma, respectively, have been assigned to chromosome 18q and no proto-oncogenes or tumor suppressor genes have been detected on 18p [7]. Partial or complete chromosomal losses are often associated with loss of tumor suppressor genes. In Wilms’ tumor, other than the abnormalities on chromosome 11, none of five other possible tumor suppressor gene loci examined, including 3p, 5p, 13p, and 22p, has shown loss of heterozygosity [8]. Continued documentation of cytogenetic abnormalities in Wilms’ tumor focuses attention on areas of the genome which may be involved in the initiation or progression of this neoplasm, for further characterization at the molecular level.
WENDY L. GOLDEN KATHRYNW.SUDDUTH MARK A. LOVELL University
Department
of Pediatrics
Department of Pathology of Virginia Health Sciences Center 300 Park Place Charlottesville, Virginia 22908
et al.
REFERENCES 1.
Beckwith JB, Kiviat NB, Bonadio
2.
Kondo K, Chilote RR, Maurer HS, Rowley JD (1984): Chromosome abnormalities in tumor cells from patients with sporadic Wilms’ tumors. Cancer Res 44:5376-5381.
3.
Grundy P, Koufos A, Morgan K, Li FP, Meadows AT, Cavenee WK (1988): Familial predisposition to Wilms’ tumor does not map to short arm of chromosome 11. Nature (Lond) 336:374-
JF (1990): Nephrogenic rests, nephroblastomatosis, and the pathogenesis of Wilms’ tumor. Pediatr Path01 lO:l-36.
376. 4.
Wang-Wuu S, Soukup S, Bove K, Gotwals B, Lampkin B (1990): Chromosome analysis of 31 Wilms’ tumors. Cancer Res 50:2786-2793.
5.
McDowell H, Howard P, Martin J, Hart C, Cramptom J (1989): Chromosome 1 studies in Wilms’ tumor. Cancer Genet Cytogenet 43:203-209.
6.
Solis V, Pritchard J, Cowell JK (1988): Cytogenetic changes in Wilms’ Tumors. Cancer Genet Cytogenet 34:223-234.
7.
Le Beau MM, Geurts van Kessel AHM (1990): Report of the committee on the genetic constitution of chromosome 18. Cytogenet Cell Genet 55:216-217.
8.
Mannens M, Devilee P, Bliek J, Mandjes I, deKraker J, Heyting C, Slater RM, Westerveld A (1990): Loss of heterozygosity in Wilms’ tumors, studied for six putative tumor suppressor regions, is limited to chromosome 11. Cancer Res 50:32793283.
