Observations of AXPs and SGRs: 1E 1048.1-5937 and SGR 1806-20
Correlation of Chromosome Abnormalities with Histológica...
7
[CANCER RESEARCH 51. 5937-5942, November 1. 1991] Correlation of Chromosome Abnormalities with Histológica! and Clinical Features in Wilms' and Other Childhood Renal Tumors1 Yasuhiko Kaneko,2 Chieko Homma, Nobuo Maseki, Masaharu Sakurai, and Jun-ichi Hata Department of Laboratory Medicine [Y. A'., C. H.] and Hematotogy Clinic [N. M., M. S./, Saitama Cancer Center Hospital, Ina, Saitama 362, Japan, and Department of Pathology, Keio University School of Medicine, Shinjuku-ku, Tokyo 160, Japan [J. H.j ABSTRACT Chromosomes and histology were successfully studied in 33 childhood renal tumors. Thirty-one tumors were classified as one of four subtypes of Wilms1 tumor. Of 24 typical Wilms' tumors, 12 had hyperdiploidy with nonrandom trisomies, mostly including +6 and/or +12. Three typical Wilms1 tumors with an Hpl3 deletion or a pericentric inversion with a break in 11pi3 were not associated with aniridia. Two other typical Wilms1 tumors with the Hpl3 deletion and one fetal rhabdomyomatous nephroblastoma with an Hpl3 translocation were associated with aniri dia. Two cystic partially differentiated nephroblastomas showed hyper diploidy with +12. Of four clear cell sarcomas of the kidney, three had normal diploidy and the other had a 2:22 translocation. Two congenital mesoblastic nephromas had hyperdiploid karyotype with trisomy 11, which was never seen in the 31 Wilms1 tumors. Our findings and a review of data on 102 reported Wilms1 tumors revealed Ilpl3 abnormalities in 24 tumors, HplS abnormalities in five tumors, and partial deletions of Ip, 7p, I Iq. 12q, 16q, or 17p or monosomy of No. 21 or No. 22 each in four or more tumors. These findings suggest that increased copy number of genes on the nonrandom trisomie chromosomes might contribute to the genesis of many Wilm's tumors and that deletion of various tumor suppressor genes other than a Wilms' tumor gene, WTl in 1Ipl3, might also play a critical role in the development of some tumors. INTRODUCTION Some chromosome abnormalities found in constitutional cells as well as tumor cells play an essential role in locating genes involved in the pathogenesis of cancers (1). An 11pi3 deletion found in constitutional cells of Wilms1 tumor-aniridia- genito-urinary abnormalities-mental retardation syndrome pa tients (2) and in tumor cells of sporadic Wilms1 tumor patients (3) suggested the position of one Wilms1 tumor gene. The proposition was further substantiated by the findings of allelic loss of the 11p 13 region, determined by restriction fragment length polymorphism analysis (4-6), and finally led to the cloning of the WTl gene (7, 8). In some Wilms1 tumors, however, allelic loss was found only in the 11pi5 region and not in the 11p 13 region (9, 10). Furthermore, linkage studies showed no association between some familial Wilms' tumor patients and DNA markers local ized in either Ilpl3 or HplS (11, 12). These findings suggest the presence of at least two other Wilms1 tumor genes, one at 11p 15 and the other somewhere other than Ilpl3 or 11p 15. Another interesting aspect of Wilms1 tumor is its markedly different incidences between East Asian and Caucasian children (13); the latter suffer from the tumor 2 to 3 times more frequently than the former. We studied chromosomes of Japanese Wilms' and other Received 5/20/91; accepted 8/19/91. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. 1This work was supported in part by Grants-in-Aid from the Ministry of Health and Welfare and the Ministry of Education, Science, and Culture of Japan. 2To whom requests for reprints should be addressed, at Department of Laboratory Medicine, Saitama Cancer Center, Ina, Saitama, 362, Japan. childhood renal tumors. Our findings and a review of data on other Wilms' tumors (14-19) suggest that increased copy num ber of genes on the nonrandomly gained chromosomes might contribute to the genesis of many Wilms1 tumors and that deletion of various tumor suppressor genes other than WTl might also play a critical role in the development of some tumors. In addition, we compared chromosome patterns be tween Japanese Wilms1 tumors and American and British ones, to clarify whether the higher incidence in Caucasian children is related to the predominance of Wilms1 tumor with specific chromosome abnormalities. MATERIALS AND METHODS Patients. Chromosomes and histology were studied in renal tumors from 40 Japanese infants and children who were consecutively admitted to various institutions (listed in "Acknowledgments'1) between Novem ber 1982 and April 1990. The tumor tissues from 38 patients were obtained by surgery and were transferred to the cytogenetic laboratory of the Saitama Cancer Center Hospital. One cell line and two xenografts established from untreated primary tumors by Dr. Yoshiro Yamashita, Niigata University, and Dr. Yoshiaki Tsuchida, National Children's Hospital, respectively, were also studied. One tumor (No. 12), from which one of the two xenografts was established, was included in the 38 tumors. Patients were staged according to the National Wilms1 Tumor Study staging system and were treated with the National Wilms1 Tumor Study protocol on the basis of their stage (20). Three patients were diagnosed as having AWTA3 (2). Histológica!Studies. The pathological diagnosis was made on routine hematoxylin/eosin-stained slides, which were prepared from primary tumors obtained before chemotherapy or radiotherapy. The tumors were classified as one of four subtypes of Wilms' tumor or as congenital mesoblastic nephroma. Typical Wilms1 tumor shows triphasic compo nents of epithelial, blastema!, and mesenchymal tissue, without any anaplastia changes (21). Fetal rhabdomyomatous nephroblastoma is a monophasic mesenchymal variant of Wilms' tumor with differentiated striated muscle cells (22). Cystic partially differentiated nephroblastoma is a cystic encapsulated tumor with septal wall composed of flattened epithelial lining, underyling cellular stroma, rhabdomyomatous cells, and other foci resembling typical Wilms' tumor and occurs before 2 years of age (23). Clear cell sarcoma of the kidney shows a diffuse proliferation of water clear cells with round normochromatic nuclei (24). It is controversial whether the sarcoma is considered to be a variant of Wilms' tumor (24, 25). Congenital mesoblastic nephroma shows a varied cellular growth of spindle cells and is considered to be a benign tumor of infancy (26). Chromosome Studies. The tumor tissue was minced with scissors, disaggregated in 0.8% collagenase type II (Worthington) in RPMI 1640 for 3 h, and cultured in plastic dishes containing ES medium (Nissui Seiyaku, Tokyo, Japan) with 15% fetal calf serum. The cells were harvested within 96 h from the start of culture. Peripheral lymphocytes were cultured for 72 h with phytohemagglutinin, to determine the constitutional karyotype. Ethidium bromide was used for 2 h before the harvest, to elongate chromosomes in the lymphocytes. Chromo somes were analyzed by Q- and/or G-banding techniques. Karyotypes were described according to the International System for Human Cy togenetic Nomenclature (27). We defined abnormal clones as two or 3The abbreviation used is: AWTA, aniridia-Wilms' tumor association. 5937 on May 30, 2019. © 1991 American Association for Cancer Research. cancerres.aacrjournals.org Downloaded from
Transcript of Correlation of Chromosome Abnormalities with Histológica...
[CANCER RESEARCH 51. 5937-5942, November 1. 1991]
Correlation of Chromosome Abnormalities with Histológica! and Clinical Featuresin Wilms' and Other Childhood Renal Tumors1
Yasuhiko Kaneko,2 Chieko Homma, Nobuo Maseki, Masaharu Sakurai, and Jun-ichi HataDepartment of Laboratory Medicine [Y. A'., C. H.] and Hematotogy Clinic [N. M., M. S./, Saitama Cancer Center Hospital, Ina, Saitama 362, Japan, and Department
of Pathology, Keio University School of Medicine, Shinjuku-ku, Tokyo 160, Japan [J. H.j
ABSTRACT
Chromosomes and histology were successfully studied in 33 childhoodrenal tumors. Thirty-one tumors were classified as one of four subtypesof Wilms1 tumor. Of 24 typical Wilms' tumors, 12 had hyperdiploidy
with nonrandom trisomies, mostly including +6 and/or +12. Three typicalWilms1 tumors with an Hpl3 deletion or a pericentric inversion with a
break in 11pi3 were not associated with aniridia. Two other typicalWilms1 tumors with the Hpl3 deletion and one fetal rhabdomyomatous
nephroblastoma with an Hpl3 translocation were associated with aniridia. Two cystic partially differentiated nephroblastomas showed hyperdiploidy with +12. Of four clear cell sarcomas of the kidney, three hadnormal diploidy and the other had a 2:22 translocation. Two congenitalmesoblastic nephromas had hyperdiploid karyotype with trisomy 11,which was never seen in the 31 Wilms1 tumors. Our findings and a reviewof data on 102 reported Wilms1 tumors revealed Ilpl3 abnormalities in
24 tumors, HplS abnormalities in five tumors, and partial deletions ofIp, 7p, I Iq. 12q, 16q, or 17p or monosomy of No. 21 or No. 22 each infour or more tumors.
These findings suggest that increased copy number of genes on thenonrandom trisomie chromosomes might contribute to the genesis ofmany Wilm's tumors and that deletion of various tumor suppressor genesother than a Wilms' tumor gene, WTl in 1Ipl3, might also play a critical
role in the development of some tumors.
INTRODUCTION
Some chromosome abnormalities found in constitutionalcells as well as tumor cells play an essential role in locatinggenes involved in the pathogenesis of cancers (1). An 11pi3deletion found in constitutional cells of Wilms1 tumor-aniridia-
genito-urinary abnormalities-mental retardation syndrome patients (2) and in tumor cells of sporadic Wilms1 tumor patients(3) suggested the position of one Wilms1 tumor gene. The
proposition was further substantiated by the findings of allelicloss of the 11p 13 region, determined by restriction fragmentlength polymorphism analysis (4-6), and finally led to thecloning of the WTl gene (7, 8).
In some Wilms1 tumors, however, allelic loss was found only
in the 11pi5 region and not in the 11p 13 region (9, 10).Furthermore, linkage studies showed no association betweensome familial Wilms' tumor patients and DNA markers local
ized in either Ilpl3 or HplS (11, 12). These findings suggestthe presence of at least two other Wilms1 tumor genes, one at
11p 15 and the other somewhere other than Ilpl3 or 11p 15.Another interesting aspect of Wilms1 tumor is its markedly
different incidences between East Asian and Caucasian children(13); the latter suffer from the tumor 2 to 3 times morefrequently than the former.
We studied chromosomes of Japanese Wilms' and other
Received 5/20/91; accepted 8/19/91.The costs of publication of this article were defrayed in part by the payment
of page charges. This article must therefore be hereby marked advertisement inaccordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1This work was supported in part by Grants-in-Aid from the Ministry ofHealth and Welfare and the Ministry of Education, Science, and Culture of Japan.
2To whom requests for reprints should be addressed, at Department of
Laboratory Medicine, Saitama Cancer Center, Ina, Saitama, 362, Japan.
childhood renal tumors. Our findings and a review of data onother Wilms' tumors (14-19) suggest that increased copy num
ber of genes on the nonrandomly gained chromosomes mightcontribute to the genesis of many Wilms1 tumors and that
deletion of various tumor suppressor genes other than WTlmight also play a critical role in the development of sometumors. In addition, we compared chromosome patterns between Japanese Wilms1 tumors and American and British ones,
to clarify whether the higher incidence in Caucasian children isrelated to the predominance of Wilms1 tumor with specific
chromosome abnormalities.
MATERIALS AND METHODS
Patients. Chromosomes and histology were studied in renal tumorsfrom 40 Japanese infants and children who were consecutively admittedto various institutions (listed in "Acknowledgments'1) between Novem
ber 1982 and April 1990. The tumor tissues from 38 patients wereobtained by surgery and were transferred to the cytogenetic laboratoryof the Saitama Cancer Center Hospital. One cell line and two xenograftsestablished from untreated primary tumors by Dr. Yoshiro Yamashita,Niigata University, and Dr. Yoshiaki Tsuchida, National Children's
Hospital, respectively, were also studied. One tumor (No. 12), fromwhich one of the two xenografts was established, was included in the38 tumors. Patients were staged according to the National Wilms1Tumor Study staging system and were treated with the National Wilms1
Tumor Study protocol on the basis of their stage (20). Three patientswere diagnosed as having AWTA3 (2).
Histológica!Studies. The pathological diagnosis was made on routinehematoxylin/eosin-stained slides, which were prepared from primarytumors obtained before chemotherapy or radiotherapy. The tumorswere classified as one of four subtypes of Wilms' tumor or as congenitalmesoblastic nephroma. Typical Wilms1 tumor shows triphasic compo
nents of epithelial, blastema!, and mesenchymal tissue, without anyanaplastia changes (21). Fetal rhabdomyomatous nephroblastoma is amonophasic mesenchymal variant of Wilms' tumor with differentiated
striated muscle cells (22). Cystic partially differentiated nephroblastomais a cystic encapsulated tumor with septal wall composed of flattenedepithelial lining, underyling cellular stroma, rhabdomyomatous cells,and other foci resembling typical Wilms' tumor and occurs before 2
years of age (23). Clear cell sarcoma of the kidney shows a diffuseproliferation of water clear cells with round normochromatic nuclei(24). It is controversial whether the sarcoma is considered to be avariant of Wilms' tumor (24, 25). Congenital mesoblastic nephroma
shows a varied cellular growth of spindle cells and is considered to bea benign tumor of infancy (26).
Chromosome Studies. The tumor tissue was minced with scissors,disaggregated in 0.8% collagenase type II (Worthington) in RPMI 1640for 3 h, and cultured in plastic dishes containing ES medium (NissuiSeiyaku, Tokyo, Japan) with 15% fetal calf serum. The cells wereharvested within 96 h from the start of culture. Peripheral lymphocyteswere cultured for 72 h with phytohemagglutinin, to determine theconstitutional karyotype. Ethidium bromide was used for 2 h beforethe harvest, to elongate chromosomes in the lymphocytes. Chromosomes were analyzed by Q- and/or G-banding techniques. Karyotypeswere described according to the International System for Human Cytogenetic Nomenclature (27). We defined abnormal clones as two or
3The abbreviation used is: AWTA, aniridia-Wilms' tumor association.
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CHROMOSOMES IN WILMS' TUMOR
more metaphase cells with identical structural and/or numerical chromosome abnormalities. When we found only normal metaphase cellsin the cultured tissue and cells spreading from the minced tumor piecesappeared to be fibroblasts, by inverted microscope analysis, the examination was considered to have failed to detect mitotic malignant cellsand, hence, to be inadequate. We considered that normal diploid cellsrepresented the karyotype of malignant cells in the tumor when all thefive or more cells we karyotyped were diploid and when the culturedtumor cells did not appear to be fibroblasts. Even with the use of thesecriteria, the possibility that normal diploid karyotype may have belonged to normal reactive cells in the tumors still exists.
RESULTS
Histológica! Studies. Thirty-three tumors whose chromosomes were successfully examined were histologically classifiedby one of the authors (J. H.). Twenty-four were classified astypical Wilms' tumor and one as fetal rhabdomyomatous neph-
roblastoma. Two tumors were classified as cystic partially differentiated nephroblastoma (Fig. 1); one (No. 384) of themincluded an area showing blastema! component. None of the27 tumors showed focal or diffuse anaplastic lesions. Fourtumors were classified as clear cell sarcoma of the kidney; one(No. 608) of them showed myxoid mesenchymal tissue witharborizing vasculature (Fig. 2). Two tumors were diagnosed ascongenital mesoblastic nephroma (Fig. 3).
Chromosome Studies. Of the 33 childhood renal tumors, 31were obtained from the primary sites at the time of diagnosisand two from the metastatic sites at relapse. Chromosomeswere analyzed in resected tumors from 30 patients, in a xeno-graft from one (No. 27), in a resected tumor and its xenograftfrom one (No. 12), and in a cell line from one (No. 22). Theexamination was unsuccessful in the remaining seven tumors;no mitotic cells were found in four, and only normal diploidcells in three whose cultured cells appeared to be fibroblasts.
Chromosomes and Histology in Wilms' Tumor and OtherChildhood Renal Tumors. Of 24 typical Wilms' tumors, four
had only normal diploid and/or tetraploid karyotypes, and theother 20 had clonal chromosome abnormalities. There were 12hyperdiploid tumors, seven pseudodiploid tumors, and onehypodiploid tumor. Modal chromosome numbers in the hyper-
Fig. l. Patient 74. Cystic partially differentiated nephroblastoma. A cysticencapsulated tumor with septal wall composed of flattened epithelial lining,underlying cellular strema, rhabdomyomatous cells, and other foci resemblingtypical Wilms' tumor. The tumor occurs before 2 years of age (23) (H & E, x
100).
..
558*'î8Fig. 2. Patient 608. Clear cell sarcoma of the kidney, showing a diffuse
proliferation of water clear cells with round normochromatic nuclei (24) (H & E,x 200).
Fig. 3. Patient 544. Congenital mesoblastic nephroma, showing a variedcellular growth of spindle cells. The tumor is considered to be a benign tumor ofinfancy (26) (H & E, x 200).
diploid tumors ranged between 47 and 65, and trisomies werefound in chromosomes 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 13, 17, 18,19, 20, and 22. The trisomies 2, 6, 7, 8, 10, 12, 13, 17, 18, and20 were each seen in four of more tumors (Table 1). Threehyperdiploid tumors had only numerical abnormalities, and theother nine had numerical as well as structural abnormalities.Partial or total Iq polysomy, i.e., trisomy, tetrasomy, or pen-tasomy, was seen in three hyperdiploid and four pseudodiploidtumors. Of seven pseudodiploid tumors, two had monosomy21. An 11pi3 deletion was found in two hyperdiploid tumorsand two pseudodiploid tumors; two of the four were associatedwith aniridia. Other partial chromosome deletions included7p—in two tumors and Ip—,2p—,llq—, 14q—,and 17p—in
one each. One tumor not associated with aniridia had aninversion with breaks in 1Ipl3 and 1Iql3.5 (Fig. 4).
Two cystic partially differentiated nephroblastomas had hyperdiploid karyotypes with 50 chromosomes, and extra chromosomes found in the two tumors were similar to those found
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Patient
CHROMOSOMES IN WILMS' TUMOR
Table 1 Clinical, histological, and karyotypic findings on 31 H'Urns' tumors and two other childhood renal tumors
Age(years) Sex Stage
Survival(months)
Histology of renaltumor"
TumorKaryotype
2 4 M II 5 Typical Wilms'tumor (F) X22* 2 F l 90+ Typical Wilms' tumor (F) C89 7.2 M I 61+ Typical Wilms'tumor (F) P
148 14 M IV 29 Typical Wilms'tumor (F) P165' I F III 56+ Typical Wilms'tumor (F) P207 2 F III 49+ Typical Wilms'tumor (F) P
275 1 F I 39+ Typical Wilms' tumor (F) P276 10 F 1 39+ Typical Wilms'tumor (F) P
312 4 F III 37+ Typical WJims'tumor (F) P
325 IMI 36+ Typical Wilms" tumor (F) P392 13 F I 28 Typical Wilms'tumor (F) M
519 3 M III 20+ Typical Wilms'tumor (F) P
521 2 F III 20+ Typical Wilms" tumor (F) P528 4 F II 20+ Typical Wilms" tumor (F) P
539 l M III 18+ Typical Wilms'tumor (F) P571 2 F II 17+ Typical Wilms'tumor (F) P575 3 M II 15+ Typical Wilms'tumor (F) P619 2 M III 11+ Typical Wilms'tumor (F) P
637 6 M IV 11+ Typical Wilms'tumor (F) P640 3 M III 11+ Typical Wilms'tumor (F) P667 3 M III 9+ Typical Wilms' tumor (F) P672 5 M II 8+ Typical Wilms' tumor (F) P
46,XY,-21.+i(lq)47,XX.+20.del(ll)(pl3pl4)48.XY.+10.+12/50.X Y.+2,+8,+10,+1246.XY.il 17q)/47.X Y,+12(SCA')
46.XX.del(ll)(pl2pl3)54,X,-X,+2,+6,+7,+12,+13.+17,+18.
+r,+mar48.XX.+3.+6
(p32),+3mar46.XX,del(11 )(pl 3p 14).dup( 1)(q21 -q44)/
46.XX,-2,del( 11)(pl 3p 14).+der(2)t( 1:2)(qll;p25)
47,XY.+8,del(14)(q22)54,X,-X,-4.+6,+7,+9,-12.+13,+20,del
( 11)(p 13p 14).+i( 1q).+dcr(4)t(4;?)(p 12:?),+4mar
46,XY,-19,-21.+i(lq).+dcr(19)t(19;?)(q13;?)
52,XX,+2?,+5?,+12.+C.+ 14?.+ 1856,XX,+5.+7.+7.+9.+10,+12,+13.+18.
+ 19.+2246.XY/92.XXYY47.XX.+646.XY5I.XY.+6.+8.+20.+der(7)t(7;?)(pl3;?),+
der(7)t(7;?)(pl3;?)46.XY/92.XXYY46,XY.inv(ll)(pI3ql3.5)46.XY.dup(l)(q21q32)65,XXY.+2,+4,+6,+6.+7.+7.+8.+ 10.+
12,+12,+13,+17,+17,+18.+20.+20.-22,+der( 14)t( 1;14)(q 12;p 13).+der( 15)t( 1; 15)(q 12;p 13),+der( 16)t( 1;16)(q 12:ql2)
74977174384299*1225759360847554412Va15232"/ii'/iiVaMFMMFMMMFMMIIIIIIIIIIIIIIVII4+2+76+31
+37+582415+1024+19+Typical
Wilms' tumor(F)TypicalW'ilms' tumor(F)Cystic
partiallydifferentiatednephroblastoma(F)Cystic
partiallydifferentiatednephroblastoma(F)Fetal
rhabdomyomatousnephroblastoma(F)Clear
cell sarcoma(U)Clearcell sarcoma(U)Clearcell sarcoma(U)Clearcell sarcoma(U)Congenital
mesoblasticne-phromaCongenital
mesoblasticne-phromaPPPPPP.
XMPPPP92.XXYY56,XX,+2,+6,+8.+9.+
10,-ll,+ 12.+13.+17,+ 18,+der(7)t( 1;7)(q2 1;p 13).+der/
1 1 \tf 1 1«'ÕWfil1•¿�*ì\IMIn 11,. M<| - 1, .)50,X
Y.+7.+ 12,+ 13,+ 18/5 1,same.+ 1750,X,-Y,+6,+
12,+ 13,+der(?)t( 1;?)(q2 1;?),+der(?)t(1;?)(q2 1;?)46.XX.t(10;ll)(pl3;pl3)46.XY46.XY46.XY46,XX,t(2;22)(q21;qll)47,X,-Y,+
11,- 17,t( 12; 15)(p 13;q22),+dcr(Yq 17q),+mar/48.same,+ 1847,XY,+
11/48.XY,+ 11,+ 11
" F. favorable histology; U, unfavorable histology.* C, cell line; P, primary tumor; M, metastatic lesion; X, xenograft.' One cell line and two xenografts were established from untreated primary tumors. The primary tumors were studied before treatment, and the metastatic lesions
were studied after treatment.' AWTA.' SCA, single-cell abnormality.
in the typical Wilms' tumors with hyperdiploidy (Table 1).
The only fetal rhabdomyomatous nephroblastoma hadt(10;l I)(pl3;13) without other changes; this translocation wasalso seen in the constitutional cells of the patient (No. 299)(Fig. 5) who had aniridia.
Of four clear cell sarcomas of the kidney, three had only-
normal diploid karyotype; a xenograft established from one ofthe three also showed normal karyotype, and the other had a2;22 translocation as a sole chromosome abnormality (Fig. 6).
Two congenital mesoblastic nephromas had hyperdiploidkaryotypes with one or two extra chromosomes 11. Trisomy 11was never seen in any of typical Wilms' tumors or cystic
partially differentiated nephroblastomas in the present series.
DISCUSSION
Chromosome Abnormalities in Wilms' Tumor. In the study of
Japanese childhood renal tumors, we found that hyperdiploidywith nonrandom trisomies was the most common cytogeneticpattern in Wilms' tumor. On the basis of karyotypes summarized from 133 Wilms' tumors reported by us and other inves
tigators (14-19), the distribution of the extra chromosomes areshown in Fig. 7. Trisomy 12 was the most common and wasfound in 36 tumors (27%), followed by trisomies of 6, 7, 8, 9,10, 13, 18, or 20; each was seen in 13 or more tumors. A partialor total Iq polysomy resulting from duplications, derivativechromosomes, or isochromosomes was seen in 28 tumors(21%). High incidences of trisomies of 6, 7, 8, 9, 10, 12, 13,
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CHROMOSOMES IN WILMS' TUMOR
18, and 20 and Iq polysomy in Wilms' tumor indicate that
genes, such as a cell growth factor or its receptor gene, may bepresent on these chromosomes or chromosome arms.
We illustrated the deleted chromosomes or chromosomesegments and the breakpoints of reciprocal translocations orinversions in the 133 Wilms' tumors in Fig. 8 (14-19). Dele
tions including 11pi3 and reciprocal translocations or an inversion with a break at 11pi3 were found in 21 and threetumors, respectively. Deletions including 1Ipl5 and reciprocaltranslocations with a break in llplS were found in three andtwo tumors, respectively. Thus, chromosome abnormalities involving 11pi3 or 11pi5 were recurrently found in Wilms'
tumor, although the incidence of the 1Ipl5 abnormalities wasmuch smaller than that of the 11pi3 abnormalities. Thesefindings are consistent with the data on allelic loss limited toIlpl3or 11p 15 in some Wilms' tumor, shown by the restriction
fragment length polymorphism study (9, 10). Other recurrentchromosome deletions included chromosome Ip, 7p, 1Iq, 12q,16q, 17p, 21, and 22. Allelic loss of 1p, 16q, 17p, or 22 hasbeen reported in various cancers (28, 29).
Correlation of Karyotypes with Histology. Of three tumorsdeveloped in AWTA patients, two with the 1Ipl 3 deletion were
Ir «-
r
?r u-
l
i2 2
Fig. 6. Partial karyotypes of two tumor cells from patient 608. Arrows,translocation breakpoints in 2q21 and 22ql 1.
35 -I
30-
25-
20-
Fig. 4. Partial karyotypes of two tumor cells from patient 640, showing apericentric inversion of chromosome 11. Arrowheads, inversion breakpoints in -5.Ilpl3and llql3.S.
10-
5 -
1 2 34 56 7 8 9 10 1112 13 14 15 16 17 18 19 20 21 22 X YFig. 7. Diagram of chromosomal gains seen in 133 Wilms' tumors. Number
of patients is on the vertical axis, and chromosome number is on the horizontal
classified as typical Wilms' tumor and one with
10 11 t(10;ll)(pl3;13) as fetal rhabdomyomatous nephroblastoma.Fig. 5. Partial karyotypes of two lymphocytes from patient 299. Arrowheads, Two of the three tumors had an 11 pi3 abnormality without
translocationbreakpointsin I0pi3 and iipi3. other changes, and the other had trisomy 20 as an additional5940
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CHROMOSOMES IN WILMS' TUMOR
Fig. 8. Diagram of chromosome or chromosome segment deletions seen in 133 Wilms'
tumors. Chromosomes with deletions found infour or more tumors are shown. The chromosome regions corresponding to the verticallines were missing. Closed circles, translocation and inversion breakpoints.
11
16 17 22
change. Tumor karyotypes were reported in four other AWTApatients in the literature (16, 18, 19). Three of the four tumorshad the 1Ipl3 deletion as a single abnormality, and the otherhad the 1Ipl3 deletion and trisomy 20. Thus, the tumor karyotypes found in the seven AWTA patients were rather simple,and none had Iq polysomy or two or more extra chromosomes.These findings suggest that only small DNA fragment deletionsor point mutations in renal cells, which may not be detected bylight microscopy, may be enough for the tumor development inAWTA patients who already have a large DNA fragment deletion in 11pi 3 in their constitutional cells.
Two tumors classified as cystic partially differentiated neph-roblastoma showed hyperdiploid karyotypes with 50 chromosomes, including No. 12 trisomy. The hyperdiploid karyotypewith No. 12 trisomy was also reported in a tumor showing thesame histology (30) and was commonly seen in typical Wilms'
tumor. The karyotypic similarities may suggest a commongenetic mechanism shared by both histológica! types of tumors.
Karyotypes have been reported in 12 sarcomatous Wilms'
tumors, mostly specified as clear cell sarcoma of the kidney;four were included in this series and eight in the literature (15,17-19, 31). Five tumors had only normal karyotype, and twoxenografts established from two of the five also showed normalkaryotype. These findings imply that some sarcomatous Wilms'
tumors may not show microscopically detectable chromosomechanges. Of the seven tumors with chromosome abnormalities,one had hypodiploidy, three had pseudodiploidy, and three hadhyperdiploidy with 47 chromosomes. None had a hyperdiploidkaryotype with 48 or more chromosomes, which was frequentlyfound in typical Wilms' tumor. Three had del(ll)(pl3pl4) orlip- chromosome and two had reciprocal translocations,which were rare in typical Wilms' tumor. The diverse kary
otypes may reflect heterogeneous subgroups among sarcomatous Wilms' tumors. Accumulation of data on the tumors, with
precise chromosomal and pathological studies, is essential toelucidate whether typical Wilms' tumor and clear cell sarcoma
of the kidney have different pathogenesis and should be classified as different entities (24, 25).
Congenital mesoblastic nephroma is considered to be a benign tumor developing in infants of <6 months of age (26). Wefound trisomy or tetrasomy 11, with or without other changes,in two of two such nephromas. Although trisomies of chromosome 12 and some other chromosomes were quite common intypical Wilms' tumor, trisomy 11 was seen in only four (3%) ofthe 133 Wilms' tumors (Fig. 7), and none in our series. Thus,
trisomy 11 may be correlated with congenital mesoblastic nephroma, and certain genes on chromosome 11 may play a rolein the pathogenesis of this histológica! type of tumor.
None of the tumors in our series showed focal or diffuseanaplastic lesions. Karyotypes from only seven anaplasticWilms' tumors were reported in the literature (15, 18, 19). Four
of them had hypodiploidy or near-triploidy, with complex chromosome abnormalities, and the others had rather simplechanges.
Karyotypic Patterns of Wilms1 Tumor between Japanese Pa
tients and American and British Patients. Since the incidence ofWilms' tumor in East Asian children was only one half to one
third of that in Caucasian children (13), we compared thechromosome and histológica! patterns between the Japanesetumors and the American and British tumors, to clarify whetherthe difference in the incidence reflects differences in karyotypeor histology (14-19). Two Japanese series (Ref. 19 and ourdata) and five American and British series (14-18) included 52and 82 tumors, respectively. There was no significant differencein the distribution of the tumor cell ploidies or in the presenceof the tumors with the Ilpl3 abnormalities between the twopopulations. There was also no significant difference in thepercentage of clear cell sarcoma or anaplastic Wilms' tumor
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CHROMOSOMES IN WILMS' TUMOR
between the two populations. Thus, the higher incidence ofVVilms' tumor in Caucasian children was not related to thepredominance of Wilms' tumors with specific chromosome
patterns or certain histológica! subtypes.In conclusion, chromosome abnormalities we reported here
were recurrent and were correlated with the histológica! typesof childhood renal tumors. The abnormalities included not onlythe already well known 11pi3 deletion but also 11pi5 abnormalities, nonrandom trisomies, and certain chromosome orchromosome segment deletions. These abnormalities likely reflect critical genetic changes which contribute to developmentand progression of these tumors.
ACKNOWLEDGMENTS
We are grateful to K. Kon for expert technical assistance and N.Kobayashi and F. Shinonaga for secretarial assistance. We thank Dr.T. Oka, Asahikawa Medical College (Asahikawa, Hokkaido); Dr. Y.Hatae, National Sapporo Hospital (Sapporo, Hokkaido); Dr. T. Hir-ama, Hokkaido Children's Medical Center (Otaru, Hokkaido); Dr. A.
Kikuta, Fukushima Medical College (Fukushima, Fukushima); Dr. Y.Yamashita, Niigata University (Niigata, Niigata); Dr. I. Sekine, National Defense Medical College (Tokorozawa, Saitama); Drs. Y. Tsu-nematsu and Y. Tsuchida, National Children's Hospital (Setagaya-ku,
Tokyo); Dr. K. Hashizume, Tokyo University (Bunkyo-ku, Tokyo); Dr.K. Nishihira, Kanagawa Children's Medical Center (Yokohama, Kan
agawa); Dr. H. Kitou, Seirei Hamamatsu Hospital (Hamamatsu, Shi-zuoka); Dr. Y. Horikoshi, Shizuoka Children's Hospital (Shizuoka,
Shizuoka); Dr. M. Sakurai, Mie University (Tsu, Mie); Dr. K. Kawa,Osaka University (Osaka, Osaka); Dr. M. Miyaké,Osaka MedicalCollege (Takatsuki, Osaka); and Dr. A. Nakagawara, Kyushu University(Fukuoka, Fukuoka) for providing chromosome samples, pathologyslides, and clinical data.
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1991;51:5937-5942. Cancer Res Yasuhiko Kaneko, Chieko Homma, Nobuo Maseki, et al. Clinical Features in Wilms' and Other Childhood Renal TumorsCorrelation of Chromosome Abnormalities with Histological and
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