Hereditary Renal Cell Carcinoma in the Rat Associated with Nonrandom Loss of Chromosomes 5 and 61

[CANCER RESEARCH 5l. 4415-4422, August 15. 1991| Hereditary Renal Cell Carcinoma in the Rat Associated with Nonrandom Loss of Chromosomes 5 and 61

Kenji Funaki,2 Jeffrey Everitt, Mitsuo Oshimura, Jerome J. Freed, Alfred G. Knudson, Jr., and Cheryl Walker1 Chemical Industry Institute of Toxicology, Research Triangle Park, North Carolina 27709 Â¡K.F.,J. Â£.,C. W.]; Tottori L'niversity, Yonago, Japan Â¡M.O./; and Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111 fJ. J. F., A. G. K.]

ABSTRACT A large body of work exists documenting the induction of RCC in rats by various chemical carcinogens (1), although the A spontaneous form of renal cell carcinoma occurs in rats that arises use of these animals as models for studying the mechanism of as the result of the inheritance of a mutation in a single autosomal gene. Cytogenetic analysis was performed on seven cell lines and four primary RCC and extrapolating this information to humans have been tumor cell preparations derived from this hereditary form of renal cell limited by the fact that spontaneous RCC in rats is very rare carcinoma. Banded karyotypes prepared from these seven lines exhibited (28). However, a line of Long-Evans rats has been developed loss and/or partial deletion of both chromosomes 5 and 6. Translocations that carries a single gene mutation that predisposes to renal involving chromosome 4, resulting in a net loss of genetic material located cell carcinoma (29). The mutation has an autosomal dominant near the centromere (4qll), were observed in three of the cell lines. pattern of inheritance with 100% penetrance (30). Rats that Monosomy, translocation, and breakage of chromosome 5 involving band inherit the mutation develop tumors bilaterally (30), and tumors 5q31 and monosomy and partial deletion of chromosome 6 involving band have been detected in these animals as early as 4 months of 6q22-q24 were independently observed in primary tumor cells from three age.5 Tumors develop spontaneously in animals that are heter of four tumors examined. Monosomy of chromosome 4 was observed in cells from a single tumor. The smallest region of deletion of chromosome ozygous for the mutation, but the mutation is lethal when 6 common to all the cell lines and tumor cells was 6q24, suggesting the homozygous (30), suggesting that at least one normal copy of presence of a tumor suppressor gene at this locus. These results indicate this gene is required for normal growth and development. that loss of genes located on chromosomes 4, 5, and 6, possibly tumor While it is clear that a single gene mutation is responsible suppressor gene(s), may be important for tumor development and/or for the inherited susceptibility to renal cell carcinoma in this progression in rat renal cell carcinoma and is consistent with the hypoth rodent model (29, 30), the location and nature of this gene esis that a gene locus on one of these chromosomes may be the site of defect are unknown. The pattern of inheritance of this suscep the original predisposing mutation. tibility and histological similarity to the human disease are both consistent with the predisposing mutation having occurred in a tumor suppressor gene. As a first step in determining whether INTRODUCTION loss of a tumor suppressor gene function might play a role in Histologically, RCC4 in rats resembles that in humans (1, 2) tumor development in this animal model, we examined cell and in both species is thought to arise from cells of the proximal lines and tumor cells derived from these hereditary rat renal convoluted tubule (1). In humans, RCC occurs in both a spon cell carcinomas for loss or partial deletion of specific taneous and a hereditary form. Both forms of the disease are chromosomes. associated with loss of genetic material on human chromosome 3 (p arm) (3-13), suggesting the presence of a tumor suppressor MATERIALS AND METHODS gene in this region. Loss or partial deletion of chromosome 3 is the most frequent cytogenetic alteration observed in renal Cell Lines. Renal cell carcinomas from individual rats carrying the Eker mutation (29) were explanted into tissue culture for the establish cell carcinoma, with alterations of 3p reported in some studies ment of cell lines (31).' Seven cell lines from ERCs were used in this in >95% of nonpapillary renal cell carcinomas examined (4). analysis: ERC 15; ERC 17; ERC 18; ERC 19; ERC 21; ERC 24; and In at least one hereditary renal cell carcinoma, inheritance of a ERC 37. Cell lines were maintained in medium consisting of 50% balanced translocation involving chromosome 3 has been re Dulbecco's minimal essential medium (high glucose) and 50% Ham's ported (7), and von Hippel-Lindau disease, which predisposes F-12, supplemented with 10% fetal bovine serum and ferrous sulfate to renal cell carcinoma as well as other tumors, shows consistent (1.6 x IO"6 M), sodium selenite (5 x IO"8 M), vasopressin (1 x IO"5 loss of heterozygosity for alÃeleson 3p in tumor DNA (14, 15). units/ml), cholesterol (1 x 10~8 M), hydrocortisone (2 x IO"7 M), transferrin (10 ng/ml), triiodothyronine (I x IO"9M), and insulin (25 In addition to chromosome 3, trisomy of chromosome 7 also /Â¿g/ml)(hereafter referred to as complete DF8 medium). All cell lines occurs frequently in human renal cell carcinoma (16, 17), and were grown at 37Â°Cin a humidified atmosphere of 5% CO2 and have the presence of an alteration on both chromosomes 3 and 7 may be associated with a more aggressive tumor phenotype been in continuous culture for over 1 year. Isolation of Primary Tumor Cells. Five female rats (A-E) and 1 male (16). The same region of chromosome 3p which is deleted in rat (EKT-1), carrying the Eker mutation, were sacrificed at approxi renal cell carcinoma is also frequently lost in other human mately 16 months of age, and the tumors were removed for cytogenetic tumors such as those arising in the lung (18-25), cervix (26), analysis. Tumor tissue was minced finely and placed in a spinner flask and mesothelioma (27). with 2.5% trypsin in Ca2*,Mg2+-free phosphate-buffered saline and incubated at 37Â°C.Aliquots were removed from the flasks at 30-min Received 2/15/91: accepted 6/10/91. The costs of publication of this article were defrayed in part by the payment intervals, and the trypsin was neutralized by the addition of serum. of page charges. This article must therefore be hereby marked advertisement in Cells were then pelleted and resuspended in complete DF8 medium accordance with 18 U.S.C. Section 1734 solely to indicate this fact. and plated into a 50:50 mixture of complete DF8 medium and Swiss ' These studies were supported in part by Department of Health and Human 3T3 fibroblast-conditioned media. Primary cultures were obtained from Services Grants CA-06927 and CA-43211. 2 Present address: Tottori University. Yonago. Japan. four of five tumors, isolated from females B, D, and E and male EKT- 3To whom requests for reprints should be addressed, at Chemical Industry 1 (tumor F). Institute of Toxicology. P. O. Box 12137. Research Triangle Park. NC 27709. ' The abbreviations used are: RCC, renal cell carcinoma: ERC, Eker rat renal *J. Everitt. unpublished observations. carcinoma. 6J. Freed and A. Knudson. manuscript in preparation. 4415

Cytogenetic Analysis. Cultures were exposed to colcemid (0.02 ng/ The chromosome number and modal karyotype for each cell ml) for 1.5-2 h before reaching confluency. Cultured cells were detached by treatment with 0.05% trypsin:EDTA for 5 min at 37Â°Cand centri- line are presented in Table 1. Four of the seven cell lines were aneuploid with chromosome number distributions ranging be fuged. Cell pellets were resuspended in a hypotonie solution of 0.075 M KC1 for 15 min at 37Â°Cand then fixed with methanohacetic acid tween In and 4n, and the remaining lines had chromosome numbers in the In or 4n range. Diploid and tetraploid cells (3:1, v/v). After three changes of fresh fixative, cell suspensions were dropped onto glass slides and air dried. Preparations stained with a 2% from the same cell line consistently contained identical chro Giemsa solution were used for chromosome counts. The chromosome mosome rearrangements, indicating that the tetraploid cells number in 45 to 100 metaphases was counted to construct the chro originated from the diploid ones. Modal chromosome numbers mosome number distribution. For chromosome banding analysis, de- were diploid or hypodiploid in five cell lines and hypotetraploid stained preparations were stained by a Q-banding method (32). Banded in two cell lines, suggesting that specific chromosome losses metaphases (10 to 15 from each cell line and 14 to 23 from each tumor) had occurred in the ERC cell lines. Karyotypes of the cells were used for determining karyotypes of the cells. The karyotype that examined revealed that each cell line had some recurrent and was most frequently observed in each cell line was judged to be modal. common chromosome changes in spite of a wide variety of Chromosome rearrangements were classified into common and recur numerical and structural alterations and that in some cases the rent abnormalities. The former is an abnormality observed in >80% of the cells examined from a cell line, and the latter is one found in >20% same chromosome changes occurred in three or more cell lines of cells examined. Primary dermal fibroblasts carrying the Eker muta (Tables 1 and 2). tion were normal diploid (2 n = 42). Numerical Alterations. Numerical chromosome aberrations were observed to be hypomodal changes; no recurrent hyper- modal alterations were observed in any of the cell lines. Recur RESULTS rent hypomodal changes in autosomes 6, 9, 14, 15, 18, and 19 Chromosome Number. Seven cell lines, five from male donors and both sex chromosomes were observed in three or more cell and two from female donors, were successfully analyzed for lines (Table 2). Chromosomes 6, 9, 14, 15, 18, and X were lost specific chromosome alterations. One additional line examined, in 3 cell lines, and chromosomes 19 and Y were missing in 4 ERC 13, was so highly aneuploid that it could not be analyzed. and 5 different cell lines, respectively. Loss of chromosome 5

Table 1 Chromosome number and modal karyotype for RCC cell lines mRangeIn of cells counted/karyotyped45/1080/1080/10 withmodalkaryotype402030 CelllineERC 3/1-4Â«34-43, karyotype38.X.-Y,- 15ERC 67-7663-8140-42. ;?)(pi 1,-3,-4,-5,-6,-9,- 10,+der( l)t( 1 l;?),+t(3q;4q),+Ml,+M2 \TERC 74, XX, â€”Y, â€”5, â€”9, â€” 11, â€” 13, â€” 18. â€” 19, â€”20, +der( 11)t( 11;13)(p 12;q 12?), +M 1, +M2, +M3. +M4 18 67-82 41, X, -X, -3. â€”4, -5, -6, +der(3)t(3;?) (q42;?) + Â¡(4),+der(6)t(6;?)(q24;?), +M1, M2 ERC19Â°ERC 86/1080/15 72-7936-41 75,-13,-15, X, -X, â€”Y, -2, â€”5, â€”6, -8, -9, 2020 â€” 18, -19, -20, ++der(6)t(6;7)(q24;ql3), +M1.+M2 21ERC 38, X, -Y, -5, â€”6, -8, -9, -10, -11, -19, inv(l)(q21q55). +der(6)t(6;9)(qll;ql3) + der(6)t(6;?)(q24;7), +t(8; 11)(q11;q 11) del(10)(q26). +der(10)t(10;?)(q26;?). +M1, +M2 24ERC 100/1093/10Chromosome38-4572-7941-43, 3942Modal 39,-19,+der(3)t(3;?)(q42;?), X, -Y, -3, -5, -6, -10, -15, SO80 +M1, +M2, +M3, M4 37Cells 84).Mode3874417538 42, X, -X, -1, -3, -6, -7, +t(lq;4q) +t(3;?), +der(6)t(4;6)(ql I;q24) +der(7)t(7;?)(q36;?), +M1% " Deviation from tetraploidy.

Table 2 Numerical and structural abnormalities for RCC cell lines Numerical abnormalities Structural abnormalities

Common Recurrent Common Recurrent ERC 15 -5,-6.-9,-10,-Y -8,-11,-19 der(l)t(l;?)(pll;?)t(3q;4q) ERC 17 â€”5,â€”9,-11,â€”13, -4,-6, â€”8,-14, der( 1)t( 1;4)(q22;q 11-12)t(3;7)(q 11;q 11) â€”18, â€”19, â€”Y -15,-16, t(3;l l)(ql l;ql l),t(3q;?)der(3)t(3;?) â€”20,-X (ql3;?),der(6)t(6;?)(q24;?)der(ll)t ( 11;13)(pl 2;q 12?)der( 15)t( 15;?)(p 12?;?) ERC 18 -X -5,-11 der(3)t(3;?)(q42;?)i(4)der (6)t(6;?)(q24;?) ERC 19 -2,â€”5,-8.-9,-13, -7.-11.-14.â€”16. der(6)t(6;7)(q24;ql3) -15.â€”18,-19,-X, -20 â€”Y ERC 21 -5 -9.-Y inv( 1)(q2 1q55)der(6)t(6;9)(q 11;ql 3)der (6)t(6;?)(q24;?)der(10)t(10;?)(q26;?),

ERC24 -5,-6,-10,-15,-18, -1.-I4 der(3)t(3;?)(q42;?) der(l)t(l;Y)(pl3;qlI) -19 ERC 37 -X -5 t( 1q;4q),t(3q;?)der(6)t(4;6) (qll\4)der(7)t(7:?) (q36;?)

4416

chromosomes 3, 4, and 6 were constant for each chromosome, the other chromosomes involved in the translocations were generally variable. Five different types of translocations between chromosome 3 and other chromosomes, with breakpoints at 3qll, were ob served in three cell lines, ERC 15, 17, and 37 (Figs. 1, 2, and 7). Two cell lines, ERC 18 and 24, contained a translocation involving 3q42. Three different types of translocations involving chromosome 4, with breakpoints at ql 1, were also found in three cell lines, ERC 15, 17, and 37 (Table 2), and a fourth cell line, ERC 18, contained an isochromosome 4 (Fig. 3). Thus, three of the four chromosome 4 alterations observed (ERC 15, 17, and 18) resulted in a net loss of genetic material near the centromere of this chromosome. Of particular interest were translocations between chromo some 6 and other chromosomes, which occurred in five cell lines, ERC 17, 18, 19, 21, and 37. These cell lines had translocations of chromosome 6 with breakpoints at q24, resulting in the deletion of 6q24â€”Â»qter(Figs.2-5, and 7). Chromosomes 5 and 6 Alterations. In all the cell lines exam Fig. 1. Q-banded karyotype of ERC15: 38,X,-Y,-l,-3,-4,-5,-6,-9,-10, ined there were hypomodal changes of chromosomes 5 and 6 +der(l)t(l;?)(pll;?),+t(3q;4q),+Ml,+M2..4/TOiv, breakpoint at 3qll which was commonly observed in several cell lines. including a partial loss of 6q, suggesting that these chromosome changes were common to the development of renal cell carci was observed in all cell lines (Figs. 1-7). Missing sex chromo noma in the Eker rat. As shown in Table 3, loss of one or two somes (one copy of the X-chromosome in the female and the copies of chromosome 5 was observed as a common abnormal Y-chromosome in the male) were found in every cell line. ity in five cell lines and as a recurrent abnormality in two cell Additionally, a variable number of unidentified marker chro lines (<40% of the cells). On the other hand, chromosome 6 mosomes were consistently observed in each cell line. consistently exhibited loss or deletion in >60% of the meta- Structural Alterations. Structural abnormalities were present phases in all the cell lines. Of the seven cell lines examined, in all the cell lines (Table 2). Recurrent or common re two (ERC 15 and 24) had lost a copy of chromosome 6, three arrangements involving chromosomes 1, 3, 4, and 6 were noted (ERC 18, 21, and 37) exhibited a deletion in 6q, and the in at least four cell lines (Table 2); rearrangements involving remaining two (ERC 17 and 19) contained metaphases with chromosome 4 were observed in four cell lines, and chromo both losses and deletion of chromosome 6. somes 1, 3, and 6 were rearranged in five cell lines. Detailed Primary Tumors. Primary tumors were dissected from 6 rats, banding analysis showed that although chromosome 1 was 5 females and 1 male, and metaphase cells suitable for cytoge- rearranged in five cell lines, each had a different breakpoint. netic analysis were successfully obtained from 4 different ani However, rearrangements involving chromosomes 3, 4, and 6 mals. Although the majority of the cells examined in primary exhibited common breakpoints in three to five different cell culture appeared to be normal and had karyotypically normal lines. Although the breakpoints of rearrangements involving diploid metaphases, some cells in every tumor cell culture

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Fig. 2. Q-banded karyotype of ERC17:73,XX,â€”Y,-3,â€”5,â€”6,â€”9, 11, 13,-14,â€”18,â€” 19,del(3)(pll),+t(3q;?),++der(6)t(6;?)(q24;?),+der (10)t(10;?)(q32;?),++der(l I)t(ll;13)(pl2 ; ql2),+Ml,+M2,3,+M4. Arrows, rearranged chromosomes. 4417

mosome 5 from tumor D and two metaphases with monosomy 6 from tumors D and E each contained one or two unidentified marker chromosomes, indicating that these metaphases were derived from tumor cells. Fig. 10 is a schematic representation of the regions of chro mosomes 4, 5, and 6 altered in the cell lines and tumor cells. The exact breakpoint on chromosome 4 involved in the translocations observed in the cell lines is difficult to establish; however, all three breakpoints clustered in the region 4qll. Breakage and translocation of chromosome 5 in all tumors involved band 5q31. Deleted regions of rearranged chromosome 6 were 6q24-qter in five cell lines and 6q22-24 in a primary tumor; the smallest common region of deletion observed in every cell line and a primary tumor was band 6q24. In all cases, monosomy of chromosome 5 and monosomy and translocation of chromosomes 4 and 6, the cytogenetic alteration resulted in a net loss of genetic material.

DISCUSSION Fig. 3. Q-banded karyotype of ERC18: 41,X,-X,-3,â€”4,-5,-6,-10, +der(3)t(3;?)(q42;?),+i(4),+der(6)t(6;?)(q24;?),+Ml,+M2,+M3. Arrows, Loss and/or partial deletion of chromosomes 5 and 6 oc rearrangedchromosomes. curred in both tumor-derived cell lines and primary tumor cell cultures from spontaneous renal cell carcinomas that developed examined had recurrent chromosome abnormalities (Table 4). in rats carrying the Eker mutation. Alterations of chromosome Numerical changes involving nearly every chromosome were 4 due to translocations in the cell lines, resulting in net loss of observed in the primary cultures, but they were generally not genetic material located near the centromere, and monosomy recurrent, with the exception of the loss of chromosomes 14 of this chromosome in the tumor cells were also observed. and 16 observed in tumor E and the loss of chromosomes 4 Chromosome 5 alterations were present as a complete loss of and 9 observed in tumor F. Loss of chromosome 5 and/or 6 one or two copies of the chromosome in the cell lines and as a was observed in tumor-derived metaphases from three tumors breakage or translocation at band 5q31 in the primary tumor examined, and monosomy of chromosome 4 was observed in a cells. Chromosome 6 anomalies in the cell lines involved mon single tumor. osomy, deletions, and/or translocations. The smallest common Of particular interest were structural changes of chromo region of deletion observed for chromosome 6 in all seven cell somes 5 and 6 observed in tumors B and D. Three of 15 lines was 6q24â€”Â»6qter.Inthe primary tumor cell preparations, metaphases from tumor B and 2 of 23 from tumor D had chromosome 6 alterations also were present as either mono breakage at band 5q31, and 1 metaphase from tumor B exhib somy or a partial deletion involving band 6q22-q24. The fre ited a translocation involving chromosome 5 with a breakpoint quency of chromosome 4, 5, and 6 alterations in the original at the same band (Fig. 8). Rearrangements of chromosome 6 tumors from which the primary cell cultures were isolated is were observed in 3 of 15 metaphases from tumor B, and all of difficult to determine with certainty, because the majority of these exhibited a common deletion of band 6q22-q24 (Fig. 9), the metaphases from these preparations were diploid, suggest which includes the smallest common region of 6q deletion ing that they were derived from normal, rather than neoplastic observed in ERC cell lines. A metaphase with a missing chro kidney tissue. Although loss of a sex chromosome occurred

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Fig. 4. Q-banded karyotype of ERC19:74,X.-X,â€”Y.-2,â€”5,â€”6.-S.-9.-13.-15.-17.â€” 18,-19,++der(6)t(6;7)(q24;q 13)(amwi),+M 1,+M2,+M3,+M4. 4418

associated with tumorigenicity in somatic cell hybrids (42). Interestingly, chromosome 5 also contains a large linkage group that is syntenic with human chromosome 1 (33). Human chro mosome 1 is frequently altered in many types of malignancies including cancers of the reproductive organs (43,44), leukemias (45-47), breast carcinoma (48, 49), melanoma (50), multiple endocrine neoplasia (51), neuroblastoma (52), and mesothelioma (27, 53-59). Human chromosome 1 also appears to contain gene(s) that can suppress tumorigenicity in somatic cell hybrids (60, 61) and contains a gene that is involved in cellular senescence (62). There are as yet no good data to suggest that a linkage group on either rat chromosome 5 or 6 is syntenic with the linkage group on human chromosome 3 thought to contain the putative human tumor suppressor gene involved in renal cell carcinoma (3-13). Several human probes map very close to the human 3p locus including RAF-1, RARB, and the anonymous probe DNF15S2. These loci have been mapped to chromosomes 4, 15, and 8 in the rat, respectively (33), suggesting that linkage Fig. 5. Q-banded karyotype of ERC21: 38,X,-Y,-5,â€”6,-8,-9,-H, -19,inv(l)(q21q55).+t(6q;9ql3),+der(6)t(6;?)(q24:?),+t(18:ll)(qll;qll). in this region of human chromosome 3 has not been highly del(10)(q26),+Ml./lrroB'i, rearranged chromosomes. conserved in the rat. However, of the seven ERC cell lines examined, chromosome 4 alterations resulting in a net loss of material near the centromere of this chromosome were observed in three cell lines, and monosomy 4 was observed in primary tumor cells. If the rat homologue to the putative human RCC tumor suppressor gene located near the RAF-1 locus on chro )C mosome 3 is linked to the c-raf-\ locus on rat chromosome 4, 4 5

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Downloaded from cancerres.aacrjournals.org on October 1, 2021. © 1991 American Association for Cancer Research. RENAL CELL CARCINOMA AND NONRANDOM LOSS OF CHROMOSOMES 5 AND 6 this gene could be involved in these chromosome 4 re arrangements. Although the frequency of chromosome 4 alter ations in the cell lines and tumors is not as high as those involving chromosomes 5 and 6, events unobservable at the level of cytogenetics (such as point mutations) could have occurred to unmask a recessive mutation in a tumor suppressor gene at this locus. In retinoblastoma, the frequency of cytogenetic alterations affecting chromosome 13, the site of the reti noblastoma tumor suppressor gene (63), is only 5-25%, whereas extra copies of 6p (possibly related to tumor progres sion) are observed in 35-70% of retinoblastomas (64). There fore, the relative frequency of cytogenetic alterations of a par ticular chromosome may not be the best criterion for assessing the role of these changes in the development of the disease. The presence of nonrandom cytogenetic alterations involving chromosomes 4, 5, and 6 in the cell lines and in primary tumor cells suggests that genes on more than one chromosome are involved in the establishment of cell lines and/or tumor devel opment and progression in this animal model. In all cases, the cell lines used for this analysis were established from relatively large tumors, since small tumors could not be successfully Fig. 9. Q-banded karyotype of primary metaphase from tumor B showing a explanted into primary culture.7 This suggests that cell lines rearrangement of chromosome 6: del(6)(q22q24) (arrow). Inset, partial karyotype with an insertion involving deletion of the same region in chromosome 6. isolated from large tumors may be representative of cells from a more advanced stage of tumor development and therefore may display additional cytogenetic alterations relative to neo- i1234^^â€”1 plastic cells present in the earliest stages of tumor development. J. I Several types of human cancer, such as colon carcinoma, have

Table 4 Chromosome abnormalities in primary Iunior cells

TumorBD karyotyped1523 abnormalities:(5)(q31)|20r

del(6)(q22q24) [7] ins(6;?)(6cen^6q22: :(5)(q3l)|9] EFCells 1419Chromosome-14(21] -16(21] -4 [16] Fig. 10. Histogram of breakpoints on chromosomes 4, 5, and 6. Top, regions -9 [16]:?::6q24-^qter)[13] of chromosome 4 deleted in cell lines ERC 15, 17, and 18. Dashed line for ERC Â°Numbers in brackets, percentage of cells with abnormality. 17, ambiguity in estimating breakpoint within 4qll region for this line. Break points on chromosome 5 are those observed in tumors B and D. Breakpoints accumulate at band 5q31. Deletions of chromosome 6 represent those observed in ERC 17, 18, 19, 21, and 37 cell lines and cells from tumor B. The smallest common region of deletion of chromosome 6 was 6q24.

been shown to exhibit multiple chromosome alterations asso ciated with tumor progression (65-67). The order of occurrence H l! n n M of chromosome 4, 5, and 6 alterations in this animal model remains to be determined. In summary, nonrandom cytogenetic alterations involving loss of material on chromosomes 4, 5, and 6 were frequently Â»â€¢il M observed in cell lines and primary tumor cells isolated from hereditary rat RCCs. While the exact number or type of genes involved in these chromosome aberrations is not known at this time, these data are consistent with the involvement of tumor suppressor gene(s) in RCC in the Eker rat model. Characteriza tion of the genes involved and identification of their human homologues will be a valuable approach to understanding the mechanisms underlying the development of human RCC.

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Downloaded from cancerres.aacrjournals.org on October 1, 2021. © 1991 American Association for Cancer Research. Hereditary Renal Cell Carcinoma in the Rat Associated with Nonrandom Loss of Chromosomes 5 and 6

Kenji Funaki, Jeffrey Everitt, Mitsuo Oshimura, et al.

Cancer Res 1991;51:4415-4422.

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