(CANCER RESEARCH 51, 4707-4711, September 1, 1991]

A Detailed Deletion Mapping of the Short Arm of Chromosome 3 in SporadicRenal Cell Carcinoma1

Kazuhiro Yamakawa, Ryoji Morita, Ei-ichi Takahashi, Tada-aki Hori, Jiro Ishikawa, and Yusuke Nakamura2

Department of Biochemistry, Cancer Institute, 1-37-1, Kami-Ikebukuro, Toshima-ku, Tokyo 170, Japan [K. Y., R. M., Y. N.J; Department of Genetic ResearchLaboratory, SRL, Inc., Komiya-machi, Hachioji, Tokyo 192, Japan [R. M.J; Division of Genetics, National Institute of Radiological Sciences, 4-9-1, Anagawa, Chiba260, Japan [E-i. T., T. H.J; and The Center for Biotechnology, Baylor College of Medicine, The Woodlands, Texas 77381 ¡J.I.]

ABSTRACT

A detailed analysis of loss of heterozygosity in 40 sporadic renal cellcarcinomas was performed by using 30 restriction fragment length polymorphism markers which were mapped on the short arm of chromosome3. A total of 30 of 38 informative cases (79%) showed loss of heterozygosity at one or more loci. Two commonly deleted regions have beenidentified at 3p 13-14.3 and 3p21.3. One of them (at 3p 13-14.3) spans

the breakpoint of the (3;8) translocation in hereditary renal cell carcinomapreviously reported (A. J. Cohen et al., N. Engl. J. Med., 301:592-595,

1979). The second common region of deletion at chromosome 3p21.3encompasses D3F15S2, at which a high incidence of loss of heterzygosityin renal cell carcinoma has been reported. In addition to the gene at 3p25being responsible for the hereditary type of renal cell carcinoma inpatients with von Hippel-Lindau disease, our results suggest that at least

two tumor suppressor genes for sporadic renal cell carcinoma exist onthe short arm of chromosome 3.

INTRODUCTION

Specific chromosomal aberrations have been reported in anumber of human malignancies and are thought to be associatedwith either the activation of protooncogenes (1) or the inacti-vation of tumor suppressor genes (2, 3). In several malignancies,candidate tumor suppressor genes have been isolated: the reti-noblastoma gene on chromosome 13q (4); the Wilms' tumor

gene on chromosome 1Ip (5); the DCC gene on chromosome18q (6); the neurofibromatosis I gene on chromosome 17q (7,8); and the MCC gene on 5q (9). The p53 gene on chromosome17p is also considered to be a tumor suppressor gene (10).

Chromosomal rearrangements and/or deletions of the shortarm of chromosome 3 have also been described in lung cancer(11), uterine cancer (12), breast cancer (13), testicular tumors(14), ovarian cancer (15, 16), and various hematological malignancies ( 17). RCC3 shows a particularly high frequency (60 to100%) of allelic loss (18-22) and specific chromosomal rearrangements (23, 24) of the short arm of chromosome 3. Inaddition, chromosomal translocations involving chromosome3 have been described in hereditary renal cell carcinomas.Members of a large Italian-American family with hereditaryrenal cell carcinoma were reported (25) to show a balancedreciprocal translocation between chromosomes 3 and 8,t(3;8)(pl4.2;q24.13) in peripheral leukocytes (26). Another hereditary RCC family has been described by Pathak et al. (27).The members of this family did not carry any constitutionalcytogenetic aberration, but one of them had an acquired (3;11)translocation in his metastatic tumor cells. The breakpoint of

Received 4/19/91; accepted 6/17/91.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 V.S.C. Section 1734 solely to indicate this fact.

' This work was supported in part by a Grant-in-Aid from the Ministry of

Education, Science, and Culture, Japan, and a grant of the Vehicle RacingCommemorative Foundation.

2To whom requests for reprints should be addressed.3The abbreviations used are: RCC, renal cell carcinoma; RFLP, restriction

fragment length polymorphism; FISH, fluorescence in situ hybridization; LOH,loss of heterozygosity; VHL, von Hippel-Lindau disease.

translocation on chromosome 3 was in the same region as thatin the family described by Cohen et al. (25). Although there aremany reports of aberrations of chromosome 3 in renal cellcarcinoma as described above, the tumor suppressor gene ofRCC on chromosome 3 has not yet been isolated. To characterize these aberrations more finely and to isolate the tumorsuppressor gene, we constructed a detailed deletion map of theshort arm of chromosome 3 in 40 sporadic renal cell carcinomasusing 30 RFLP markers. A large number of markers on chromosome 3 used in this study was recently isolated (28, 29). Wealso compared by fluorescence in situ hybridization the commonly deleted region and the breakpoint of t(3;8) chromosomein hereditary renal cell carcinoma (25), which have been considered to be a locus of a tumor suppressor gene (18, 30).

MATERIALS AND METHODS

Tumor Specimens. Normal and tumorous tissues were obtained frompatients diagnosed histologically as having renal cell carcinoma inradical nephrectomy specimens. Tissues from 39 patients were obtainedat the Kobe National Hospital or the School of Medicine at KobeUniversity, Kobe, Japan, and that from one patient was obtained at theCancer Institute Hospital, Tokyo, Japan. All tissues were dissected inthe operation room, frozen in liquid nitrogen, and stored at —85°C.

Clinical data of these patients are summarized in Table 1.DNA Extraction and Southern Blotting. Frozen tissue samples were

ground to a very fine powder using a mortar and pestle at liquid nitrogentemperature. The powdered material was transferred to lysis buffer andextracted by phenol-chloroform-isoamyl alcohol as described elsewhere(31). Five jig of DNA were digested overnight with 50 units of restriction enzymes (Boehringer Mannheim) and electrophoresed using 1.2%(for Ddel) or 1% (for Mspl, Taql, Pvull, Pstl, Bglll, Hindlll) agarosegel. The DNAs were then transferred to nylon membranes (Pall; Biod-yne) in 0.1 N NaOH-0.1 M NaCl and fixed by UV cross-linking.

Probes and Hybridization. AH probes used in this study are listed inTable 2. cCI3 markers have been localized finely on chromosome 3 byfluorescence in situ hybridization (28), and the loci were confirmed bylinkage analysis (29). pMSl-37(D3S3) (32) and p627 (human c-ra/-l)(33) were obtained from the Japanese Cancer Research Resources Bank.pH3H2 (D3F15S2) (34) was obtained from the American Type CultureCollection. Probes were labeled with [32P]dCTP by random primer

extension (35). Prehybridization, hybridization, and autoradiographywere carried out as described elsewhere (31). The membranes werestripped in 0.4 N NaOH and repeatedly rehybridized.

Fluorescence in Situ Hybridization. In order to characterize the t(3;8)breakpoint of hereditary RCC, we performed FISH using a fibroblastcell line from a member of the family reported by Cohen et al. (25).CCI3-373, -382, -488, -528, -610, and -721 were used as probes. Themethod of FISH has been described in detail elsewhere (36).

RESULTS

Deletion Mapping of Chromosome 3. Using 30 markersmapped on chromosome 3, we performed RFLP analysis of 40sporadic renal cell carcinomas. Fig. 1 shows the results ofSouthern blots of tumors which have interstitial deletion onchromosome 3p. Tumors 2 and 24 show LOH around the

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DELETION MAPPING OF CHROMOSOME 3 IN SPORADIC RCC

Table 1 Patient statusPatient"1234567810111214IS161718192021222324252629323334353637383940414344454759Stage*T2V0N„M„T4V,N0M,TjVoNoMoTjVjNoMoT,V„N„M,T2V,N„M0T2V0N„M„T.V.NíM,T2V„N„M,T2V„N„M0T3V„N„M„T2VoN„M„T2V,N0M0T,V2N0M,T2V0N0M„TjV„N„M0T2V„N0MoT3V2N„MoT2V0NoMoT2V0N0MoTjVoNoM,TjV.NoMoT2V0N0MoT,V,NoM,T2V„N0M0T2V0N0MoT2V„N0MoT2V„N0M0T.VoNoM»T,V0N4M0T2V„N0M„TjV,N0MoT4V,N0M,T2V0N0M,T4V2N„MXT2V0N„M0T,V0N0M0T2V,N0MoT2V0N0M0TxVxNxMxGrade*131222232131122212112221112122122232222XHistopathology*AlveolarSolidAlveolarAlveolarAlveolarAlveolarAlveolarSolidCysticAlveolarSolidAlveolarAlveolarAlveolarAlveolarAlveolarAlveolarAlveolarAlveolarAlveolarAlveolarAlveolarAlveolarAlveolarPapillaryAlveolarAlveolarAlveolarAlveolarSolidAlveolarAlveolarAlveolarCysticPapillaryAlveolarTubularAlveolarAlveolarNACCelltype*ClearSpindleClearClearClearClearClearGranularClearClearGranularClearClearClearClearClearClearClearClearClearClearClearClearClearClearClearClearClearClearGranularClearClearClearGranularClearClearClearClearClearNA

°Some patients had to be excluded for technical reasons.* Stage, grade, histopathology, and cell type of tumor were determined accord

ing to the Japanese Pathological Society (42).c NA, not available.

chromosome region 3p21.3. Tumor 38 shows LOH at a pointdistal to 3p21.3 and proximal to 3pl4.2, but it retained heter-ozygosity at 3pl4.3-3p21.3. Alíelelosses in Tumor 36 arerestricted to the region proximal to 3p21.3.

A total of 38 of 40 cases were informative in at least onelocus, and 30 of 38 tumors (79%) showed LOH in at least onelocus on chromosome 3. The data of LOH in 38 tumors aresummarized as deletion maps in Fig. 2, and the rate of alíelelosses is summarized in Table 2. The positions and order ofmarkers in Figs. 1 and 2 were determined by FISH (28) andlinkage analysis (29). Of the 38 informative samples, 12 (32%)showed LOH at all informative loci tested and 8 (21%) showedno loss at any loci on chromosome 3p. Eighteen of 38 informative samples (47%) showed interstitial or partial deletion onchromosome 3p. Common regions of deletion were segregatedinto two parts, 3pl3-14.3 and 3p21.3.

CCI3-533, -563, -604, -610, pH3H2, and pMSl-37, whichwere polymorphic to some extent in Caucasians, were notpolymorphic among our Japanese patients.

In Situ Hybridization. Fig. 3 shows the result of fluorescencein situ hybridization performed on prometaphase R-bandedchromosomes which contain t(3;8) chromosomes by usingcCI3-610 as a probe. Discrete signals can be seen on normalchromosome 3 and on chromosome 8 derivative which contains3pl4.2-3pter. This result indicates that the clone cCI3-610exists at a point distal to the breakpoint. The results of FISHare summarized in Fig. 4. cCI3-373, -488, and -528 were

mapped at a point proximal to the breakpoint, and cCI3-382,-610, and -721 were mapped at a point distal to the breakpoint.

DISCUSSION

We described the detailed deletion map of the short arm ofchromosome 3 in renal cell carcinoma (Fig. 2). In this study,30 of 38 informative cases (79%) showed LOH on the shortarm of one chromosome 3, which is comparable with theprevious data ( 19, 20). Four (Nos. 4,8,10, and 25) of 8 patients,who showed no LOH at any loci on chromosome 3, also showedno LOH at any loci on other chromosomes (22). This might bebecause of the contamination of normal tissue to tumor samples. Another 4 patients (Nos. 17, 39, 40, and 44), however,showed LOH clearly on other chromosomes (22). These tumorsmay be caused by the mutational events of other chromosomesor by submicroscopic deletions or point mutations on chromosome 3 which could not be detected with the set of probes inthis study.

From the maps which have interstitial deletions (Figs. 1 and2), two commonly deleted regions could be recognized at 3p21.3(between cCI3-515 and cCI3-524) and at 3p 13-14.3 (betweenCCI3-721 and YNZ86.1). The common deletion region at3p21.3 contains cCI3-9 which showed LOH in 3 of 3 informative samples (100%). Linkage analysis using 40 families revealed that the recombination fraction between cCI3-9 andD3F15S2 is zero (lod score = 21.48). Although pH3H2(D3F15S2) was not polymorphic in our study, high frequenciesof LOH at the D3F15S2 locus in renal cell carcinoma havebeen reported in many groups (18-21). This locus encodes a3.3-kilobase mRNA which is expressed in normal lung andnormal kidney. This gene was reportedly expressed in 4 of 5small cell lung cancer cell lines (37); it was expressed only at aseverely reduced level or not at all in 11 of 15 primary renalcell carcinomas (38). This gene might just be "linked butunessential" for RCC development, but the commonly deleted

region which contains D3F15S2 would likely encode one of theRCC tumor suppressor genes.

Table 2 Markers used for deletion mapping of chromosome 3 and loss ofheterozygosity in RCC

Probe"CCI3-369CCI3-343p627CCI3-326CCI3-544cCI3-305cCCI3-312CCI3-417CC13-245cCB-515'cCI3-9ccCB-524CCI3-382PEFD145CCI3-652CDI3-514CCI3-721CCI3-528CCI3-556CCI3-488pYNZ86.1CCI3-373cCI

3-757cCI3-315cLocus

symbolD3S1085D3S858RAF1D3S656D3S689D3S649D3S651D3S669D3S647D3S685D3S643D3S686D3S660D3S32D3S717D3S898D3S936D3S687D3S907D3S678D3S30D3S659D3S960D3S654EnzymePst\Taq\TaqlBgmMsp\Dde\Pvu\\TaqlBgmMsplPvullTaqlPvullTaqlPvullPstlMsplMsplBgniMsplMsplPvullPstlDdelChromosomal/

localization3p25-263p25-263p253p253p253p253p253p25.13p233p21.33p21.33p21.33p21.2-2l.33p21.2-21.33p2

1.2-21.33p21.-21.23p21.3pl4.

-14.23pl4.-14.23pl4.-14.23pl33pl33pl23pl2Ulele

loss/informativecases3/3(100)"5/11(45)0/1

(0)4/7(57)0/1(0)7/11(64)4/6(67)7/10(70)5/1

1(45)18/27(67)3/3(100)6/10(60)2/6

(33)9/15(60)3/6

(50)7/8(88)4/1

1(36)8/13(62)2/6

(33)7/10(70)8/16(50)8/11

(73)2/2(100)4/13(31)

°Markers are arranged in order from 3pter to 3cen. cCI3-533, CC13-563, cCI3-604, CCI3-610, pH3H2, and pMSl-37 were not polymorphic for all patients.

* Numbers in parentheses, percentage.c Variable number of tandem repeat marker (43).

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DELETION MAPPING OF CHROMOSOME 3 IN SPORADIC RCC

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Fig. 1. Results of Southern blots of tumors that have interstitial deletions on chromosome 3p. The left side of each blot shows DN A from normal kidney, and theright side shows DNA from RCC. Positions of probes indicated beside the karyogram were determined according to linkage data (29) and physical data (28). Fullnames of the probes appear in Table 2.

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', | :; ': '',':',:'', / i: :;::] ' ¡l¡| D11rj•LOH CZZZl RETAINED

Fig. 2. Deletion maps of chromosome 3p in 38 RCCs are shown. The tumor number is indicated on the top of each deletion map. The names of probes are indicatedbeside the karyogram. See Table 2 for full names.

The breakpoint of t(3;8) chromosome in hereditary renal cellcarcinoma reported by Cohen et al. (25) has been considered tocode for a tumor suppressor gene for renal cell carcinoma (18,30). By fluorescence in situ hybridization (Figs. 3 and 4), thebreakpoint was revealed to exist between two contiguous markers, CCI3-528 and cCI3-610, which are 10 CM (centimorgan)

apart from each other (29). cCI3-528 was contained in thecommonly deleted region at 3pl3-14.3, and this supports thehypothesis that the breakpoint codes for a tumor suppressorgene.

RCC has been observed in as many as 50% of VHL patientsat autopsy, and a case of proximal 3p deletion has been reported

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DELETION MAPPING OF CHROMOSOME 3 IN SPORADIC RCC

Fig. 3. Localization of the cosmid DNAcCI3-610 at prometaphase chromosome whichhas (3;8)(pl4.2;q24.l3) translocation by fluorescence in situ hybridization. The whole cos-mid was used as a probe under the conditionsthat suppress signals from repetitive DNA sequences, and replicated R-bands were stainedwith propidium iodide. An arrow indicates fluorescent signals on normal chromosome 3, andan arrowhead indicates signals on the derivative of chromosome 8 which has the short armof chromosome 3 (3pl4.2-3pter).

H3 derivative

8q21 13

fl-(Jor ivativr

Fig. 4. cCI3 markers mapped on t(3;8)(pl4.2;q24.13) chromosomes withhereditary renal cell carcinoma by fluorescence in situ hybridization. Full probenames appear in Table 2.

in the RCC of a patient with VHL (39). The gene responsiblefor VHL has been linked to RAF1; locus for an oncogenelocated at 3p25 (40, 41). Bergerheim et al. (19) reported thatone alíeleat the RAF1 locus was always lost in informativepatients, when their RCC samples had other losses of hetero-zygosity on chromosome 3p. Taken together these findingssuggest that the gene of VHL might be one of the tumorsuppressor genes of RCC. However, small deletions restrictedto 3p25 were not observed in our study (Fig. 2). This suggeststhat the gene of VHL is not essential for the development ofall sporadic RCCs, but may have a role in the development ofa proportion of these tumors.

ACKNOWLEDGMENTS

We acknowledge with thanks the supply of fibroblast cells of thefamily reported by Cohen et al. (25) from Frederick P. Li and tumorsamples from Sadao Kamidono and Sakan Maeda. We also thankKiyoshi Noguchi for technical assistance.

REFERENCES

1. Klein, G., and Klein, E. myc/\g juxtaposition by chromosomal translocations:some new insights, puzzles, and paradoxes, luminimi. Today, 6: 208-215,1985.

2. Knudson. A. G. Hereditary cancer, oncogenes, and antioncogenes. CancerRes., 45: 1437-1443, 1985.

3. Nordenskjold, M., and Cavenee, W. Genetics and the etiology of solid tumors.In: J. B. De Vita (ed.). Important Advances in Oncology, Vol. IV, pp. 83-101. Philadelphia: Lippincott. 1988.

4. Friend, S. H., Bernards, R.. Rogelj. S., Weinberg, R. A., Rapaport, J. M.,Albert, D. M., and Dryja, T. P. A human DNA segment with properties ofthe gene that predisposes to retinoblastoma and osteosarcoma. Nature(Lond.), 323: 643-646, 1986.

4710

on June 8, 2020. © 1991 American Association for Cancer Research. cancerres.aacrjournals.org Downloaded from

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5. Call, K. M., Glaser, T., Ito, C. Y., Buckler, A. J., Pellrtier, J., Haber, D. A.,Rose, E. A., Krai, A., Yeger, H., Lewis, W. H., Jones, C., and Housman, D.E. Isolation and characterization of a zinc finger polypeptide gene at thehuman chromosome 11 Wilms' tumor locus. Cell, 60: 509-520, 1990.

6. Fearon, E. R., Cho, K. R., Nigro, J. M., Kern, S. E., Simons, J. W., Ruppert,J. M., Hamilton, S. R., Preisinger, A. C, Thomas, G., Kinzler, K. W., andVogelstein, B. Identification of chromosome 18q gene that is altered incolorectal cancers. Science (Washington, DC), 247:49-56, 1990.

7. Wallace, M. R., Marchuk, D. A., Andersen, L. B., Letcher, R.. Odeh, H. M.,Saulino, A. M., Fountain, J. W., Brereton, A., Nicholson, J., Mitchell, A.L., Brownstein, B. H., and Collins, F. S. Type 1 neurofibromatosis gene:identification of a large transcript disrupted in three NFI patients. Science(Washington, DC), 249: 181-186, 1990.

8. Xu, G., O'Connell, P., Viskochil, D., Cawthon, R., Robertson, M., Culver,

M., Dunn, D., Steven, J., Gesteland, R., White, R., and Weiss, R. Theneurofibromatosis type 1 gene encodes a protein related to GAP. Cell, 62:599-608, 1990.

9. Kinzler, K. W., Nilbert, M. C, Vogelstein, B., Bryan. T. M., Levy, D. B.,Smith, K. J., Preisinger, A. C., Hamilton, S. R., Hedge, P., Markham, A.,Carlson, M., Joslyn, G., Groden, J., White, R., Miki, Y., Miyoshi, Y.,Nishisho, !.. and Nakamura, Y. Identification of a chromosome 5q21 genethat is mutated in colorectal cancers. Science (Washington, DC), 251: 1366-1369, 1991.

10. Finlay, C. A., Hinds, P. W., and Levine, A. J. The p53 proto-oncogene canact as a suppressor of transformation. Cell, 57: 1083-1093, 1989.

11. Brauch, H., Tory, K., Kotler, F., Gazdar, A. F., Pettengill, O. S., Johnson,B., Graziano, S., Winton, T., Buys, C. H. C. M., Sorenson, G. D., Poiesz,B. J., Minna, J. D., and /liar, B. Molecular mapping of deletion sites in theshort arm of chromosome 3 in human lung cancer. Genes, Chromosomes,and Cancer, /: 247-255, 1990.

12. Yokota, J., Tsukada, Y., Nakajima, T., Gotoh, M., Shimosato, Y., Mori, N.,Tsunokawa, Y., Sugimura, T., and Terada, M. Loss of heterozygosity on theshort arm of chromosome 3 in carcinoma of the uterine cervix. Cancer Res.,49: 3598-3601, 1989.

13. Devilee, P., van den Broek, M., Dukshoorn, N. K., Koluri, R., Khan, P. M.,Pearson, P. L., and Cornelisse, C. J. At least four different chromosomalregions are involved in loss of heterozygosity in human breast carcinoma.Genomics, 5: 554-560, 1989.

14. Lothe, R. A., Fossa, S. D., Stenwig, A. E., Nakamura, Y., White, R.,Borrensen, A. L., and Brogger, A. Loss of 3p or 1Ip alíelesis associated withtesticular cancer tumors. Genomics, 5: 134-138, 1989.

15. Whang-Peng, J., Knutsen, T., Douglass. E. C., Chu, E., Ozols, R. F.. Hogan.W. M., and Young, R. C. Cytogenetic studies in ovarian cancer. CancerGenet. Cytogenet., //: 91-106, 1984.

16. Trent, J. M., Thompson, F. H., and Buick, R. N. Generation of clonalvariants in a human ovarian carcinoma studied by chromosome bandinganalysis. Cancer Genet. Cytogenet., 14: 153-161, 1985.

17. Trent, J. M.. Kaneko, Y., and Mitelman, F. Report of the committee onstructural chromosome changes in neoplasia. Tenth International Workshopon Human Gene Mapping. Cytogenet. Cell Genet., 51: 533-562, 1989.

18. Kovacs, G., Erlandsson, R., Boldog, F., Ingvarsson, S., Muller-Brechlin, R.,Klein, J., and Sumegi, J. Consistent chromosome 3p deletion and loss ofheterozygosity in renal cell carcinoma. Proc. Nati. Acad. Sci. USA, 85:1571-1575, 1988.

19. Bergerheim, U., Nordenskjold, M., and Collins, V. P. Deletion mapping inhuman renal cell carcinoma. Cancer Res., 49: 1390-1396, 1989.

20. /bar. B., Brauch, H., Talmadge, C., and Linehan, M. Loss of alíelesof locion the short arm of chromosome 3 in renal cell carcinoma. Nature (Lond.),327:721-724, 1987.

21. Van der Hout, A. H., Kok, K., van den Berg, A., Oosterhuis, J. W., Carritt,B., and Buys, C. H. C. M. Direct molecular analysis of a deletion of 3p intumor from patients with sporadic renal cell carcinoma. Cancer Genet.Cytogenet., 32: 281-285, 1988.

22. Morita, M., Ishikawa, J., Tsutsumi, M., Hikiji, K., Tsukada, Y., Kamidono,S., Maeda, S., and Nakamura, Y. Allelotype of renal cell carcinoma. CancerRes., 51: 820-823, 1991.

23. Kovacs, G., Szucs, S., de Riese, W., and Baumgartel, H. Specific chromosomal aberration in human renal cell carcinoma. Int. J. Cancer, 40: 171-178, 1987.

24. Yoshida, A. H., Oyashiki, K.. Ochi, H.. Gibas, Z., Pontes, J. E., Prout, G.R., Hüben,R., and Sandberg, A. A. Cytogenetic studies of tumor tissue frompatients with nonfamilial renal cell carcinoma. Cancer Res.. 46: 2139-2147,1986.

25. Cohen, A. J., Li, F. P., Berg, S., Marchetto, D. J., Tsai, S., Jacobs, S. C,and Brown, R. S. Hereditary renal-cell carcinoma associated with a chromosomal translocation. N. Engl. J. Med., 301: 592-595, 1979.

26. Wang, N., and Perkins, K. L. Involvement of Band 3pl4 in t(3;8) hereditaryrenal cell carcinoma. Cancer Genet. Cytogenet., //: 479-481, 1984.

27. Pathak, S., Strong, L. C, Ferrei, R. E., and Trindade, A. Familial renal cellcarcinoma with a 3:11 chromosome translocation limited to tumor cells.Science (Washington, DC), 217: 939-941, 1982.

28. Yamakawa, K., Takahashi, E., Saito, H., Sato, T., Oshimura, M., Hori, T.,and Nakamura, Y. Isolation and mapping of 75 new DNA markers on humanchromosome 3. Genomics, 9: 536-543, 1991.

29. Yamakawa, K., Morita, R.. Takahashi. E., Hori, T.. Lathrop, M., andNakamura, Y. Construction of a genetic linkage map of 41 markers forhuman chromosome 3. Genomics, in press, 1991.

30. Boldog, F., Erlandsson, R., Klein, G., and Sumegi, J. Long-range restrictionmaps of DNF15S2, D3S2, and c-ra/7 loci on the short arm of humanchromosome 3. Cancer Genet. Cytogenet., 42: 295-306, 1989.

31. Sato, T., Tanigami, A., Yamakawa, K., Akiyama, F., Kasumi, F., Sakamoto.G., and Nakamura, Y. Allelotype of breast cancer: accumulative alíelelossespromote tumor progression in primary breast cancer. Cancer Res., 50:7184-7189, 1990.

32. Gerber, M. J., Miller, W. E., Drabkin, H. A., and Scoggin, C. H. Regionalassignment of the polymorphic probe D3S3 to 3pl4 by molecular hybridization. Cytogenet. Cell Genet., 42: 72-74. 1986.

33. Bonner, T., O'Brian, S. J., Nash, W. G., Rapp, U. R.. Morton, C. C., and

Leder, P. The human homologs of the raf(mil) oncogene are located onhuman chromosomes 3 and 4. Science (Washington, DC), 233:71-74, 1984.

34. Carril, B., Welch, H. M., and Parry-Jones, N. J. Sequences homologous tothe human D1SÃŒlocus present on human chromosome 3. Am. J. Hum.Genet., 38: 428-436, 1986.

35. Feinberg, A. P., and Vogelstein, B. A technique for radiolabeling DNArestriction endonuclease fragments for high specific activity. Anal. Biochem.,13 7: 266-267, 1984.

36. Takahashi, E., Hori, T., and Sutherland, G. R. Mapping of the human typeII collagen gene (CoI2Al) proximal to fra(12)(ql3.1) by nonisotopic in situhybridization. Cytogenet. Cell Genet., 54:84-85, 1990.

37. Naylor, S. L., Marshall, A., Hensel, C., Martinez, P. F., Holley, B., andSakaguchi, Y. The DNF15S2 locus at 3p21 is transcribed in normal lung andsmall cell lung cancer. Genomics, 4: 355-361, 1989.

38. Erlandsson, R., Bergerheim, U., Boldog, F., Marcsek, Z., Rimimi. K., Lin,B., Ingvarsson, S., Castresana, J.. Lee, W., Lee, E., Klein, G., and Sumegi,J. A gene near the D3F15S2 site on 3p is expressed in normal human kidneybut not or only at a severely reduced level in 11 of 15 primary renal cellcarcinomas (RCC). Oncogene, 5: 1207-1211, 1990.

39. King, C. R., Schimke, R. N., Arthur, T,. Davoren, B., and Collins, D.Proximal 3p deletion in renal cell carcinoma cells from a patient with vonHippel-Lindau disease. Cancer Genet. Cytogenet., 27: 345-348, 1987.

40. Seizinger, B. R., Rouleau, G. A., Ozelius, L. J., Lane, A. H., Farmar, G. E.,Lamiell, J. M., Haines, J., Yuen, J. W. M., Collins, D., Majoor-Krakauer,D., Bonner, T., Mathew, C., Rubenstein, A., Halperin, J., McConkie-Rosell,A., Green, J. S., Trofatter, J. A., Ponder, B. A., Eierman, L., Bowmer, M.I., Schimke, R., Oostra, B., Aronin, N., Smith, D. I., Drabkin, H., Waziri,M. H., Hobbs, W. J., Martuza, R. L., Conneally, P. M., Hsia, Y. E., andGusella, J. F. von Hippel-Lindau disease maps to the region of chromosome3 associated with renal cell carcinoma. Nature (Lond.), 322: 268-269, 1988.

41. Tory, K.. Brauch, H.. Linehan, M.. Barba, D., Oldfield, E., Filling-Katz. M.,Seizinger, B., Nakamura, Y., White, R., Marshall, F. F., Lerman, M. I., and/bar. B. Specific genetic change in tumors associated with von Hippel-Lindau disease. J. Nati. Cancer Inst., 81: 1097-1101, 1989.

42. Japanese Urologica! Association, the Japanese Pathological Society, and theJapan Radiological Society. General Rules for Clinical and PathologicalStudies on Renal Cell Carcinoma. Ed. 1, pp. 68-73. Tokyo: Kanehara, 1983.

43. Nakamura, Y., Leppert, M., O'Connell, P., Wolff, R., Holm, T., Culver, M.,

Martin, C., Fujimoto, E., Hoff, M., Kumlin, E., and White, R. Variablenumber of tandem repeat (VNTR) markers for human gene mapping. Science(Washington, DC), 325: 1616-1622, 1987.

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1991;51:4707-4711. Cancer Res   Kazuhiro Yamakawa, Ryoji Morita, Ei-ichi Takahashi, et al.   in Sporadic Renal Cell CarcinomaA Detailed Deletion Mapping of the Short Arm of Chromosome 3

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