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. 1995 Sep;86(9):795–799. doi: 10.1111/j.1349-7006.1995.tb03087.x

Contribution of Chromosome 9p21‐22 Deletion to the Progression of Human Renal Cell Carcinoma

Hidefumi Kinoshita 1,2, Hitoshi Yamada 1,2, Osamu Ogawa 1, Yoshiyuki Kakehi 1, Mitsuhiko Osaka 2, Eijiro Nakamura 1, Mutsuki Mishina 1, Tomonori Habuchi 1,2, Rei Takahashi 2, Taketoshi Sugiyama 2, Osamu Yoshida 1,✉
PMCID: PMC5920923  PMID: 7591954

Abstract

To investigate the possible role of genomic aberrations of chromosome 9p21‐22 in the tumorigenesis of human renal cell carcinoma (RCC), 10 RCC cell lines, 55 primary RCCs and 5 metastatic lesions were studied by Southern blotting and polymerase chain reaction‐based analysis. Nine of 10 RCC cell lines showed a homozygous deletion of MTS1/CDKN2/(p16), while only 1 in 55 primary tumors had this deletion. Loss of heterozygosity on 9p21‐22 was observed in 5 of 10 informative primary RCCs from patients with metastasis, but in only 4 of 31 informative tumors (13%) without metastasis (P= 0.025). Furthermore, 3 of 5 metastatic tumors (60%) showed hemi‐ or homozygous deletion of MTS1/CDKN2. These results indicate that the 9p21‐22 deletion may be a relatively late event in RCC tumorigenesis and could be associated with RCC metastasis.

Keywords: Renal cell carcinoma, Chromosome 9p21‐22, Loss of heterozygosity, Homozygous deletion, MTS1/CDKN2/(pl6)

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REFERENCES

  • 1. ) Knudson , A. G.Antioncogenes and human cancer . Proc. Natl. Acad. Sci. USA , 90 , 10914 – 10921 ( 1993. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2. ) Friend , S. H. , Bernards , R. , Rogelj , S. , Weinberg , R. A. , Rapaport , J. M. , Albert , D. M. and Drja , T. P.A human DNA segment with properties of the gene that predisposes to retinoblastoma and osteosarcoma . Nature , 323 , 643 – 646 ( 1986. ). [DOI] [PubMed] [Google Scholar]
  • 3. ) Call , K. M. , Glaser , T. , Ito , C. Y. , Bockler , A. J. , Pelletier , J. , Haber , D. A. , Rose , E. A. , Kral , A. , Yeger , H. , Lewis , W. H. , Jones , C. and Housman , D. E.Isolation and characterization of a zinc finger polypeptide gene at the human chromosome 11 Wilms' tumor locus . Cell , 60 , 509 – 520 ( 1990. ). [DOI] [PubMed] [Google Scholar]
  • 4. ) Kamb , A. , Gruis , N. A. , Weaver‐Feldhaus , J. , Liu , Q. , Harshman , K. , Tavtigian , S. V. , Stockert , E. , Day , R. S. , III , Johnson , B. E. and Skolnick , M. H.A cell cycle regulator potentially involved in genesis of many tumor types . Science , 264 , 436 – 440 ( 1994. ). [DOI] [PubMed] [Google Scholar]
  • 5. ) Nobori , T. , Miura , K. , Wu , D. J. , Lois , A. , Takabayashi , K. and Carson , D. A.Deletions of the cyclin‐dependent kinase‐4 inhibitor gene in multiple human cancers . Nature , 368 , 753 – 756 ( 1994. ). [DOI] [PubMed] [Google Scholar]
  • 6. ) Serrano , M. , Hannon , G. J. and Beach , D.A new regulatory motif in cell‐cycle control causing specific inhibition of cyclin D/CDK4 . Nature , 366 , 704 – 707 ( 1993. ). [DOI] [PubMed] [Google Scholar]
  • 7. ) Fountain , J. W. , Karayiorgou , M. , Ernstoff , M. S. , Kirkwood , J. M. , Vlovok , D. R. , Titus‐Ernstoff , L. , Bouchard , B. , Vijayasaradhi , S. , Houghton , A. N. , Lahti , J. , Kidd , V. J. , Housman , D. E. and Dracopoli , N. C.Homozygous deletions within human chromosome band 9p21 in melanoma . Proc. Natl. Acad. Sci. USA , 89 , 10557 – 10561 ( 1992. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8. ) Diaz , M. O. , Rubin , C. M. , Harden , A. , Ziemin , S. , Larson , R. A. , Le Beau , M. M. and Rowley , J. D.Deletions of interferon genes in acute lymphoblastic leukemia . N. Engl. J. Med. , 322 , 77 – 82 ( 1990. ). [DOI] [PubMed] [Google Scholar]
  • 9. ) Olopade , O. I. , Buchhagen , D. L. , Malik , K. , Sherman , J. , Nobori , T. , Bader , S. , Nau , M. M. , Gazder , A. F. , Minna , J. D. and Diaz , M. O.Homozygous loss of the interferon genes defines the critical region on 9p that is deleted in lung cancers . Cancer Res. , 53 , 2410 – 2415 ( 1993. ). [PubMed] [Google Scholar]
  • 10. ) James , C. D. , He , J. , Collins , V. P. , Allalunis‐Turner , M. J. and Day , R. S. , III . Localization of chromosome 9p homozygous deletions in glioma cell lines with markers constituting a continuous linkage group . Cancer Res. , 53 , 3674 – 3676 ( 1993. ). [PubMed] [Google Scholar]
  • 11. ) Cheng , J. Q. , Jhanwar , S. C. , Lu , Y. Y. and Testa , J. R.Homozygous deletions within 9p21‐p22 identify a small critical region of chromosomal loss in human malignant mesotheliomas . Cancer Res. , 53 , 4761 – 4763 ( 1993. ). [PubMed] [Google Scholar]
  • 12. ) Stadler , W. M. , Sherman , J. , Bohlander , S. K. , Roulston , D. , Dreyling , M. , Rukstalis , D. and Olopade , O. I.Homozygous deletions within chromosomal bands 9p21‐22 in bladder cancer . Cancer Res. , 54 , 2060 – 2063 ( 1994. ). [PubMed] [Google Scholar]
  • 13. ) Igaki , H. , Sasaki , H. , Kishi , T. , Sakamoto , H. , Tachimori , Y. , Kato , H. , Watanabe , H. , Sugimura , T. and Terada , M.Highly frequent homozygous deletion of the p16 gene in esophageal cancer cell lines . Biochem. Biophys. Res. Commun. , 203 , 1090 – 1095 ( 1994. ). [DOI] [PubMed] [Google Scholar]
  • 14. ) Zhou , X. , Tarmin , L. , Yin , J. , Jiang , H‐Y. , Suzuki , H. , Rhyu , M.‐G. , Abraham , J. M. and Meltzer , S. J.The MTS1 gene is frequently mutated in primary human esophageal tumors . Oncogene , 9 , 3737 – 3741 ( 1994. ). [PubMed] [Google Scholar]
  • 15. ) Sakata , K. , Tamura , G. , Maesawa , C. , Suzuki , Y. , Terashima , M. , Satoh , K. , Eda , Y. , Suzuki , A. , Sekiya , S. and Satodate , R.Loss of heterozygosity on the short arm of chromosome 9 without p16 gene mutation in gastric carcinomas . Jpn. J. Cancer Res. , 86 , 333 – 335 ( 1995. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16. ) Cairns , P. , Mao , L. , Merlo , A. , Lee , D. J. , Schwab , D. , Eby , Y. , Tokino , K. , van der Riet , P. , Blaugrund , J. E. and Sidransky , D.Rates of p16 (MTS1) mutations in primary tumors with 9p loss . Science , 265 , 415 – 416 ( 1994. ). [DOI] [PubMed] [Google Scholar]
  • 17. ) Spruck , C. H. , III , Gonzalez‐Zulueta , M. , Shibata , A. , Simoneau , A. R. , Lin , M.‐F. , Gonzales , F. , Tsai , Y. C. and Jones , P. A.p16 gene in uncultured tumours . Nature , 370 , 183 – 184 ( 1994. ). [DOI] [PubMed] [Google Scholar]
  • 18. ) Zhang , S.‐Y. , Klein‐Szanto , A. J. P. , Sauter , E. R. , Shafarenko , M. , Mitsunaga , S. , Nobori , T. , Carson , D. A. , Ridge , J. A. and Goodrow , T. L.Higher frequency of alterations in the p16/CDKN2 gene in squamous cell carcinoma cell lines than in primary tumors of the head and neck . Cancer Res. , 54 , 5050 – 5053 ( 1994. ). [PubMed] [Google Scholar]
  • 19. ) Cheng , J. Q. , Jhanwar , S. C. , Klein , W. M. , Bell , D. W. , Lee , W.‐C. , Altomare , D. A. , Nobori , T. , Olopade , O. I. , Buckler , A. J. and Testa , J. R.p16 alterations and deletion mapping of 9p21‐p22 in malignant mesothelioma . Cancer Res. , 54 , 5547 – 5551 ( 1994. ). [PubMed] [Google Scholar]
  • 20. ) Ohta , M. , Nagai , H. , Shimizu , M. , Rasio , D. , Berd , D. , Mastrangelo , M. , Singh , A. D. , Shields , J. A. , Shields , C. L. , Croce , C. M. and Huebner , K.Rarity of somatic and germline mutations of the cyclin‐dependent kinase 4 inhibitor gene, CDK4I, in melanoma . Cancer Res. , 54 , 5269 – 5272 ( 1994. ). [PubMed] [Google Scholar]
  • 21. ) Xu , L. , Sgroi , D. , Sterner , C. J. , Beauchamp , R. L. , Pinney , D. M. , Keel , S. , Ueki , K. , Rutter , J. L. , Buckler , A. J. , Louis , D. N. , Gusella , J. F. and Ramesh , V.Mutational analysis of CDKN2(MTS1/p16ink4) in human breast carcinomas . Cancer Res. , 54 , 5262 – 5264 ( 1994. ). [PubMed] [Google Scholar]
  • 22. ) Funaki , K. , Everitt , J. , Oshimura , M. , Freed , J. J. , Knudson , A. G. and Walker , C.Hereditary renal cell carcinoma in the rat associated with nonrandom loss of chromosome 5 and 6 . Cancer Res. , 51 , 4415 – 4422 ( 1991. ). [PubMed] [Google Scholar]
  • 23. ) Testa , J. R. , Taguchi , T. , Knudson , A. G. and Hino , O.Localization of the interferon‐α gene cluster to rat chromosome bands 5q31‐q33 by fluorescence in situ hybridization . Cytogenet. Cell Genet. , 60 , 247 – 249 ( 1992. ). [DOI] [PubMed] [Google Scholar]
  • 24. ) Habuchi , T. , Kinoshita , H. , Yamada , H. , Kakehi , Y. , Ogawa , O. , Wu , W.‐J. , Takahashi , R. , Sugiyama , T. and Yoshida , O.Oncogene amplification in urothelial cancers with p53 gene mutation or MDM2 amplification . J. Natl. Cancer Inst. , 86 , 1331 – 1335 ( 1994. ). [DOI] [PubMed] [Google Scholar]
  • 25. ) Hoehn , W. and Schroeder , F. H.Renal cell carcinoma: two new cell lines and a serially transplantable nude mouse tumor (NC 65): preliminary report . Invest. Urol. , 16 , 106 – 112 ( 1978. ). [PubMed] [Google Scholar]
  • 26. ) Goldrosen , M. H. , Huben , R. , Miller , G. A. , Lewis , D. A. , Ochi , H. , Sandberg , A. A. and Pontes , J. E.Characterization of a renal cell carcinoma cell line suitable as a target for immunological studies in vitro and in the nu/nu mouse . J. Urol. , 134 , 1271 – 1275 ( 1985. ). [DOI] [PubMed] [Google Scholar]
  • 27. ) Cannon‐Albright , L. A. , Goldgar , D. E. , Meyer , L. J. , Lewis , C. M. , Anderson D. E. , Fountain , J. W. , Hegi , M. E. , Wiseman , R. W. , Petty , E. M. , Bale , A. E. , Olopade , O. I. , Diaz , M. O. , Kwiatkowski , D. J. , Piepkorn , M. W. , Zone , J. J. and Skolnick , M. H.Assignment of a locus for familial melanoma, MLM, to chromosome 9p13‐p22 . Science , 258 , 1148 – 1152 ( 1992. ). [DOI] [PubMed] [Google Scholar]
  • 28. ) Anglard , P. , Trahan , E. , Liu , S. , Latif , F. , Merino , M. J. , Lerman , M. I. , Zbar , B. and Linehan , W. M.Molecular and cellular characterization of human renal cell carcinoma cell lines . Cancer Res. , 52 , 348 – 356 ( 1992. ). [PubMed] [Google Scholar]
  • 29. ) Habuchi , T. , Takahashi , R. , Yamada , H. , Ogawa , O. , Kakehi , Y. , Ogura , K. , Hamazaki , S. , Toguchida , J. , Ishizaki , K. , Fujita , J. , Sugiyama , T. and Yoshida , O.Influence of cigarette smoking and schistosomiasis on p53 gene mutation in urothelial cancer . Cancer Res. , 53 , 3795 – 3799 ( 1993. ). [PubMed] [Google Scholar]
  • 30. ) Mori , T. , Miura , K. , Aoki , T. , Nishihira , T. , Mori , S. and Nakamura , Y.Frequent somatic mutation of the MTS1/CDK4I (multiple tumor suppressor/cyclin‐dependent kinase 4 inhibitor) gene in esophageal squamous cell carcinoma . Cancer Res. , 54 , 3396 – 3397 ( 1994. ). [PubMed] [Google Scholar]
  • 31. ) Cairns , P. , Tokino , K. , Eby , Y. and Sidransky , D.Localization of tumor suppressor loci on chromosome 9 in primary human renal cell carcinomas . Cancer Res. , 55 , 224 – 227 ( 1995. ). [PubMed] [Google Scholar]
  • 32. ) Kamb , A. , Shattuck‐Eidens , D. , Eeles , R. , Liu , Q. , Gruis , N. A. , Ding , W. , Hussey , C. , Tran , T. , Miki , Y. , Weaver‐Feldhaus , J. , McClure , M. , Aitken , J. F. , Anderson , D. E. , Bergman , W. , Frants , R. , Goldgar , D. E. , Green , A. , MacLennan , R. , Martin , N. G. , Meyer , L. J. , Youl , P. , Zone , J. J. , Skolnick , M. H. and Cannon‐Albright , L. A.Analysis of the p16 (CDKN2) as a candidate for the chromosome 9p melanoma susceptibility locus . Nature Genet. , 8 , 22 – 26 ( 1994. ). [DOI] [PubMed] [Google Scholar]
  • 33. ) Latif , F. , Tory , K. , Gnarra , J. , Yao , M. , Duh , F.‐M. , Orcutt , M. L. , Stackhouse , T. , Kuzmin , I. , Modi , W. , Geil , L. , Schmidt , L. , Zhou , F. , Li , H. , Wei , M. H. , Chen , F. , Glenn , G. , Choyke , P. , Walther , M. M. , Weng , Y. , Duan , D.‐S. R. , Dean , M. , Glavac , D. , Richards , F. M. , Crossey , P. A. , Ferguson‐Smith , M. A. , Paslier , D. L. , Chumakov , I. , Cohen , D. , Chinault , A. C. , Maher , E. R. , Linehan , W. M. , Zbar , B. and Lerman , M. I.Identification of the von Hippel‐Lindau disease tumor suppressor gene . Science , 260 , 1317 – 1320 ( 1993. ). [DOI] [PubMed] [Google Scholar]
  • 34. ) Shuin , T. , Kondo , K. , Torigoe , S. , Kishida , T. , Kubota , Y. , Hosaka , M. , Nagashima , Y. , Kitamura , H. , Latif , F. , Zbar , B. , Lerman , M. I. and Yao , M.Frequent somatic mutations and loss of heterozygosity of the von Hippel‐Lindau tumor suppressor gene in primary human renal cell carcinomas . Cancer Res. , 54 , 2852 – 2855 ( 1994. ). [PubMed] [Google Scholar]

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