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Japanese Journal of Cancer Research : Gann logoLink to Japanese Journal of Cancer Research : Gann
. 1994 Dec;85(12):1247–1256. doi: 10.1111/j.1349-7006.1994.tb02937.x

Alteration of the p53 Tumor Suppressor Gene Occurs Independently of K‐ras Activation and More Frequently in Serous Adenocarcinomas than in Other Common Epithelial Tumors of the Human Ovary

Masami Fujita 1, Takayuki Enomoto 1,2,3,✉, Masaki Inoue 1,4, Osamu Tanizawa 1, Masami Ozaki 3, Jerry M Rice 5, Taisei Nomura 2
PMCID: PMC5919385  PMID: 7852189

Abstract

To clarify the role of the p53 tumor suppressor gene in the development of human ovarian epithelial tumors and to study the association of p53 alterations with K‐ras activation, a series of 70 common epithelial ovarian tumors from Japanese patients was studied. These included 31 serous adenocarcinomas, 12 mucinous adenocarcinomas, 5 mutinous tumors of borderline malignancy, 13 endometrioid adenocarcinomas, and 9 clear cell carcinomas. Allelic loss, recognized at the polymorphic site in codon 72 of the p53 gene, was detected in 14 of 36 (39%) informative cases by restriction fragment length polymorphism analysis and by single‐strand conformation polymorphism (SSCP) analysis of polymerase chain reaction(PCR)‐amplified DNA fragments. Mutations in the highly conserved regions of the p53 gene were detected by SSCP analysis of PCR‐amplifled fragments. Mutations were found in 22 of 70 (31%) ovarian tumors, including 1 of 5 mucinous tumors of borderline malignancy. Mutations were subsequently characterized by direct sequencing. Single missense base substitutions were detected in 13 ovarian carcinomas and in one case of mucinous tumor of borderline malignancy. Short (1‐8 bp) deletions and insertions were found in 8 cases. Mutations in the p53 gene occurred more frequently in serous adenocarcinomas (14/31, 45%) than in all nonserous types of malignant epithelial tumors combined (7/34, 21%;P=0.032). Point mutations in K‐ras were identified by dot blot hybridization analysis of PCR‐amplified fragments with mutation‐specific oligonucleotides and by direct sequencing. The overall frequency of K‐ras mutations was 19/70 (27%).K‐ras mutations were found in 12 of 17 (71%) mucinous tumors (8/12 mucinous carcinomas [67%] and 4/5 mucinous tumors of borderline malignancy [80%]), and occurred more frequently than in serous carcinomas (4/31, 13%;P=0.00009) or in all nonmucinous types of ovarian epithelial tumors combined (7/53, 13%; p=0.00002). These data suggest that different combinations of oncogenes and/or tumor suppressor genes may be involved in the genesis and development of histologically distinct categories of common epithelial tumors of the human ovary.

Keywords: Ovarian cancer, p53, K‐ras, Gene

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REFERENCES

  • 1. ) Fearon , E. R. and Vogelstein , B.A genetic model for colorectal tumorigenesis . Cell , 61 , 759 – 767 ( 1990. ). [DOI] [PubMed] [Google Scholar]
  • 2. ) Enomoto , T. , Weghorst , C. M. , Inoue , M. , Tanizawa , O. and Rice , J. M.K‐ras activation occurs frequently in mutinous adenocarcinomas and rarely in other common epithelial tumors of the human ovary . Am. J. Pathol , 139 , 777 – 785 ( 1991. ). [PMC free article] [PubMed] [Google Scholar]
  • 3. ) Enomoto , T. , Inoue , M. , Perantoni , A. O. , Terakawa , N. , Tanizawa , O. and Rice , J. M.K‐ras activation in neoplasms of the human female reproductive tract . Cancer Res. , 50 , 6139 – 6145 ( 1990. ). [PubMed] [Google Scholar]
  • 4. ) Masuda , H. , Battifora , H. , Yokota , J. , Meltzer , S. and Cline , M. J.Specificity of proto‐oncogene amplification in human malignant diseases . Mol Biol. Med. , 4 , 213 – 227 ( 1987. ). [PubMed] [Google Scholar]
  • 5. ) Filmus , J. E. and Buick , R. N.Stability of c‐K‐ras amplification during progression in a patient with adenocarcinoma of the ovary . Cancer Res. , 45 , 4468 – 4472 ( 1985. ). [PubMed] [Google Scholar]
  • 6. ) Boltz , E. M. , Kefford , R. F. , Leary , J. A. , Houghton , C. R. and Friedlander , M. L.Amplification of c‐rasKi oncogene in human ovarian tumours . Int. J. Cancer , 43 , 428 – 430 ( 1989. ). [DOI] [PubMed] [Google Scholar]
  • 7. ) Zhou , D. J. , Gonzalez‐Cadavid , N. , Ahuja , H. , Battifora , H. , Moore , G. E. and Cline , M. J.A unique pattern of proto‐oncogene abnormalities in ovarian adenocarcinomas . Cancer , 62 , 1573 – 1576 ( 1988. ). [DOI] [PubMed] [Google Scholar]
  • 8. ) Slamon , D. J. , Godolphin , W. , Jones , L. A. , Holt , J. A. , Wong , S. G. , Keith , D. E. , Levin , W. J. , Stuart , S. G. , Udove , J. , Ullrich , A. and Press , M. F.Studies of the HER‐2/neu proto‐oncogene in human breast and ovarian cancer . Science , 244 , 707 – 712 ( 1989. ). [DOI] [PubMed] [Google Scholar]
  • 9. ) Berchuck , A. , Kamel , A. , Whitaker , R. , Kerns , B. , Olt , G. , Kinney , R. , Soper , J. T. , Dodge , R. , Clarke‐Pearson , D. L. , Marks , P. , McKenzie , S. , Yin , S. and Bast , R. C. , Jr.Overexpression of HER‐2/neu is associated with poor survival in advanced epithelial ovarian cancer . Cancer Res. , 50 , 4087 – 4091 ( 1990. ). [PubMed] [Google Scholar]
  • 10. ) Lee , J. H. , Kavanagh , J. J. , Wharton , J. T. , Wildrick , D. M. and Blick , M.Allele loss at the c‐Ha‐ras 1 locus in human ovarian cancer . Cancer Res. , 49 , 1220 – 1222 ( 1989. ). [PubMed] [Google Scholar]
  • 11. ) Lee , J. H. , Kavanagh , J. J. , Wildrick , D. M. , Wharton , J. T. and Blick , M.Frequent loss of heterozygosity on chromosomes 6q, 11, and 17 in human ovarian carcinomas . Cancer Res. , 50 , 2724 – 2728 ( 1990. ). [PubMed] [Google Scholar]
  • 12. ) Ehlen , T. and Dubeau , L.Loss of heterozygosity on chromosomal segments 3p, 6q, and 1 Ip in human ovarian carcinomas . Oncogene , 5 , 219 – 223 ( 1990. ). [PubMed] [Google Scholar]
  • 13. ) Sato , T. , Saito , H. , Morita , R. , Koi , S. , Lee , J. H. and Nakamura , Y.Allelotype of human ovarian cancer . Cancer Res. , 51 , 5118 – 5122 ( 1991. ). [PubMed] [Google Scholar]
  • 14. ) Li , S. , Schwartz , P. E. , Lee , W.‐H. and Yang‐Feng , T. L.Allele loss at the retinoblastoma locus in human ovarian cancer . J. Natl. Cancer Inst. , 83 , 637 – 640 ( 1991. ). [DOI] [PubMed] [Google Scholar]
  • 15. ) Levine , A. J. , Momand , J. and Finlay , C. A.The p53 tumor suppressor gene . Nature , 351 , 453 – 456 ( 1991. ). [DOI] [PubMed] [Google Scholar]
  • 16. ) Nigro , J. M. , Baker , S. J. , Preisinger , A. C. , Jessup , J. M. , Hosteller , R. , Cleary , K. , Signer , S. H. , Davidson , N. , Baylin , S. , Devilee , P. , Glover , T. , Collins , F. S. , Weston , A. , Modali , R. , Harris , C. C. and Vogelstein , B.Mutations in the p53 gene occur in diverse human tumor types . Nature , 342 , 705 – 708 ( 1989. ). [DOI] [PubMed] [Google Scholar]
  • 17. ) Okamoto , A. , Sameshima , Y. , Yokoyama , S. , Terashima , Y. , Sugimura , T. , Terada , M. and Yokota , J.Frequent allelic losses and mutations of the p53 gene in human ovarian cancer . Cancer Res. , 51 , 5171 – 5176 ( 1991. ). [PubMed] [Google Scholar]
  • 18. ) Mazars , R. , Pujol , P. , Maudelonde , T. , Jeanteur , P. and Theillet , C.p53 mutations in ovarian cancer: a late event ? Oncogene , 6 , 1685 – 1690 ( 1991. ). [PubMed] [Google Scholar]
  • 19. ) Kihana , T. , Tsuda , H. , Teshima , S. , Okada , S. , Matsuura , S. and Hirohashi , S.High incidence of p53 gene mutation in human ovarian cancer and its association with nuclear accumulation of p53 protein and tumor DNA aneuploidy . Jpn. J. Cancer Res. , 83 , 978 – 984 ( 1992. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20. ) Teneriello , M. G. , Ebina , M. , Linnoila , R. L , Henry , M. , Nash , J. D. , Park , R. C. and Birrer , M. J.p53 and K‐ras gene mutations in epithelial ovarian neoplasms . Cancer Res. , 53 , 3103 – 3108 ( 1993. ). [PubMed] [Google Scholar]
  • 21. ) Kohler , M. F. , Marks , J. R. , Wiseman , R. W. , Jacobs , I. J. , Davidoff , A. M. , Clarke‐Pearson , D. L. , Soper , J. T. , Bast , R. C. , Jr. and Berchuck , A.Spectrum of mutation and frequency of allelic deletion of the p53 gene in ovarian cancer . J. Natl. Cancer Inst. , 85 , 1513 – 1519 ( 1993. ). [DOI] [PubMed] [Google Scholar]
  • 22. ) Kupryjanczyk , J. , Thor , A. D. , Beauchamp , R. , Merritt , V. , Edgerton , S. M. , Bell , D. A. and Yandell , D. W.p53 gene mutations and protein accumulation in human ovarian cancer . Proc. Natl. Acad. Sci. USA , 90 , 4961 – 4965 ( 1993. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23. ) Meltzer , S. J. , Yin , J. , Huang , Y. , McDaniel , T. K. , Newkirk , C. , Iseri , O. , Vogelstein , B. and Resau , J. H.Reduction to homozygosity involving p53 in esophageal cancers demonstrated by the polymerase chain reaction . Proc. Natl. Acad. Sci. USA , 88 , 4976 – 4980 ( 1991. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24. ) Orita , M. , Suzuki , Y. , Sekiya , T. and Hayashi , K.Rapid and sensitive detection of point mutations and DNA polymorphisms using the polymerase chain reaction . Genomics , 5 , 874 – 879 ( 1989. ). [DOI] [PubMed] [Google Scholar]
  • 25. ) Poulsen , H. E. , Taylor , C. W. and Sobin , L. H.Histological typing of female genital tract tumors . In “ International Histological Classification of Tumors, ” No. 13 , pp. 63 – 73 ( 1975. ). World Health Organization; , Geneva . [Google Scholar]
  • 26. ) Enomoto , T. , Inoue , M. , Perantoni , A. O. , Buzard , G. S. , Miki , H. , Tanizawa , O. and Rice , J. M.K‐ras activation in premalignant and malignant epithelial lesions of the human uterus . Cancer Res. , 51 , 5308 – 5314 ( 1991. ). [PubMed] [Google Scholar]
  • 27. ) Buchman , V. L. , Chumakov , P. M. , Ninkina , N. N. , Samarina , O. P. and Georgiev , G. P.A variation in the structure of the protein‐coding region of the human p53 gene . Gene , 70 , 245 – 252 ( 1988. ). [DOI] [PubMed] [Google Scholar]
  • 28. ) Enomoto , T. , Fujita , M. , Inoue , M. , Rice , J. M. , Nakajima , R. , Tanizawa , O. and Nomura , T.Alterations of the p53 tumor suppressor gene and its association with activation of the c‐K‐ras‐2 protooncogene in premalignant and malignant lesions of the human uterine endometrium . Cancer Res. , 53 , 1883 – 1888 ( 1993. ). [PubMed] [Google Scholar]
  • 29. ) Fujita , M. , Inoue , M. , Tanizawa , O. , Iwamoto , S. and Enomoto , T.Alterations of the p53 gene in human primary cervical carcinoma with and without human papillomavirus infection . Cancer Res. , 52 , 5323 – 5328 ( 1992. ). [PubMed] [Google Scholar]
  • 30. ) Gad , S. and Weil , C. S. “ Statistics and Experimental Design for Toxicologists, ” 2nd Ed. , pp. 54 – 55 ( 1988. ). Telford Press; , Caldwell , NJ . [Google Scholar]
  • 31. ) Laurent‐Puig , P. , Olschwang , S. , Delattre , O. , Validire , P. , Melot , T. , Mosseri , V. , Salmon , R. J. and Thomas , G.Association of Ki‐ras mutation with differentiation and tumor formation pathways in colorectal carcinoma . Int. J. Cancer , 49 , 220 – 223 ( 1991. ). [DOI] [PubMed] [Google Scholar]
  • 32. ) Kobayashi , T. , Tsuda , H. , Noguchi , M. , Hirohashi , S. , Shimosato , Y. , Goya , T. and Hayata , Y.Association of point mutation in c‐ki‐ras oncogene in lung adenocarcinoma with particular reference to cytologic subtypes . Cancer , 66 , 289 – 294 ( 1990. ). [DOI] [PubMed] [Google Scholar]
  • 33. ) Miki , H. , Ohmori , M. , Perantoni , A. O. and Enomoto , T.K‐ras activation in gastric epithelial tumors in Japanese . Cancer Lett. , 58 , 107 – 113 ( 1991. ). [DOI] [PubMed] [Google Scholar]
  • 34. ) Tada , M. , Omata , M. and Ohio , M.Analysis of ras gene mutations in human hepatic malignant tumors by polymerase chain reaction and direct sequencing . Cancer Res. , 50 , 1121 – 1124 ( 1990. ). [PubMed] [Google Scholar]
  • 35. ) Domagala , W. , Harezga , B. , Szadowska , A. , Markiewski , M. , Weber , K. and Osborn , M.Nuclear p53 protein accumulates preferentially in medullary and high‐grade ductal but rarely in lobular breast carcinomas . Am. J. Pathol , 142 , 669 – 674 ( 1993. ). [PMC free article] [PubMed] [Google Scholar]
  • 36. ) Foulkes , W. D. , Black , D. M , Stamp , G. W. H. , Solomon , E. and Trowsdale , J.Very frequent loss of heterozygosity throughout chromosome 17 in sporadic ovarian carcinoma . Int. J. Cancer , 54 , 220 – 225 ( 1993. ). [DOI] [PubMed] [Google Scholar]
  • 37. ) Coles , C. , Thompson , A. M. , Elder , P. A. , Cohen , B. B. , Mackenzie , I. M. , Cranston , G. , Chetty , U. , Mackay , J. , Macdonald , M. , Nakamura , Y. , Hoyheim , B. and Steel , C. M.Evidence implicating at least two genes on chromosome 17p in breast carcinogenesis . Lancet , 336 , 761 – 763 ( 1990. ). [DOI] [PubMed] [Google Scholar]
  • 38. ) Tsao , S.‐W. , Mok , C.‐H. , Dike , K , Muto , M , Goodman , H. M. , Sheets , E. E. , Berkowitz , R. S. , Knapp , R. C. and Lau , C. C.Involvement of p53 gene in the allelic deletion of chromosome 17p in human ovarian tumors . Anticancer Res. , 11 , 1975 – 1982 ( 1991. ). [PubMed] [Google Scholar]
  • 39. ) Phillips , N. , Ziegler , M. , Saha , B. and Xynos , F.Allelic loss on chromosome 17 in human ovarian cancer . Int. J. Cancer , 54 , 85 – 91 ( 1993. ). [DOI] [PubMed] [Google Scholar]
  • 40. ) Mok , S. C.‐H. , Bell , D. A. , Knapp , R. C. , Fishbaugh , P. M. , Welch , W. R , Muto , M. G. , Berkowitz , R. S. and Tsao , S. W.Mutation of K‐ras protooncogene in human ovarian epithelial tumors of borderline malignancy . Cancer Res. , 53 , 1489 – 1492 ( 1993. ). [PubMed] [Google Scholar]
  • 41. ) Ichikawa , Y. , Nishida , M , Suzuki , H. , Yoshida , S. , Tsunoda , H. , Kubo , T. , Uchida , K. and Miwa , M.Mutation of K‐ras protooncogene is associated with histological subtypes in human mucinous ovarian tumors . Cancer Res. , 54 , 33 – 35 ( 1994. ). [PubMed] [Google Scholar]
  • 42. ) Komishi , N. , Enomoto , T. , Buzard , G. , Ohshima , M. , Ward , J. M. and Rice , J. M.K‐ras activation and ras p21 expression in latent prostatic carcinomas in Japanese men , Cancer , 69 , 2293 – 2299 ( 1992. ). [DOI] [PubMed] [Google Scholar]
  • 43. ) Sundaresan , V. , Ganly , P. , Hasleton , P. , Rudd , R. , Sinha , G. , Bleehen , N. M , and Rabbitts , P.p53 and chromosome 3 abnormalities, characteristic of malignant lung tumors, are detectable in preinvasive lesions of the bronchus . Oncogene , 1 , 1989 – 1997 ( 1992. ). [PubMed] [Google Scholar]
  • 44. ) Casson , A. G. , Mukhopadhyay , T. , Cleary , K. R. , Ro , J. Y. , Levin , B. and Roth , J. A.p53 gene mutations in Barrett's epithelium and esophageal cancer . Cancer Res. , 51 , 4495 – 4499 ( 1991. ). [PubMed] [Google Scholar]
  • 45. ) Baker , S. J. , Preisinger , A. C. , Jessup , J. M. , Paraskeva , C. , Markowitz , S. , Wilson , J. K. V. , Hamilton , S. and Vogelstein , B.p53 gene mutations occur in combination with 17p allelic deletions as late events in colorectal tumorigenesis . Cancer Res. , 50 , 7717 – 7722 ( 1990. ). [PubMed] [Google Scholar]
  • 46. ) Sidransky , D. , Mikkelsen , T. , Schwechheimer , K. , Rosenblum , M. L. , Cavanee , W. and Vogelstein , B.Clonal expansion of p53 mutant cells is associated with brain tumor progression . Nature , 355 , 846 – 847 ( 1992. ). [DOI] [PubMed] [Google Scholar]
  • 47. ) Cha , R. S. , Zarbl , H. , Keohavong , P. and Thilly , W. G.Mismatch amplification mutation assay (MAMA): Application to the c‐H‐ras gene . PCR Methods Appl , 2 , 14 – 20 ( 1992. ). [DOI] [PubMed] [Google Scholar]
  • 48. ) Inoue , M. , Fujita , M. , Enomoto , T. , Morimoto , H. , Monden , T. , Shimano , T. and Tanizawa , O.Immuno‐histochemical analysis of p53 in gynecologic tumors . Am. J. Clin. Pathol. ( 1994. ), in press . [DOI] [PubMed]
  • 49. ) Bodner , S. M. , Minna , J. D. , Jensen , S. M. , Ď'Amico , D. , Carbone , D. , Mitsudomi , T. , Fedorko , J. , Buchhagen , D. L. , Nau , M. M. , Gazdar , A. F. and Linnoila , R. I.Expression of mutant p53 proteins in lung cancer correlates with the class of p53 gene mutation . Oncogene , 7 , 743 – 749 ( 1992. ). [PubMed] [Google Scholar]
  • 50. ) Mitsudomi , T. , Steinberg , S. M. , Nau , M. M. , Carbone , D. , D'Amico , D. , Bodner , S. , Oie , H. K. , Linnoila , R. L , Mulshine , J. L. , Minna , J. D. and Gazdar , A. F.p53 gene mutations in non‐small‐cell lung cancer cell lines and their correlation with the presence of ras mutations and clinical features . Oncogene , 7 , 171 – 180 ( 1992. ). [PubMed] [Google Scholar]

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