Skip to main content
The American Journal of Pathology logoLink to The American Journal of Pathology
. 1991 Oct;139(4):777–785.

K-ras activation occurs frequently in mucinous adenocarcinomas and rarely in other common epithelial tumors of the human ovary.

T Enomoto 1, C M Weghorst 1, M Inoue 1, O Tanizawa 1, J M Rice 1
PMCID: PMC1886299  PMID: 1656759

Abstract

To explore the role of mutational activation of members of the ras family of cellular protooncogenes in the development of human ovarian neoplasms, a series of 37 ovarian tumors from Japanese patients was studied. These included 30 common epithelial tumors (1 mucinous tumor of borderline malignancy, 7 mucinous adenocarcinomas, and 22 nonmucinous carcinomas: 10 serous, 3 clear cell, 8 endometrioid, and 1 undifferentiated), 5 tumors of germ cell origin, and 2 sex cord/stromal cell tumors. Polymerase chain reaction was performed from selected areas of deparaffinized sections of formalin-fixed paraffin-embedded tissue, and the presence of activating point mutations in codons 12, 13, and 61 of the H-, N-, and K-ras genes was probed by dot-blot hybridization analysis with mutation specific oligonucleotides. Mutations in K-ras were also looked for by direct genomic sequencing. The overall frequency of ras gene mutations was 10/37 (27%). Mutations were detected only in K-ras, and were found in most of the mucinous tumors, including the one such tumor of borderline malignancy (6/8; 75%). In one mucinous adenocarcinoma, two mutations were detected in paraffin-embedded material that had not previously been found in high molecular weight DNA isolated from frozen tissue from the same case. K-ras mutations occurred significantly more frequently in mucinous tumors (6/8, 75%) than in serous carcinomas (2/10, 20%; P = 0.031) or in all nonmucinous types of epithelial ovarian tumors combined (3/22, 14%; P = 0.0031).

Full text

PDF
777

Images in this article

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Almoguera C., Shibata D., Forrester K., Martin J., Arnheim N., Perucho M. Most human carcinomas of the exocrine pancreas contain mutant c-K-ras genes. Cell. 1988 May 20;53(4):549–554. doi: 10.1016/0092-8674(88)90571-5. [DOI] [PubMed] [Google Scholar]
  2. Barbacid M. ras genes. Annu Rev Biochem. 1987;56:779–827. doi: 10.1146/annurev.bi.56.070187.004023. [DOI] [PubMed] [Google Scholar]
  3. Berchuck A., Kamel A., Whitaker R., Kerns B., Olt G., Kinney R., Soper J. T., Dodge R., Clarke-Pearson D. L., Marks P. Overexpression of HER-2/neu is associated with poor survival in advanced epithelial ovarian cancer. Cancer Res. 1990 Jul 1;50(13):4087–4091. [PubMed] [Google Scholar]
  4. Bos J. L., Fearon E. R., Hamilton S. R., Verlaan-de Vries M., van Boom J. H., van der Eb A. J., Vogelstein B. Prevalence of ras gene mutations in human colorectal cancers. 1987 May 28-Jun 3Nature. 327(6120):293–297. doi: 10.1038/327293a0. [DOI] [PubMed] [Google Scholar]
  5. Bos J. L. The ras gene family and human carcinogenesis. Mutat Res. 1988 May;195(3):255–271. doi: 10.1016/0165-1110(88)90004-8. [DOI] [PubMed] [Google Scholar]
  6. Bos J. L. ras oncogenes in human cancer: a review. Cancer Res. 1989 Sep 1;49(17):4682–4689. [PubMed] [Google Scholar]
  7. Enomoto T., Inoue M., Perantoni A. O., Terakawa N., Tanizawa O., Rice J. M. K-ras activation in neoplasms of the human female reproductive tract. Cancer Res. 1990 Oct 1;50(19):6139–6145. [PubMed] [Google Scholar]
  8. Farr C. J., Saiki R. K., Erlich H. A., McCormick F., Marshall C. J. Analysis of RAS gene mutations in acute myeloid leukemia by polymerase chain reaction and oligonucleotide probes. Proc Natl Acad Sci U S A. 1988 Mar;85(5):1629–1633. doi: 10.1073/pnas.85.5.1629. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Fearon E. R., Vogelstein B. A genetic model for colorectal tumorigenesis. Cell. 1990 Jun 1;61(5):759–767. doi: 10.1016/0092-8674(90)90186-i. [DOI] [PubMed] [Google Scholar]
  10. Fenoglio C. M., Ferenczy A., Richart R. M. Mucinous tumors of the ovary. Ultrastructural studies of mucinous cystadenomas with histogenetic considerations. Cancer. 1975 Nov;36(5):1709–1722. doi: 10.1002/1097-0142(197511)36:5<1709::aid-cncr2820360526>3.0.co;2-7. [DOI] [PubMed] [Google Scholar]
  11. Forrester K., Almoguera C., Han K., Grizzle W. E., Perucho M. Detection of high incidence of K-ras oncogenes during human colon tumorigenesis. 1987 May 28-Jun 3Nature. 327(6120):298–303. doi: 10.1038/327298a0. [DOI] [PubMed] [Google Scholar]
  12. Fujita J., Kraus M. H., Onoue H., Srivastava S. K., Ebi Y., Kitamura Y., Rhim J. S. Activated H-ras oncogenes in human kidney tumors. Cancer Res. 1988 Sep 15;48(18):5251–5255. [PubMed] [Google Scholar]
  13. Hirai H., Kobayashi Y., Mano H., Hagiwara K., Maru Y., Omine M., Mizoguchi H., Nishida J., Takaku F. A point mutation at codon 13 of the N-ras oncogene in myelodysplastic syndrome. Nature. 1987 Jun 4;327(6121):430–432. doi: 10.1038/327430a0. [DOI] [PubMed] [Google Scholar]
  14. Lee J. H., Kavanagh J. J., Wharton J. T., Wildrick D. M., Blick M. Allele loss at the c-Ha-ras1 locus in human ovarian cancer. Cancer Res. 1989 Mar 1;49(5):1220–1222. [PubMed] [Google Scholar]
  15. Lee J. H., Kavanagh J. J., Wildrick D. M., Wharton J. T., Blick M. Frequent loss of heterozygosity on chromosomes 6q, 11, and 17 in human ovarian carcinomas. Cancer Res. 1990 May 1;50(9):2724–2728. [PubMed] [Google Scholar]
  16. Lyons J., Landis C. A., Harsh G., Vallar L., Grünewald K., Feichtinger H., Duh Q. Y., Clark O. H., Kawasaki E., Bourne H. R. Two G protein oncogenes in human endocrine tumors. Science. 1990 Aug 10;249(4969):655–659. doi: 10.1126/science.2116665. [DOI] [PubMed] [Google Scholar]
  17. McMahon G., Davis E., Wogan G. N. Characterization of c-Ki-ras oncogene alleles by direct sequencing of enzymatically amplified DNA from carcinogen-induced tumors. Proc Natl Acad Sci U S A. 1987 Jul;84(14):4974–4978. doi: 10.1073/pnas.84.14.4974. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Miki H., Ohmori M., Perantoni A. O., Enomoto T. K-ras activation in gastric epithelial tumors in Japanese. Cancer Lett. 1991 Jun 14;58(1-2):107–113. doi: 10.1016/0304-3835(91)90031-c. [DOI] [PubMed] [Google Scholar]
  19. Neri A., Knowles D. M., Greco A., McCormick F., Dalla-Favera R. Analysis of RAS oncogene mutations in human lymphoid malignancies. Proc Natl Acad Sci U S A. 1988 Dec;85(23):9268–9272. doi: 10.1073/pnas.85.23.9268. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Ruano G., Fenton W., Kidd K. K. Biphasic amplification of very dilute DNA samples via 'booster' PCR. Nucleic Acids Res. 1989 Jul 11;17(13):5407–5407. doi: 10.1093/nar/17.13.5407. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Shibata D. K., Arnheim N., Martin W. J. Detection of human papilloma virus in paraffin-embedded tissue using the polymerase chain reaction. J Exp Med. 1988 Jan 1;167(1):225–230. doi: 10.1084/jem.167.1.225. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Shimizu K., Goldfarb M., Perucho M., Wigler M. Isolation and preliminary characterization of the transforming gene of a human neuroblastoma cell line. Proc Natl Acad Sci U S A. 1983 Jan;80(2):383–387. doi: 10.1073/pnas.80.2.383. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. 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. Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science. 1989 May 12;244(4905):707–712. doi: 10.1126/science.2470152. [DOI] [PubMed] [Google Scholar]
  24. Smit V. T., Boot A. J., Smits A. M., Fleuren G. J., Cornelisse C. J., Bos J. L. KRAS codon 12 mutations occur very frequently in pancreatic adenocarcinomas. Nucleic Acids Res. 1988 Aug 25;16(16):7773–7782. doi: 10.1093/nar/16.16.7773. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Tada M., Omata M., Ohto M. Analysis of ras gene mutations in human hepatic malignant tumors by polymerase chain reaction and direct sequencing. Cancer Res. 1990 Feb 15;50(4):1121–1124. [PubMed] [Google Scholar]
  26. Visvanathan K. V., Pocock R. D., Summerhayes I. C. Preferential and novel activation of H-ras in human bladder carcinomas. Oncogene Res. 1988;3(1):77–86. [PubMed] [Google Scholar]
  27. Vogelstein B., Fearon E. R., Hamilton S. R., Kern S. E., Preisinger A. C., Leppert M., Nakamura Y., White R., Smits A. M., Bos J. L. Genetic alterations during colorectal-tumor development. N Engl J Med. 1988 Sep 1;319(9):525–532. doi: 10.1056/NEJM198809013190901. [DOI] [PubMed] [Google Scholar]
  28. van 't Veer L. J., Hermens R., van den Berg-Bakker L. A., Cheng N. C., Fleuren G. J., Bos J. L., Cleton F. J., Schrier P. I. ras oncogene activation in human ovarian carcinoma. Oncogene. 1988 Feb;2(2):157–165. [PubMed] [Google Scholar]

Articles from The American Journal of Pathology are provided here courtesy of American Society for Investigative Pathology

RESOURCES