Infrequent mutations of Archipelago (hAGO, hCDC4, Fbw7) in primary ovarian cancer

Eunice L. Kwak, Kenneth H. Moberg, Doke C R Wahrer, Jennifer E. Quinn, Paula M. Gilmore, Colin A. Graham, Iswar K. Hariharan, D. Paul Harkin, Daniel A. Haber*, Daphne W. Bell

*Corresponding author for this work

Research output: Contribution to journalArticle

37 Citations (Scopus)

Abstract

Objective: Archipelago (AGO, also known as hCdc4, Fbw7, or Sel-10) is an F-box containing component of the SCF complex implicated in the ubiquitination and proteolysis of cyclin E and c-Myc, and found to be mutated in 16% of endometrial carcinomas. We have previously reported somatic mutations in AGO in 3/10 ovarian cancer cell lines, but the frequency of such mutations in primary ovarian cancer is unknown.

Methods: The coding sequence of AGO was analyzed in 95 primary sporadic ovarian tumors and 16 cases of familial ovarian cancer, and correlated with levels of cyclin E and c-Myc protein expression. Constructs encoding mutations in AGO were transfected into an AGO-null cell line to directly test their ability to regulate cyclin E and c-Myc levels.

Results: Mutations were present in only 2 of 95 sporadic cases: a premature stop within the WD domain (471 Ter) and a missense change near the F-box (S245T). Both primary tumor specimens containing these mutations showed high levels of cyclin E and c-Myc, but reconstitution of an AGO-null cell line with constructs encoding these mutations showed 471 Ter to be inactive in regulating endogenous cyclin E and c-Myc levels, while the S245T mutant was indistinguishable from wild-type. No germ-line mutations were found in familial cases of ovarian cancer.

Conclusion: Somatic AGO mutations are infrequent in primary ovarian cancers and are unlikely to contribute to familial ovarian cancer. Reconstitution experiments, rather than measuring tumor levels of cyclin E and c-Myc, provide an effective approach to determine the functional significance of AGO mutations identified in human cancers.
Original languageEnglish
Pages (from-to)124-128
Number of pages5
JournalGynecologic Oncology
Volume98
Issue number1
DOIs
Publication statusPublished - Jul 2005

Keywords

  • Archipelago
  • c-Myc
  • Cyclin E
  • Mutation
  • Ovarian tumor

ASJC Scopus subject areas

  • Obstetrics and Gynaecology
  • Oncology

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    Kwak, E. L., Moberg, K. H., Wahrer, D. C. R., Quinn, J. E., Gilmore, P. M., Graham, C. A., Hariharan, I. K., Harkin, D. P., Haber, D. A., & Bell, D. W. (2005). Infrequent mutations of Archipelago (hAGO, hCDC4, Fbw7) in primary ovarian cancer. Gynecologic Oncology, 98(1), 124-128. https://doi.org/10.1016/j.ygyno.2005.04.007