© 1999 by Oxford University Press
Journal of the National Cancer Institute, Vol. 91, No. 4, 339-346,
February 17, 1999
© 1999 Oxford University Press
ARTICLES |
Association Between Nonrandom X-Chromosome Inactivation and BRCA1 Mutation in Germline DNA of Patients With Ovarian Cancer
Affiliations of authors: R. E. Buller (Division of Gynecologic Oncology and Department of Pharmacology), A. K. Sood, T. Lallas, T. Buekers, J. S. Skilling (Division of Gynecologic Oncology), the Departments of Obstetrics and Gynecology, The University of Iowa Hospitals and Clinics, Iowa City.
Correspondence to: Richard E. Buller, M.D., Ph.D., Division of Gynecologic Oncology, Departments of Obstetrics and Gynecology, 200 Hawkins Dr., #4630 JCP, Iowa City, IA 52242-1009 (e-mail: richard-buller{at}uiowa.edu).
Present address: J. S. Skilling, Department of Obstetrics & Gynecology, Division of Gynecologic Oncology, University of California, Davis Medical Center, Sacramento, CA.
BACKGROUND: Most human female cells contain two X chromosomes, only one of which is active. The process of X-chromosome inactivation, which occurs early in development, is usually random, producing tissues with equal mixtures of cells having active X chromosomes of either maternal or paternal origin. However, nonrandom inactivation may occur in a subset of females. If a tumor suppressor gene were located on the X chromosome and if females with a germline mutation in one copy of that suppressor gene experienced nonrandom X-chromosome inactivation, then some or all of the tissues of such women might lack the wild-type suppressor gene function. This scenario could represent a previously unrecognized mechanism for development of hereditary cancers. We investigated whether such a mechanism might contribute to the development of hereditary ovarian cancers. METHODS: Patterns of X-chromosome inactivation were determined by means of polymerase chain reaction amplification of the CAG-nucleotide repeat of the androgen receptor (AR) gene after methylation-sensitive restriction endonuclease digestion of blood mononuclear cell DNA from patients with invasive (n = 213) or borderline (n = 44) ovarian cancer and control subjects without a personal or family history of cancer (n = 50). BRCA1 gene status was determined by means of single-strand conformational polymorphism analysis and DNA sequencing. All statistical tests were two-sided. RESULTS AND CONCLUSIONS: Among individuals informative for the AR locus, nonrandom X-chromosome inactivation was found in the DNA of 53% of those with invasive cancer versus 28% of those with borderline cancer (P = .005) and 33% of healthy control subjects (P = .016). Nonrandom X-chromosome inactivation can be a heritable trait. Nine of 11 AR-informative carriers of germline BRCA1 mutations demonstrated nonrandom X-chromosome inactivation (.0002 < P < .008, for simultaneous occurrence of both). IMPLICATIONS: Nonrandom X-chromosome inactivation may be a predisposing factor for the development of invasive, but not borderline, ovarian cancer.
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