© 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.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  A. Thakur, K. W. Rahman, J. Wu, A. Bollig, H. Biliran, X. Lin, H. Nassar, D. J. Grignon, F. H. Sarkar, and J. D. Liao Aberrant Expression of X-Linked Genes RbAp46, Rsk4, and Cldn2 in Breast Cancer Mol. Cancer Res., February 1, 2007; 5(2): 171 - 181. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J P Struewing, M A Pineda, M E Sherman, J Lissowska, L A Brinton, B Peplonska, A Bardin-Mikolajczak, and M Garcia-Closas Skewed X chromosome inactivation and early-onset breast cancer J. Med. Genet., January 1, 2006; 43(1): 48 - 53. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M Kristiansen, G P S Knudsen, P Maguire, S Margolin, J Pedersen, A Lindblom, and K H Orstavik High incidence of skewed X chromosome inactivation in young patients with familial non-BRCA1/BRCA2 breast cancer J. Med. Genet., November 1, 2005; 42(11): 877 - 880. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. D. Jones, M. Wang, J. N. Eble, G. T. MacLennan, A. Lopez-Beltran, S. Zhang, A. Cocco, and L. Cheng Molecular Evidence Supporting Field Effect in Urothelial Carcinogenesis Clin. Cancer Res., September 15, 2005; 11(18): 6512 - 6519. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. L. Terry, I. De Vivo, L. Titus-Ernstoff, M.-C. Shih, and D. W. Cramer Androgen Receptor Cytosine, Adenine, Guanine Repeats, and Haplotypes in Relation to Ovarian Cancer Risk Cancer Res., July 1, 2005; 65(13): 5974 - 5981. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S M Domchek, S L Merillat, J Tigges, A J Tweed, M Weinar, J Stopfer, and B L Weber Sex ratio skewing of offspring in families with hereditary susceptibility to breast cancer J. Med. Genet., June 1, 2005; 42(6): 511 - 513. [Full Text] [PDF]
|
|
|
|
 |
|
 I. S. Brum, P. M. Spritzer, F. Paris, M. A. Maturana, F. Audran, and C. Sultan Association Between Androgen Receptor Gene CAG Repeat Polymorphism and Plasma Testosterone Levels in Postmenopausal Women Reproductive Sciences, February 1, 2005; 12(2): 135 - 141. [Abstract] [PDF]
|
|
|
|
|
|
K Kotar, J-S Brunet, P Moller, L Hugel, E Warner, J McLaughlin, N Wong, S A Narod, and W D Foulkes Ratio of female to male offspring of women tested for BRCA1 and BRCA2 mutations J. Med. Genet., August 1, 2004; 41(8): e103 - e103. [Full Text] [PDF]
|
|
|
|
 |
|
 F. Modugno Ovarian Cancer and Polymorphisms in the Androgen and Progesterone Receptor Genes: A HuGE Review Am. J. Epidemiol., February 15, 2004; 159(4): 319 - 335. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. de la Hoya, J. M. Fernandez, A. Tosar, J. Godino, A. Sanchez de Abajo, J. A. Vidart, P. Perez-Segura, E. Diaz-Rubio, and T. Caldes Association Between BRCA1 Mutations and Ratio of Female to Male Births in Offspring of Families With Breast Cancer, Ovarian Cancer, or Both JAMA, August 20, 2003; 290(7): 929 - 931. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. Krop, P. Maguire, J. Lahti-Domenici, G. Lodeiro, A. Richardson, H. K. Johannsdottir, H. Nevanlinna, A. Borg, R. Gelman, R. B. Barkardottir, et al. Lack of HIN-1 Methylation in BRCA1-linked and "BRCA1-like" Breast Tumors Cancer Res., May 1, 2003; 63(9): 2024 - 2027. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. L.G. Sieben, S. M. Kolkman-Uljee, A. M. Flanagan, S. le Cessie, A.-M. Cleton-Jansen, C. J. Cornelisse, and G. J. Fleuren Molecular Genetic Evidence for Monoclonal Origin of Bilateral Ovarian Serous Borderline Tumors Am. J. Pathol., April 1, 2003; 162(4): 1095 - 1101. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. L. Hilton, J. P. Geisler, J. A. Rathe, M. A. Hattermann-Zogg, B. DeYoung, and R. E. Buller Inactivation of BRCA1 and BRCA2 in Ovarian Cancer J Natl Cancer Inst, September 18, 2002; 94(18): 1396 - 1406. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. A. Jazaeri, C. J. Yee, C. Sotiriou, K. R. Brantley, J. Boyd, and E. T. Liu Gene Expression Profiles of BRCA1-Linked, BRCA2-Linked, and Sporadic Ovarian Cancers J Natl Cancer Inst, July 3, 2002; 94(13): 990 - 1000. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M Kristiansen, A Langerod, G P Knudsen, B L Weber, A-L Borresen-Dale, and K H Orstavik High frequency of skewed X inactivation in young breast cancer patients J. Med. Genet., January 1, 2002; 39(1): 30 - 33. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Gu, L. M. Roth, C. Younger, H. Michael, F. W. Abdul-Karim, S. Zhang, T. M. Ulbright, J. N. Eble, and L. Cheng Molecular Evidence for the Independent Origin of Extra-ovarian Papillary Serous Tumors of Low Malignant Potential J Natl Cancer Inst, August 1, 2001; 93(15): 1147 - 1152. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. Mahavni, S. C Kim, T. A Benda, L. Sanders, and R. E Buller The androgen receptor and DXS15-134 markers show a high rate of discordance for germline X chromosome inactivation J. Med. Genet., July 1, 2001; 38(7): 474 - 478. [Full Text]
|
|
|
|
|
|
R. E. Buller, A. K. Sood, T. Lallas, T. Buekers, and J. S. Skilling RESPONSE: Re: Association Between Nonrandom X-Chromosome Inactivation and BRCA1 Mutation in Germline DNA of Patients With Ovarian Cancer J Natl Cancer Inst, September 1, 1999; 91(17): 1508 - 1509. [Full Text] [PDF]
|
|
|
|
|
|
J. Boyd and S. A. Narod Re: Association Between Nonrandom X-Chromosome Inactivation and BRCA1 Mutation in Germline DNA of Patients With Ovarian Cancer J Natl Cancer Inst, September 1, 1999; 91(17): 1507b - 1508b. [Full Text] [PDF]
|
|
|
|
|
|
C. J. Brown Skewed X-Chromosome Inactivation: Cause or Consequence? J Natl Cancer Inst, February 17, 1999; 91(4): 304 - 305. [Full Text] [PDF]
|
|