TY - JOUR
T1 - Association between nonrandom X-chromosome inactivation and BRCA1 mutation in germline DNA of patients with ovarian cancer
AU - Buller, Richard E.
AU - Sood, Anil K.
AU - Lallas, Thomas
AU - Buekers, Thomas
AU - Skilling, Jeffrey S.
PY - 1999/2/17
Y1 - 1999/2/17
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=0033577046&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0033577046&partnerID=8YFLogxK
U2 - 10.1093/jnci/91.4.339
DO - 10.1093/jnci/91.4.339
M3 - Article
C2 - 10050867
AN - SCOPUS:0033577046
SN - 0027-8874
VL - 91
SP - 339
EP - 346
JO - Journal of the National Cancer Institute
JF - Journal of the National Cancer Institute
IS - 4
ER -