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https://hdl.handle.net/2440/52122
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Type: | Journal article |
Title: | Skewed X chromosome inactivation and breast and ovarian cancer status: Evidence for X-linked modifiers of BRCA1 |
Author: | Lose, F. Duffy, D. Kay, G. Kedda, M. Spurdle, A. Oehler, M. |
Citation: | Journal of the National Cancer Institute, 2008; 100(25):1519-1529 |
Publisher: | Oxford Univ Press Inc |
Issue Date: | 2008 |
ISSN: | 0027-8874 1460-2105 |
Statement of Responsibility: | Felicity Lose, David L. Duffy, Graham F. Kay, Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer, Australian Ovarian Cancer Study Management Group, Mary A. Kedda, Amanda B. Spurdle |
Abstract: | <h4>Background</h4>X chromosome inactivation, which silences gene expression from one of the two X chromosomes in females, is usually random. Skewed X inactivation has been implicated in both the expression and the suppression of X-linked disease phenotypes and has been reported to occur more frequently in breast and ovarian cancer patients, including BRCA1 or BRCA2 mutation carriers, than in control subjects.<h4>Methods</h4>We assessed the pattern of X chromosome inactivation using methylation-specific polymerase chain reaction amplification of the exon 1 microsatellite region of the X-linked androgen receptor (AR) gene in DNA from blood samples obtained from control subjects without a personal history of breast or ovarian cancer (n = 735), ovarian cancer patients (n = 313), familial breast cancer patients who did not carry mutations in BRCA1 or BRCA2 (n = 235), and affected and unaffected carriers of mutations in BRCA1 (n = 260) or BRCA2 (n = 63). We defined the pattern of X chromosome inactivation as skewed when the same X chromosome was active in at least 90% of cells. The association between skewed X inactivation and disease and/or BRCA mutation status was assessed by logistic regression analysis. The association between skewed X inactivation and age at cancer diagnosis was assessed by Cox proportional hazards regression analysis. All statistical tests were two-sided.<h4>Results</h4>The age-adjusted frequency of skewed X inactivation was not statistically significantly higher in ovarian cancer or familial breast cancer case subjects compared with control subjects. Skewed X inactivation was higher in BRCA1 mutation carriers than in control subjects (odds ratio [OR] = 2.7, 95% confidence interval [CI] = 1.1 to 6.2; P = .02), particularly among unaffected women (OR = 6.1, 95% CI = 1.5 to 31.8; P = .005). Among BRCA1 mutation carriers, those with skewed X inactivation were older at diagnosis of breast or ovarian cancer than those without skewed X inactivation (hazard ratio [HR] of breast or ovarian cancer = 0.37, 95% CI = 0.14 to 0.95; P = .04). Among BRCA2 mutation carriers, skewed X inactivation also occurred more frequently in unaffected carriers than in those diagnosed with breast or ovarian cancer (OR = 5.2, 95% CI = 0.5 to 28.9; P = .08) and was associated with delayed age at onset (HR = 0.59, 95% CI = 0.37 to 0.94; P = .03).<h4>Conclusions</h4>Skewed X inactivation occurs at an increased frequency in BRCA1 (and possibly BRCA2) mutation carriers compared with control subjects and is associated with a statistically significant increase in age at diagnosis of breast and ovarian cancer. |
Keywords: | Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer Australian Ovarian Cancer Study Management Group Chromosomes, Human, X Humans Breast Neoplasms Ovarian Neoplasms Genetic Predisposition to Disease Receptors, Androgen DNA, Neoplasm DNA Primers Logistic Models Proportional Hazards Models Odds Ratio Case-Control Studies Polymerase Chain Reaction Age Factors DNA Methylation Up-Regulation Base Sequence Genotype Heterozygote Mutation Genes, BRCA1 Genes, BRCA2 Molecular Sequence Data Adolescent Adult Aged Aged, 80 and over Middle Aged Female X Chromosome Inactivation Genes, X-Linked Kaplan-Meier Estimate |
DOI: | 10.1093/jnci/djn345 |
Published version: | http://dx.doi.org/10.1093/jnci/djn345 |
Appears in Collections: | Aurora harvest 5 Obstetrics and Gynaecology publications |
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