Journal of the National Cancer Institute Advance Access published online on October 28, 2008
JNCI Journal of the National Cancer Institute, doi:10.1093/jnci/djn345
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© The Author 2008. Published by Oxford University Press.
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Skewed X Chromosome Inactivation and Breast and Ovarian Cancer Status: Evidence for X-Linked Modifiers of BRCA1
Affiliations of authors: Cancer and Cell Biology Division (FL, GFK, ABS) and Population Studies and Human Genetics Division (DLD), Queensland Institute of Medical Research, Brisbane, Queensland, Australia; School of Medicine, Central Clinical Division, University of Queensland, Royal Brisbane Hospital, Brisbane, Queensland, Australia (FL); Peter MacCallum Cancer Centre, Melbourne, Australia (kConFaB, AOCS management group); School of Public Health, Institute of Health and Biomedical Innovation, Queensland University of Technology (MAK)
Correspondence to: Amanda B. Spurdle, PhD, Cancer and Cell Biology Division, Queensland Institute of Medical Research, 300 Herston Road, Herston, Brisbane, Queensland, Australia 4006 (e-mail: amanda.spurdle{at}qimr.edu.au).
Background: 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.
Methods: 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.
Results: 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).
Conclusions: 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.
| Context and Caveats Prior knowledge X chromosome inactivation silences gene expression from one of the two X chromosomes in females and is usually random. Nonrandom (ie, 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 mutation carriers, than in control subjects. Study design A molecular genetic analysis of X chromosome inactivation patterns using methylation-specific polymerase chain reaction amplification of the exon 1 microsatellite region of the X-linked androgen receptor gene in peripheral blood lymphocyte DNA from cancer-free female control subjects, ovarian cancer patients, familial breast cancer patients who did not carry mutations in BRCA1 or BRCA2, and unaffected and breast or ovarian cancer–affected carriers of mutations in BRCA1 or BRCA2. Contribution Skewed X inactivation occurs at increased frequency in unaffected BRCA1 (and possibly BRCA2) mutation carriers compared with control subjects and is associated with an older age at breast or ovarian cancer diagnosis in female BRCA1 mutation carriers. Implications Skewed X inactivation may be a mechanism that favors expression of an X-linked allele that protects against cancer and that may be increased in BRCA1 mutation carriers due to BRCA1 mutation–related overexpression of X-linked genes. Limitations Data interpretations were based on small numbers of individuals who displayed skewed X inactivation. From the Editors
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Manuscript received April 28, 2008; revised August 8, 2008; accepted August 26, 2008.
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J Natl Cancer Inst 2008 100: 1485.
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