Skewed X chromosome inactivation and breast and ovarian cancer status : evidence for X-linked modifiers of BRCA1
Lose, Felicity, Duffy, David L., Kay, Graham F., Cuningham, Kathleen, Kedda, Mary A., & Spurdle, Amanda B. (2008) Skewed X chromosome inactivation and breast and ovarian cancer status : evidence for X-linked modifiers of BRCA1. Journal of the National Cancer Institute, 100(21), pp. 1519-1529.
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.
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|Item Type:||Journal Article|
|Divisions:||Current > QUT Faculties and Divisions > Faculty of Health|
Current > Institutes > Institute of Health and Biomedical Innovation
Current > Schools > School of Public Health & Social Work
|Deposited On:||15 Jun 2009 14:47|
|Last Modified:||11 Aug 2011 01:44|
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