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In females one of the two X chromosomes is inactivated in early embryonic life, thus making females mosaics for two cell lines. Most females have a 50:50 distribution of the two cell lines. A deviation from this distribution is called a skewed X inactivation. Skewed X inactivation may be a result of a chance event, due to genetic factors or a selection mechanism. Older females have an increased frequency of skewed X inactivation in peripheral blood cells. An association between skewed X inactivation and BRCA1 mutation in germline DNA of patients with ovarian cancer was recently reported (Buller et al 1999). A significant increase in skewed X inactivation pattern was also found in patients with invasive cancer compared to patients with borderline cancer and healthy controls, indicating that skewed X inactivation is a predisposing factor for the development of invasive ovarian cancer.
We have analysed X inactivation pattern in peripheral blood from 216 female patients with breast cancer and 26 cancer patients with documented BRCA1 germline mutation. Controls were female blood donors. X-inactivation was classified as skewed when 90% or more of the peripheral blood cells preferentially used one X-chromosome.
Among females with documented BRCA1 germline mutation, 15% had a skewed X inactivation compared to 8% of female patients without BRCA1 mutation (P = 0.20) and 1% of control females (P = 0.008). Females who developed breast cancer at young ages (25-45 years) had a significantly higher frequency of skewed X inactivation than control females of the same age group (P = 0.009). A germline mutation in an X chromosome tumour suppressor gene could give a proliferative advantage to cells with this mutation on the active X chromosome, thus causing skewed X inactivation.