High frequency of skewed X inactivation in young breast cancer patients.
BACKGROUND
Patients with invasive ovarian cancer were recently shown to have a higher frequency of skewed X chromosome inactivation in peripheral blood cells compared to patients with borderline cancer and controls. In this study, we analysed the X inactivation pattern in peripheral blood from 216 breast cancer patients.


METHODS
X inactivation analysis was performed using HpaII predigestion of DNA followed by PCR of the highly polymorphic CAG repeat of the androgen receptor gene (AR), which amplifies the undigested inactive X chromosome only. The X inactivation pattern was classified as skewed when 90% or more of the cells preferentially used one X chromosome.


RESULTS
Young breast cancer patients (27-45 years) had a higher frequency of skewed X inactivation than young controls (13 and 1%, respectively) (p=0.009), whereas no difference was found for middle aged and older patients compared to controls of a similar age.


CONCLUSIONS
A germline mutation in an X linked tumour suppressor gene may give a proliferative advantage to cells with this mutation on the active X chromosome, thus causing skewed X inactivation and an increased risk for developing cancer. Another possible explanation could be that females with a constitutionally skewed X inactivation pattern are more susceptible to develop breast cancer because of an X linked low penetrance susceptibility allele that is affected by the inactivation pattern.
Kristiansen
M
M
Institute of Medical Genetics, University of Oslo, Oslo, Norway.
Langerød
A
A
Knudsen
G P
GP
Weber
B L
BL
Børresen-Dale
A L
AL
Orstavik
K H
KH
D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D001943:Breast Neoplasms / Q000235:genetics*; D004303:Dosage Compensation, Genetic; D005260:Female; D006801:Humans; D008875:Middle Aged; D018911:Trinucleotide Repeats / Q000235:genetics; D014960:X Chromosome / Q000235:genetics*