High frequency of skewed X inactivation in young breast cancer patients
- 1Institute of Medical Genetics, University of Oslo, Oslo, Norway
- 2Department of Genetics, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo, Norway
- 3Department of Medical Genetics, Rikshospitalet University Hospital, Oslo, Norway
- 4Cancer Centre, University of Pennsylvania, Philadelphia, USA
- 5Institute for Laboratory Medicine, University of Oslo, Norway
- Correspondence to: Dr K H Ørstavik, Department of Medical Genetics, Rikshospitalet University Hospital, 0027 Oslo, Norway;
- Accepted 5 October 2001
- Revised 2 October 2001
Introduction: 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.