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High frequency of skewed X inactivation in young breast cancer patients
  1. M Kristiansen1,
  2. A Langerød2,
  3. G P Knudsen3,
  4. B L Weber4,
  5. A-L Børresen-Dale2,5,
  6. K H Ørstavik3
  1. 1Institute of Medical Genetics, University of Oslo, Oslo, Norway
  2. 2Department of Genetics, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo, Norway
  3. 3Department of Medical Genetics, Rikshospitalet University Hospital, Oslo, Norway
  4. 4Cancer Centre, University of Pennsylvania, Philadelphia, USA
  5. 5Institute for Laboratory Medicine, University of Oslo, Norway
  1. Correspondence to:
 Dr K H Ørstavik, Department of Medical Genetics, Rikshospitalet University Hospital, 0027 Oslo, Norway;


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.

  • X chromosome
  • skewed X inactivation
  • breast cancer
  • AR, androgen receptor
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