Abstract for presentation at 11th International Congress of Human Genetics

Purpose: X chromosome inactivation (Xi) is a mammalian mechanism which serves to silence expression of genes from one of the two X chromosomes in females, so that males and females express similar levels of X-linked genes. This process is usually random however, non-random or skewed Xi has been reported to occur in cancer patients. It has been found that skewed Xi is more common in invasive ovarian cancer patients (particularly those carrying a mutation in the BRCA1 gene) and also BRCA1/2-mutation negative young breast cancer patients, than in control populations. This indicates a possible role for this mechanism in these female cancers. The findings from these studies may be interpreted to suggest the presence of an X-linked breast or ovarian cancer susceptibility gene, which may act to cause disease de novo or possibly to modify the onset of disease in BRCA1 carriers.
Methods: We aim to investigate a large panel of breast cancer and ovarian cancer subjects and age-matched controls for skewed Xi in peripheral blood cells. Our population includes BRCA1/2-mutation carriers and BRCA1/2-mutation negative (BRCAX) cases from multiple case breast and breast/ovarian cancer families, and population-based ovarian cancer cases and controls. We are using the most recently published method of bisulfite–modification along with a methylation-specific PCR (MSP) designed for investigation of skewed Xi. This is a more reliable technique than was used in the above-mentioned studies, and we have optimised the protocol to use as little as 100ng gDNA and reduce cost by 65%.
Results/Conclusions: Preliminary results indicate an interesting trend in the BRCA1 carrier breast cancer population - regardless of the percentage of skewing that is designated as 'skewed Xi' i.e. 75%, 90% etc, the BRCA1 carrier breast cancer population consistently showed a greater number of individuals displaying skewed Xi. We are currently investigating additional cases to confirm this finding. The BRCA2 carrier population displayed a similar rate of skewed Xi to controls. We will also be presenting results from the BRCAX breast cancer, ovarian cancer and additional control populations.