Abstract
BackgroundThe aim of this study was to examine the association of non-random X chromosome inactivation (XCI) and loss of heterozygosity (LOH) at Xq25 with breast cancer development.MethodsSeventy-nine breast cancer patients, 39 female lung cancer patients, 30 other cancer patients and 77 healthy females were analysed for LOH using a panel of 11 microsatellite markers spanning Xq25. The androgen receptor (AR) gene was chosen as an XCI marker.ResultsLOH of at least one microsatellite locus at Xq25 was identified in 46/65 breast cancers examined, while only 10/25 cancers of other origins demonstrated LOH in this region (p = 0.014). The critical deletion region in breast cancer was around marker DXS1047 (47.23%). Moreover, we found that tissues from eight breast cancers showed LOH at all of the informative loci tested at Xq25, while the other 38 showed partial (interstitial or telomeric) alterations at Xq25. Interestingly, the pattern of XCI of these eight breast cancers tended to be non-random. We estimated the frequencies of AR alleles and found that women with two long AR alleles (≥21 CAG repeats) had an increased risk of developing breast cancer, while those with two short AR alleles (<21 CAG repeats) were likely to be normal (p = 0.00069).ConclusionsThe extraordinary high frequencies of LOH at Xq25 found in this study strongly imply that there might be one or more tumour suppressor genes (TSGs) related to the development of breast cancer at Xq25 in the Taiwanese female population.
Highlights
The aim of this study was to examine the association of non-random X chromosome inactivation (XCI) and loss of heterozygosity (LOH) at Xq25 with breast cancer development
The extraordinary high frequencies of LOH at Xq25 found in this study strongly imply that there might be one or more tumour suppressor genes (TSGs) related to the development of breast cancer at Xq25 in the Taiwanese female population
The frequency of LOH at other microsatellite markers was below 30%
Summary
The aim of this study was to examine the association of non-random X chromosome inactivation (XCI) and loss of heterozygosity (LOH) at Xq25 with breast cancer development. To compensate for X chromosome gene dosage, one X chromosome in each female cell condenses to form a Barr body Genes on this chromosome are shut down in a phenomenon known as X chromosome inactivation (XCI). Which X chromosome undergoes condensation is generally random, theoretically the ratio of paternal inactivation vs maternal should be 1:1 in a given mass of cells. This phenomenon is known as Lyonization [1,2]. Females are carriers of X chromosome mutations and do not usually express the phenotype because the normal allele can compensate for the defect, men are more likely to be affected by X-linked recessive diseases. Nonrandom XCI in women can mimic the effects of the single X chromosome in men if the mutated X chromosome is active and the normal X chromosome is inactive, leading to expression of X-linked recessive diseases in women
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