Androgen receptor CAG repeats, non-random X chromosome inactivation, and loss of heterozygosity at Xq25 in relation to breast cancer risk

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.

A Review of the Epidemiology of Breast Cancer in Asia: Focus on Risk Factors

“…Lan NH, et al (Lan et al, 2013) -OS rates at 1, 3, and 5 years following diagnosis were 0.94, 0.83 and 0.74 respectively. (Chen et al, 2014a), mitochondrial DNA content (Jiang et al, 2014), mitochondrial D-loop insertions (Tipirisetti et al, 2014), and telomere length (Qu et al, 2013). The studies included in this review identified several associations between BC risk and genes that encode apoptotic regulators (e.g.…”

Re‐expression ofLactotransferrin, a candidate tumor suppressor inactivated by promoter hypermethylation, impairs the malignance of oral squamous cell carcinoma cells.

“…And, then, re‐expression of LTF after the treatment of 5‐Aza‐Cdc told the truth that the decreased expression of LTF was, at least partially, a result of hypermethylation. However, of course, other factors, such as loss of heterozygosity ( LOH ), a high‐frequence incident in 3p21.3 region , DNA point mutations, as well as regulations of upstream genes, could not been ignored considering that 5‐Aza‐Cdc only exerted limited influence in restoring the expression of LTF . Therefore, additional efforts are necessary to be taken on elucidating the exact mechanisms of LTF inactivation in future work.…”

Revisiting the X-Chromosome Inactivation and Its Impact on Female Longevity

“…Both events, the increased longevity and the so-called "healthy ageing", which result in a smaller skewing or a greater delay in X inactivation, could be explained by the fact that, as long as the deviation process has not yet begun and the two cellular populations (Xp and Xm) remain thus in a 50:50 ratio, the compensatory effects that arise effectively counteract the expression of recessive mutant alleles [73]. On the other side of the coin, age-dependent XCI skewing can be also involved in favoring the expression of deleterious alleles, as evidenced by the late-onset of certain X-linked disorders such as Graves' disease and Hashimoto thyroiditis, scleroderma and X-linked sideroblastic anaemia, and cancer, among others [74]- [77].…”