Androgen Receptor Gene Methylation and Exon One CAG Repeat Length in Ovarian Cancer: Differences from Breast Cancer

Abstract

SummaryMore than one neoplastic founder clone can exist in benign epithelial tumours. Although theories of clonal selection make pluriclonality appear unlikely in carcinomas, published data do not exclude this possibility. This study looked for evidence of multiclonal X inactivation in ovarian carcinoma using AR methylation as a marker. Fifteen unifocal ovarian carcinomas and 14 multifocal carcinomas all in Scottish patients were studied. One representative formalin-fixed paraffin-embedded tumour block was chosen for each of the former and two for the latter. From each of these 43 tumour blocks three samples each of *10 4 carcinoma cells were obtained by microdissection (129 in all). DNA released by proteinase K digestion was subjected to PCR amplification of the androgen receptor gene AR exon I CAG repeat polymorphism with and without prior digestion with methylation-sensitive restriction enzymes HpaII and HhaI. Complex amplification patterns were consistent with mosaic X inactivation in some ovarian carcinomas but acquired anomalies of AR methylation cannot be excluded. Parallel analysis of other Xlinked polymorphic loci would strengthen the inference of clonality status from DNA methylation data in tumour X studies. Strikingly, the number of CAG repeats in the 29 ovarian tumour patients (median 16, range 11 -20) was substantially fewer than in 34 previously studied breast cancer patients from the same scottish population (median 21, range 14 -26; P 5 0.0001), and women homozygous for the AR CAG repeat were over-represented in the ovarian cancer patients but not in the breast cancer series. These findings reinforce recent suggestions that AR may have a role in ovarian carcinogenesis.

The androgen receptor cytosine-adenine-guanine repeat length contributes to the development of epithelial ovarian cancer

“…Then, Dagan et al [ 19 ] explore the association of AR CAG repeat length with risk of ovarian cancer in Jewish Israeli women who are BRCA1/2 mutation carriers, and null results were concluded due to the small sample size. Since, several studies published recently found shorter CAG repeat length could increase risk of ovarian cancer [ 12 , 14 , 24 , 25 ], while two studies published previously showed inversed results [ 6 , 23 ]. One possible reason is the ethnically diverse populations, for which potential lifestyle and cultural factors, as well as other genetic factors, that may modify risk.…”

Androgen receptor polymorphisms and endometrial cancer risk

“…The AR CAG repeat polymorphism has also been shown to have a role in cancer susceptibility. Inconsistent associations between breast,16, 17, 18, 19, 20, 21, 22, 23, 24, 25 ovarian23, 25, 26, 27, 28 and prostate cancer16, 29, 30, 31, 32 and the AR CAG repeat polymorphism have been observed. Two small epidemiological studies have observed a positive association between increased CAG repeat length and endometrial cancer risk 33, 34…”

MED12-Related Disease in a Chinese Girl: Clinical Characteristics and Underlying Mechanism

“…To test the X-chromosome inactivation pattern of the patient and her nuclear family, we carried out a methylation-based analysis on the human androgen receptor (AR) gene (Allen et al, 1992), according to a reported protocol (Kassim et al, 2004). Briefly, 200 ng of DNA from peripheral blood cells was digested with HpaII (New England Biolabs, Ipswich, MA, USA) at 37°C overnight followed by enzymatic inactivation by heating at 95°C for 10 min.…”