CAG repeat length in exon 1 of the androgen receptor gene is related to age of diagnosis but not germ line BRCA1 mutation status in ovarian cancer

Abstract

It has been postulated that androgens, through their interaction with androgen receptors (AR), may play an important role in the development of ovarian cancer. Exon 1 of the AR gene contains three highly polymorphic trinucleotide repeats. The length of the (CAG)n repeat segment 1 is inversely correlated with the transactivation function of the AR. Recent studies have shown that BRCA1 may function as an AR coregulator or coactivator and play positive roles in androgen-induced cell death in cancer cells as well as other androgen/AR target organs. We hypothesize that the AR gene, involved in endocrine signaling, may modify BRCA1-associated ovarian cancer risk. To test this hypothesis, potential associations between the (CAG)n repeat length, germ line BRCA1 mutation status, and age of diagnosis for ovarian cancer were investigated. One hundred and eleven ovarian cancer patients (27 hereditary and 84 sporadic) were included. All the cases were allelotyped for CAG repeat length and genotyped for mutations in the BRCA1 gene by direct sequencing. No association between CAG repeat length and BRCA1 mutation status was identified. Furthermore, there were no differences between hereditary and sporadic ovarian cancer in the number of (CAG)n repeats of the short allele (P= 0.336), long allele (P= 0.875), or average allele length (P= 0.550). However, ovarian cancer patients from both groups (hereditary and sporadic) who carried any AR allele of (CAG)n < or = 22 repeats were diagnosed on average 8.17 years (95% confidence interval [1.3, 15.0]) earlier than the patients whose shortest AR allele (CAG)n was >22 (P= 0.020). In conclusion, it is suggested that the CAG repeat length in AR exon 1 may affect the age of diagnosis of ovarian cancer but does so independent of germ line BRCA1 carrier status.

Increased expression of ACTH (MC2R) and androgen (AR) receptors in giant bilateral myelolipomas from patients with congenital adrenal hyperplasia

“…It has been postulated that androgens, through their interaction with androgen receptors, may play an important role in the development of specific tumors, such as ovarian and prostate cancer [16,17]. Exon 1 of the AR gene contains highly polymorphic trinucleotide repeats, and the length of the nCAG repeat segment is inversely correlated with the transactivation function of the AR gene [18].…”

The Role of Androgen Receptor Signaling in Ovarian Cancer

“…In two studies comprising patients with both hereditary and sporadic ovarian cancers, those with shorter CAG repeats were shown to be diagnosed an average of 7.2 (CAG <15; 95% CI = 2.3–12.1, P = 0.004) [34] or 10.45 (CAG ≤22; 95% CI = 1.28–19.62, P = 0.02) [35] years earlier than those with longer repeats. Correspondingly, as seen in prostate cancer [36], case-control studies involving ovarian cancer patients and unaffected control subjects have indicated that short CAG repeats are associated with a significantly higher risk of developing ovarian tumor in African Americans in the US [37], Polish Caucasians [38], or Han Chinese [39,40].…”

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

“…There are several published studies that addressed the association between AR repeat polymorphisms and ovarian cancer [ 6 , 12 , 14 – 17 ]. However, none was conducted in non-Asians.…”