Short androgen receptor allele length is a poor prognostic factor in epithelial ovarian carcinoma.

Abstract

Epidemiological evidence implicates a heightened androgenic state in women with epithelial ovarian cancer. Androgen activity may be modulated by altered expression or activity of the androgen receptor (AR) or AR polymorphisms. Exon 1 of the AR gene contains a polymorphic (CAG)(n) sequence whose length is inversely correlated with transcriptional activity. Differential expression of AR mRNA and protein was examined in 46 primary cultures of normal human ovarian surface epithelium (HOSE) and malignant Cedars-Sinai ovarian cancer (CSOC) ovarian epithelial cells. AR allele length was characterized by genotyping in 77 ovarian cancer specimens. AR mRNA expression was higher in CSOC primary cultures (1.58 +/- 0.17) when compared with HOSE (1 +/- 0.09, P = 0.005), but protein expression was not statistically different. CAG repeat lengths were shorter in CSOC (20.6 +/- 1.2) than in HOSE (23.4 +/- 0.9, P = 0.04). Patients with an AR allele containing < or =19 CAG repeats had a shorter time to recurrence (5.5 versus 19.4 months, P < 0.0001) and overall survival (9 versus 32.6 months, P = 0.0007). There was no correlation between AR allelotype and age of diagnosis, stage, or grade; however, a short CAG length < or =19 repeats was associated with decreased surgical cytoreducibility (44.4 versus 10.3%, P = 0.035). Multivariate analyses confirmed a short AR allele as an independent prognostic factor (P = 0.02). These data support epidemiological evidence linking heightened androgenicity to the pathogenesis and tumor biology of epithelial ovarian cancer.