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Androgen Receptor Cytosine, Adenine, Guanine Repeats, and Haplotypes in Relation to Ovarian Cancer Risk

¹ Obstetrics and Gynecology Epidemiology Center, ² Channing Laboratory, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School; and Departments of ³ Epidemiology and ⁴ Biostatistics, Harvard School of Public Health, Boston, Massachusetts; and ⁵ Norris Cotton Cancer Center and the Department of Community and Family Medicine, Dartmouth Medical School, Lebanon, New Hampshire

Requests for reprints: Kathryn L. Terry, Obstetrics and Gynecology Epidemiology Center, Brigham and Women's Hospital, 221 Longwood Avenue, Boston, MA 02115. Phone: 617-732-8596; Fax: 617-732-4899; E-mail: kterry{at}hsph.harvard.edu.

Biological and epidemiologic evidence suggest that androgen or its receptor may play a role in ovarian cancer pathogenesis. The most notable genetic factor influencing androgen receptor (AR) activity is the functional cytosine, adenine, guanine (CAG) repeat in which length is inversely proportional to its transactivational activity. Additional genetic variation due to single nucleotide polymorphisms in the AR gene may be captured through haplotypes. We genotyped the CAG microsatellite and six haplotype-tagging single nucleotide polymorphisms (rs962458, rs6152, rs1204038, rs2361634, rs1337080, rs1337082) of the androgen receptor gene in 987 ovarian cancer cases and 1,034 controls from a study conducted in New Hampshire and eastern Massachusetts between May 1992 and July 2003. We estimated haplotype frequencies and calculated odds ratios with 95% confidence intervals to evaluate the association between the haplotypes and the AR CAG microsatellite with ovarian cancer risk. We observed that carriage of two alleles with 22 CAG repeats was associated with an increased risk of ovarian cancer compared with carriage of two alleles with <22 CAG repeats (covariate-adjusted odds ratios, 1.31; 95% confidence intervals, 1.01-1.69). Five common haplotypes in the AR gene were identified, but no association between these and ovarian cancer risk was observed. Our results suggest that possession of two long AR alleles (22 CAG repeats) may be associated with increased risk of ovarian cancer compared with women with two short AR alleles (<22 CAG repeats).

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