Androgen receptor htSNPs in relation to androgen levels and OC use in young women from high-risk breast cancer families.
High testosterone levels have been associated with breast cancer. BRCA1 may function as an androgen receptor (AR) co-regulator. We aimed to examine AR haplotype-tagging single-nucleotide polymorphisms (AR htSNPs) and diplotypes in relation to in vivo androgen levels, combined OC use, CAG and GGC genotypes, and BRCA1/2/X family status in 269 young healthy women from breast cancer high-risk families and 56 additional BRCA1/2 mutation carriers. Testosterone, androstenedione, dehydroepiandrosterone sulfate, and body constitution were measured on cycle days 18-23. Six AR htSNPs and CAG and GGC repeat lengths were genotyped. Most OC users had lower androgen levels than non-users (all Ps<0.0001). Rare variant diplotypes were associated with higher testosterone levels in OC users than in non-users (P(interaction)=0.011). The interaction remained after adjustment for family clustering. Neither individual AR htSNPs nor other diplotypes were significantly associated with androgen levels and did not tag for CAG or GGC genotypes. In the first included woman from each family, the odds of having the most common diplotype was lower in BRCA1 families compared to other families OR 0.41 (95% CI 0.22-0.78). In conclusion, we found few associations between AR htSNPs or diplotypes and androgen levels in women. Diplotypes cannot replace genotyping of microsatellites CAG or GGC. Since testosterone levels are not affected the same way by combined OC use among all women, young women who have higher testosterone levels during combined OC use may belong to the subgroup of women who will not be helped by combined OCs for treatment of androgen-dependent conditions and may be at higher risk for early-onset breast cancer. Whether these women can be identified with AR genotyping needs to be confirmed in an independent cohort.
Hietala
Maria
M
Department of Oncology, Clinical Sciences, Lund University, Barngatan 2B, 221 85 Lund, Sweden.
Henningson
Maria
M
Törngren
Therese
T
Olsson
Håkan
H
Jernström
Helena
H
D000328:Adult; D000728:Androgens / Q000097:blood*; D001483:Base Sequence; D001943:Breast Neoplasms / Q000453:epidemiology / Q000235:genetics*; D003277:Contraceptives, Oral, Combined; D005260:Female; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D005819:Genetic Markers; D006239:Haplotypes; D006801:Humans; D018895:Microsatellite Repeats; D020641:Polymorphism, Single Nucleotide; D011944:Receptors, Androgen / Q000235:genetics*; D012307:Risk Factors; D055815:Young Adult
D000728:Androgens; D003277:Contraceptives, Oral, Combined; D005819:Genetic Markers; D011944:Receptors, Androgen