Department of Oncology, Clinical Sciences, Lund University, Barngatan 2B, 221 85 Lund, Sweden.
Mol Genet Metab. 2011 Jan;102(1):82-90. doi: 10.1016/j.ymgme.2010.09.006. Epub 2010 Sep 25.
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.
高睾酮水平与乳腺癌有关。BRCA1 可能作为雄激素受体 (AR) 的共调节剂发挥作用。我们旨在研究 AR 单核苷酸多态性 (AR SNPs) 单体型标记和单体型与体内雄激素水平、联合 OC 使用、CAG 和 GGC 基因型以及 BRCA1/2/X 家族状态之间的关系，研究对象为 269 名来自乳腺癌高危家族的年轻健康女性和另外 56 名 BRCA1/2 突变携带者。在周期第 18-23 天，测量了睾酮、雄烯二酮、硫酸脱氢表雄酮和体质。对 6 个 AR SNPs 和 CAG 和 GGC 重复长度进行了基因分型。大多数 OC 用户的雄激素水平低于非使用者（所有 P<0.0001）。在 OC 用户中，罕见变异单体型与较高的睾酮水平相关（P（交互作用）=0.011）。经家族聚类调整后，这种相互作用仍然存在。个体 AR SNPs 或其他单体型与雄激素水平均无显著相关性，也不能标记 CAG 或 GGC 基因型。在每个家族中首先纳入的女性中，与其他家族相比，BRCA1 家族中最常见单体型的几率较低，OR 为 0.41（95% CI 0.22-0.78）。总之，我们发现女性中 AR SNPs 或单体型与雄激素水平之间的相关性很少。单体型不能替代 CAG 或 GGC 微卫星的基因分型。由于在所有女性中，联合 OC 使用对睾酮水平的影响方式不同，因此在联合 OC 使用期间睾酮水平较高的年轻女性可能属于不能通过联合 OC 治疗雄激素依赖性疾病且可能有更高的早发性乳腺癌风险的女性亚组。是否可以通过 AR 基因分型来识别这些女性，需要在独立队列中进行验证。
