Tamimi Rulla M, Cox David G, Kraft Peter, Pollak Michael N, Haiman Christopher A, Cheng Iona, Freedman Matthew L, Hankinson Susan E, Hunter David J, Colditz Graham A
Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, 181 Longwood Avenue, Boston, MA 02115, USA.
Breast Cancer Res. 2007;9(1):R18. doi: 10.1186/bcr1655.
Mammographic density is one of the strongest risk factors for breast cancer and is believed to represent epithelial and stromal proliferation. Because of the high heritability of breast density, and the role of the insulin-like growth factor (IGF) pathway in cellular proliferation and breast development, we examined the association between common genetic variation in this pathway and mammographic density.
We conducted a cross-sectional analysis among controls (n = 1,121) who were between the ages of 42 and 78 years at mammography, from a breast cancer case-control study nested within the Nurses' Health Study cohort. At the time of mammography, 204 women were premenopausal and 917 were postmenopausal. We genotyped 29 haplotype-tagging SNPs demonstrated to capture common genetic variation in IGF1, IGF binding protein (IGFBP)-1, and IGFBP-3.
Common haplotype patterns in three of the four haplotype blocks spanning the gene encoding IGF1 were associated with mammographic density. Haplotype patterns in block 1 (p = 0.03), block 3 (p = 0.009), and block 4 (p = 0.007) were associated with mammographic density, whereas those in block 2 were not. None of the common haplotypes in the three haplotype blocks spanning the genes encoding IGFBP-1/IGFBP-3 were significantly associated with mammographic density. Two haplotype-tagging SNPs in IGF1, rs1520220 and rs2946834, showed a strong association with mammographic density. Those with the homozygous variant genotype for rs1520220 had a mean percentage mammographic density of 19.6% compared with those with the homozygous wild-type genotype, who had a mean percentage mammographic density of 27.9% (p for trend < 0.0001). Those that were homozygous variant for rs2946834 had a mean percentage mammographic density of 23.2% compared with those who were homozygous wild-type with a mean percentage mammographic density of 28.2% (p for trend = 0.0004). Permutation testing demonstrated that results as strong as these are unlikely to occur by chance (p = 0.0005).
Common genetic variation in IGF1 is strongly associated with percentage mammographic density.
乳腺钼靶密度是乳腺癌最强的风险因素之一，被认为代表上皮和间质增生。由于乳腺密度具有高度遗传性，且胰岛素样生长因子（IGF）途径在细胞增殖和乳腺发育中起作用，我们研究了该途径中常见基因变异与乳腺钼靶密度之间的关联。
我们对来自护士健康研究队列中的一项乳腺癌病例对照研究中，年龄在42至78岁之间进行乳腺钼靶检查的对照组（n = 1121）进行了横断面分析。在进行乳腺钼靶检查时，204名女性处于绝经前，917名处于绝经后。我们对29个单倍型标签SNP进行了基因分型，这些SNP被证明可捕获IGF1、IGF结合蛋白（IGFBP）-1和IGFBP-3中的常见基因变异。
跨越编码IGF1基因的四个单倍型块中的三个的常见单倍型模式与乳腺钼靶密度相关。第1块（p = 0.03）、第3块（p = 0.009）和第4块（p = 0.007）的单倍型模式与乳腺钼靶密度相关，而第2块的则不相关。跨越编码IGFBP-1/IGFBP-3基因的三个单倍型块中的任何常见单倍型均与乳腺钼靶密度无显著关联。IGF1中的两个单倍型标签SNP，rs1520220和rs2946834，与乳腺钼靶密度有很强的关联。rs1520220纯合变异基因型的人乳腺钼靶密度平均百分比为19.6%，而纯合野生型基因型的人乳腺钼靶密度平均百分比为27.9%（趋势p < 0.0001）。rs2946834纯合变异的人乳腺钼靶密度平均百分比为23.2%，而纯合野生型的人乳腺钼靶密度平均百分比为28.2%（趋势p = 0.0004）。置换检验表明，如此强的结果不太可能偶然出现（p = 0.0005）。
IGF1中的常见基因变异与乳腺钼靶密度百分比密切相关。
