Kawase Takakazu, Matsuo Keitaro, Suzuki Takeshi, Hiraki Akio, Watanabe Miki, Iwata Hiroji, Tanaka Hideo, Tajima Kazuo
Division of Epidemiology and Prevention, Aichi Cancer Center, Nagoya 464-8681, Japan.
Int J Cancer. 2009 Oct 15;125(8):1946-52. doi: 10.1002/ijc.24505.
Recently, 2 genome-wide association studies demonstrated that single nucleotide polymorphisms (SNPs) of the fibroblast growth factor receptor 2 (FGFR2) gene at intron 2 are significantly associated with the risk of female breast cancer. As the next step, it is necessary to evaluate the interaction between these SNPs and known risk factors of breast cancer because such an evaluation could elucidate mechanisms of carcinogenesis and lead to preventive advances. We conducted a case-control study of 456 newly and histologically diagnosed breast cancer cases and 912 age- and menopausal status-matched noncancer controls. The impact of 5 FGFR2 intronic SNPs on the risk of breast cancer and the interactions between these SNPs and various known risk factors of breast cancer were evaluated in both pre and postmenopausal women. We observed a statistically significant association between 4 SNPs and breast cancer risk and these 4 SNPs were in strong linkage disequilibrium in the Japanese population. rs2420946 was associated with a population-attributable risk of 17.7%. We found that FGFR2 polymorphisms interact with family history of breast cancer (interaction p = 0.003) and reproductive risk factors, namely, age at menarche (interaction p = 0.019) and parity (interaction p = 0.026). Of note, a significant association between body mass index (BMI) > or = 25 and FGFR2 polymorphism was observed among postmenopausal women (trend p = 0.012), but not among premenopausal women. In contrast, BMI < 25 had no significant association with this polymorphism regardless of menopausal status. These findings suggest that FGFR2 intronic SNPs affect the reproductive hormone-related pathway and contribute to the development of female breast cancer in the Japanese population.
最近，两项全基因组关联研究表明，成纤维细胞生长因子受体2（FGFR2）基因内含子2的单核苷酸多态性（SNP）与女性乳腺癌风险显著相关。下一步，有必要评估这些SNP与已知乳腺癌风险因素之间的相互作用，因为这样的评估可以阐明致癌机制并带来预防方面的进展。我们对456例新确诊且经组织学诊断的乳腺癌病例以及912例年龄和绝经状态匹配的非癌症对照进行了病例对照研究。在绝经前和绝经后女性中，评估了5个FGFR2内含子SNP对乳腺癌风险的影响以及这些SNP与各种已知乳腺癌风险因素之间的相互作用。我们观察到4个SNP与乳腺癌风险之间存在统计学显著关联，并且这4个SNP在日本人群中处于强连锁不平衡状态。rs2420946的人群归因风险为17.7%。我们发现FGFR2多态性与乳腺癌家族史（相互作用p = 0.003）以及生殖风险因素，即初潮年龄（相互作用p = 0.019）和产次（相互作用p = 0.026）相互作用。值得注意的是，在绝经后女性中观察到体重指数（BMI）≥25与FGFR2多态性之间存在显著关联（趋势p = 0.012），而在绝经前女性中未观察到。相反，无论绝经状态如何，BMI < 25与这种多态性均无显著关联。这些发现表明，FGFR2内含子SNP影响生殖激素相关途径，并在日本人群中促进女性乳腺癌的发生。
