Hormone-dependent effects of FGFR2 and MAP3K1 in breast cancer susceptibility in a population-based sample of post-menopausal African-American and European-American women
Hormone-dependent effects of FGFR2 and MAP3K1 in breast cancer susceptibility in a population-based sample of post-menopausal African-American and European-American women
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DOI：
10.1093/carcin/bgn247
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发表时间：
2009-02-01
期刊：
影响因子：
4.7
通讯作者：
Strom, Brian L.
中科院分区：
文献类型：
--
作者：
Rebbeck, Timothy R.;DeMichele, Angela;Strom, Brian L.
FGFR2和MAP3K1是RAS/RAF/MEK/ erk信号通路的成员，已从全基因组关联研究中确定为乳腺癌易感基因。这些基因的潜在相互作用以及它们在肿瘤标志物、激素因素和种族方面对乳腺癌风险的作用尚未得到探讨。我们在1225名欧美女性（EA）和584名非裔美国女性（AA）的基于人群的病例对照样本中检测了FGFR2和MAP3K1变异、乳腺肿瘤特征和激素暴露。FGFR2 rs1219648和rs2981582基因型仅在雌激素受体阳性（ER+）、孕激素受体阳性（PR+）和HER2/ neu阴性（HER2-）肿瘤中与EA的乳腺癌显著相关。MAP3K1与EA女性的乳腺癌无关，但与AA女性的乳腺癌相关，同样仅限于ER+、PR+和HER2-肿瘤。在EA女性中，联合激素替代治疗与FGFR2 rs1219648基因型对乳腺癌风险存在相互作用（P = 0.010）。最后，我们观察到在AA而非EA女性中，MAP3K1 rs889312和FGFR2 rs2981582之间存在显著的相互作用（P = 0.022）。这些结果证实，FGFR2和MAP3K1参与乳腺癌易感性，并主要在ER+和PR+肿瘤中发挥作用。我们进一步报道，这些基因在HER2-肿瘤中发挥作用，相互作用赋予AA女性乳腺癌易感性，并与AA和EA女性的激素暴露相互作用。
FGFR2 and MAP3K1 are members of the RAS/RAF/MEK/ERK-signaling pathway and have been identified from genome-wide association studies to be breast cancer susceptibility genes. Potential interactions of these genes and their role with respect to tumor markers, hormonal factors and race on breast cancer risk have not been explored. We examined FGFR2 and MAP3K1 variants, breast tumor characteristics and hormone exposures in a population-based case-control sample of 1225 European-American (EA) and 584 African-American (AA) women. FGFR2 rs1219648 and rs2981582 genotypes were significantly associated with breast cancer in EA only in estrogen receptor-positive (ER+), progesterone receptor-positive (PR+) and HER2/Neu-negative (HER2-) tumors. MAP3K1 was not associated with breast cancer in EA women, but it was associated with breast cancer in AA women, again limited to ER+, PR+ and HER2- tumors. An interaction was observed between combined hormone replacement therapy use and FGFR2 rs1219648 genotypes on breast cancer risk in EA women (P = 0.010). Finally, we observed a significant interaction between MAP3K1 rs889312 and FGFR2 rs2981582 (P = 0.022) in AA but not EA women. These results confirm that FGFR2 and MAP3K1 are involved in breast cancer susceptibility and confer their effects primarily in ER+ and PR+ tumors. We further report that these genes confer their effects in HER2- tumors, interact with one another to confer breast cancer susceptibility in AA women and interact with hormone exposures in AA and EA women.