Association of genetic variation in genes implicated in the beta-catenin destruction complex with risk of breast cancer.
Association of genetic variation in genes implicated in the beta-catenin destruction complex with risk of breast cancer.
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DOI：
10.1158/1055-9965.epi-08-0134
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发表时间：
2008-08
期刊：
影响因子：
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通讯作者：
Couch FJ
中科院分区：
文献类型：
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作者：
Wang X;Goode EL;Fredericksen ZS;Vierkant RA;Pankratz VS;Liu-Mares W;Rider DN;Vachon CM;Cerhan JR;Olson JE;Couch FJ
在广泛的人类恶性肿瘤中观察到异常Wnt/β-连环蛋白信号传导导致癌基因产物β-连环蛋白的核积聚。Wnt/β-连环蛋白途径中的破坏复合物对于调节细胞质和细胞核中的β-连环蛋白水平至关重要。在这里，我们报告了一个全面的研究，在六个基因编码的β-连环蛋白破坏复合物（APC，轴蛋白1，轴蛋白2，CSNK 1D，CSNK 1 E和GSK 3B）的遗传变异的贡献，乳腺癌使用马约诊所乳腺癌病例对照研究。在798例侵袭性病例和843例未受影响的对照中，共对79个候选功能和tagSNPs进行了基因分型。其中，APC肿瘤抑制基因中的rs 454886与乳腺癌风险增加相关（每等位基因比值比（OR）= 1.23; 95% CI，1.05-1.43; Ptrend = 0.01）。AXIN 2基因的5个SNPs与乳腺癌发病风险增加相关（Ptrend < 0.05）。基于单倍型的检验确定了APC（P ≤ 0.03）和AXIN 2（P = 0.03）中特定单倍型与乳腺癌风险之间的显著相关性。APC和AXIN 2变体的进一步表征表明AXIN 2 rs 4791171与绝经前妇女的风险显著相关（Ptrend = 0.0002; q = 0.02），但与绝经后妇女的风险无关。结合我们的研究结果和大量的遗传和功能研究表明，APC和AXIN 2执行关键的肿瘤抑制功能，表明AXIN 2和APC SNP对乳腺癌风险的贡献需要进一步研究。
Aberrant Wnt/β-catenin signaling leading to nuclear accumulation of the oncogene product β-catenin is observed in a wide spectrum of human malignancies. The destruction complex in the Wnt/β-catenin pathway is critical for regulating the level of β-catenin in the cytoplasm and in the nucleus. Here we report a comprehensive study of the contribution of genetic variation in six genes encoding the β-catenin destruction complex (APC, AXIN1, AXIN2, CSNK1D, CSNK1E and GSK3B) to breast cancer using a Mayo Clinic Breast Cancer Case-Control Study. A total of 79 candidate functional and tagSNPs were genotyped in 798 invasive cases and 843 unaffected controls. Of these, rs454886 in the APC tumor suppressor gene was associated with increased breast cancer risk (per-allele odds ratio (OR) = 1.23; 95% CI, 1.05–1.43; Ptrend = 0.01). In addition, five SNPs in AXIN2 were associated with increased risk of breast cancer (Ptrend < 0.05). Haplotype-based tests identified significant associations between specific haplotypes in APC (P ≤ 0.03) and AXIN2 (P = 0.03) and breast cancer risk. Further characterization of the APC and AXIN2 variants suggested that AXIN2 rs4791171 was significantly associated with risk in premenopausal (Ptrend = 0.0002; q = 0.02) but not in postmenopausal women. The combination of our findings and numerous genetic and functional studies showing that APC and AXIN2 perform crucial tumor suppressor functions suggest that further investigation of the contribution of AXIN2 and APC SNPs to breast cancer risk are needed.