A risk variant in an miR-125b binding site in BMPR1B is associated with breast cancer pathogenesis.
A risk variant in an miR-125b binding site in BMPR1B is associated with breast cancer pathogenesis.
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DOI：
10.1158/0008-5472.can-09-1201
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发表时间：
2009-09-15
期刊：
影响因子：
11.2
通讯作者：
Larson GP
中科院分区：
文献类型：
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作者：
Saetrom P;Biesinger J;Li SM;Smith D;Thomas LF;Majzoub K;Rivas GE;Alluin J;Rossi JJ;Krontiris TG;Weitzel J;Daly MB;Benson AB;Kirkwood JM;O'Dwyer PJ;Sutphen R;Stewart JA;Johnson D;Larson GP
微小RNA（MicroRNAs）调节多种细胞过程，并在癌症发病机制中起着不可或缺的作用。因此，微小RNA靶位点内的基因组变异可能是癌症风险遗传差异的重要来源。为了研究这种可能性，我们将国际人类基因组单体型图（HapMap）中的单核苷酸多态性（SNPs）定位到在雌激素受体分层的乳腺肿瘤中失调的基因内假定的微小RNA识别位点，并利用局部连锁不平衡（LD）模式在癌症易感性遗传标记（CGEMS）乳腺癌全基因组关联研究（GWAS）中确定排名靠前的单核苷酸多态性以进行进一步测试。在CGEMS研究中排名前100的两个单核苷酸多态性rs1970801和rs11097457与rs1434536处于强连锁不平衡状态，rs1434536是一个位于骨形态发生蛋白受体1B型（BMPR1B）基因3'非翻译区（3'UTR）的微小RNA - 125b靶位点内的单核苷酸多态性，该基因编码一种跨膜丝氨酸/苏氨酸激酶。我们在从有多个病例病史的家庭中确定的一个经过混合校正的独立病例队列中验证了rs1970801的CGEMS关联发现。随后对这些病例以及具有估算基因型的CGEMS对照进行rs1434536的关联测试支持了这种关联。此外，荧光素酶报告基因分析以及微小RNA - 125b模拟物的过表达结合定量逆转录聚合酶链反应（RT - PCR）表明，BMPR1B转录本是微小RNA - 125b的直接靶标，并且微小RNA - 125b对rs1434536的C和T等位基因有差异调节作用。这些结果表明，微小RNA - 125b对BMPR1B的等位基因特异性调节解释了所观察到的疾病风险。我们的方法具有普遍性，可以帮助识别和解释影响微小RNA调节的等位基因与疾病关联背后的机制。
MicroRNAs regulate diverse cellular processes and play an integral role in cancer pathogenesis. Genomic variation within miRNA target sites may therefore be important sources for genetic differences in cancer risk. To investigate this possibility, we mapped HapMap SNPs to putative miRNA recognition sites within genes dysregulated in estrogen receptor stratified breast tumors and used local linkage disequilibirum (LD) patterns to identify high-ranking SNPs in the Cancer Genetic Markers of Susceptibility (CGEMS) breast cancer genome wide association study (GWAS) for further testing. Two SNPs, rs1970801 and rs11097457, scoring in the top 100 from the CGEMS study, were in strong LD with rs1434536 – a SNP that resides within a miR-125b target site in the 3'UTR of the Bone Morphogenic Receptor Type 1B (BMPR1B) gene encoding a transmembrane serine/threonine kinase. We validated the CGEMS association findings for rs1970801 in an independent cohort of admixture corrected cases identified from families with multiple case histories. Subsequent association testing of rs1434536 for these cases and CGEMS controls with imputed genotypes supported the association. Furthermore, luciferase reporter assays and overexpression of miR-125b-mimics combined with quantitative RT-PCR showed that BMPR1B transcript is a direct target of miR-125b and that miR-125b differentially regulates the C and T alleles of rs1434536. These results suggest that allele-specific regulation of BMPR1B by miR-125b explains the observed disease risk. Our approach is general and can help identify and explain the mechanisms behind disease-association for alleles that affect miRNA regulation.