Polymorphism rs4919510:C>G in mature sequence of human microRNA-608 contributes to the risk of HER2-positive breast cancer but not other subtypes.
Polymorphism rs4919510:C>G in mature sequence of human microRNA-608 contributes to the risk of HER2-positive breast cancer but not other subtypes.
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DOI：
10.1371/journal.pone.0035252
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Shao ZM
中科院分区：
文献类型：
--
作者：
Huang AJ;Yu KD;Li J;Fan L;Shao ZM
成熟的 microRNA 序列中存在一些多态性。这种多态性可以直接影响 microRNA 与数百个目标 mRNA 的结合。目前尚不清楚位于成熟 miR-608 中的 rs4919510:C>G 是否会改变乳腺癌易感性。 rs4919510:C>G 与乳腺癌风险和病理特征的关联在两项独立的病例对照研究中进行了调查，第一组包括 1,138 名散发性乳腺癌患者（包括 927 名浸润性导管癌患者，其中 777 名已知亚型：496 名管腔样患者、133 名 HER2 阳性和 148 名三阴性患者）和 1,434 名社区对照。第二组包括 294 名家族性/早发性乳腺癌患者和 500 名医院无癌对照者。通过逻辑回归估计优势比（OR）。对 miR-608 的预测靶点和包含 rs4919510:C>G 的互补序列进行了调查，以揭示潜在的病理机制。在第一组中，虽然rs4919510:C>G与一般患者的乳腺癌无关，但变异基因型（CG/GG）与HER2阳性亚型风险增加特别相关（调整OR = 1.97，95% CI，隐性模型中为1.34−2.90）。变异 G 等位基因是风险等位基因，OR 为 1.62（95% CI，1.23−2.15）。携带GG基因型的患者也有较大的HER2阳性肿瘤（Kruskal-Wallis检验的P = 0.006）。 rs4919510:C>G 与 HER2 阳性亚组风险之间的关系在第二组中得到验证（Bonferroni 校正 P = 0.06）。对于 GG 基因型，隐性模型中调整后的组合 OR（总共 164 例 HER2 阳性病例）为 1.97（95% CI，1.43−2.72）（校正后的 P = 1.1×10−4）。生物信息分析表明，HER2诱导肿瘤发生所需的HSF1可能是miR-608的靶标。祖先-miR-608（C-等位基因）与HSF1结合的最小自由能是-35.9 kcal/mol，而变体形式（G-等位基因）是-31.5 kcal/mol，表明变体-miR-608与HSF1 mRNA的亲和力较低。成熟 miR-608 中的 rs4919510:C>G 可能影响 HER2 阳性乳腺癌风险和肿瘤增殖。
A few polymorphisms are located in the mature microRNA sequences. Such polymorphisms could directly affect the binding of microRNA to hundreds of target mRNAs. It remains unknown whether rs4919510:C>G located in the mature miR-608 alters breast cancer susceptibility. The association of rs4919510:C>G with risk and pathologic features of breast cancer were investigated in two independent case-control studies, the first set including 1,138 sporadic breast cancer patients (including 927 invasive ductal carcinoma patients, 777 of them with known subtypes: 496 luminal-like, 133 HER2-positive, and 148 triple-negative) and 1,434 community-based controls, and the second set including 294 familial/early-onset breast cancer patients and 500 hospital-based cancer-free controls. Odds ratios (ORs) were estimated by logistic regression. Predicted targets of miR-608 and complementary sequences containing rs4919510:C>G were surveyed to reveal potential pathological mechanism. In the first set, although rs4919510:C>G was unrelated to breast cancer in general patients, variant genotypes (CG/GG) were specifically associated with increased risk of HER2-positive subtype (Adjusted OR = 1.97, 95% CI, 1.34−2.90 in the recessive model). Variant G-allele was the risk allele with OR of 1.62 (95% CI, 1.23−2.15). Patients carrying GG-genotype also had larger HER2-positive tumors (P for Kruskal-Wallis test = 0.006). The relationship between rs4919510:C>G and risk of HER2-positive subgroup was validated in the second set (Bonferroni corrected P = 0.06). The adjusted combined OR (total 164 HER2-positive cases) in the recessive model was 1.97 (95% CI, 1.43−2.72) for GG genotype (corrected P = 1.1×10−4). Bioinformatic analysis indicated that, HSF1, which is required for HER2-induced tumorigenesis, might be a target of miR-608. The minimum free-energy of ancestral-miR-608 (C-allele) binding to HSF1 is −35.9 kcal/mol, while that of variant-form (G-allele) is −31.5 kcal/mol, indicating a lower affinity of variant-miR-608 to HSF1 mRNA. rs4919510:C>G in mature miR-608 may influence HER2-positive breast cancer risk and tumor proliferation.
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