Functional study of risk loci of stem cell-associated gene lin-28B and associations with disease survival outcomes in epithelial ovarian cancer
Functional study of risk loci of stem cell-associated gene lin-28B and associations with disease survival outcomes in epithelial ovarian cancer
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DOI：
10.1093/carcin/bgs243
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发表时间：
2012-11-01
期刊：
影响因子：
4.7
通讯作者：
Yu, Herbert
中科院分区：
文献类型：
--
作者：
Lu, Lingeng;Katsaros, Dionyssios;Yu, Herbert
干细胞相关基因LIN-28B的几个单核苷酸多态(SNPs)已经被发现与卵巢癌和卵巢癌相关的危险因素相关。然而，这些SNP是否是功能性的，或者可能是卵巢癌预后的潜在生物标记物仍是未知的。本研究的目的是探讨LIN-28B单核苷酸多态与卵巢上皮性癌(EOC)预后的关系，以及LIN-28B单核苷酸多态性与卵巢上皮性癌(EOC)预后的关系。我们分别采用Taqman(R)SNP基因分型技术和SYBR Green实时荧光定量聚合酶链式反应技术分析了211例卵巢癌组织中LIN-28B基因的5个SNPs和mRNA水平。对全基因组关联识别的内含子rs314276区域的RNA二级结构进行了理论分析和圆二色谱实验。结果表明，rs314276在加性模型和显性模型中都是一个顺式作用的数量性状基因座(EQTL)，而rs7759938和rs314277仅在显性模型中达到显著或边缘显著水平。Rs314276变异显著影响RNA二级结构。没有单靠SNPs与患者生存相关。然而，我们发现，在最初对化疗有反应的患者中，LIN-28B高表达的患者比低表达的患者有更高的死亡风险(风险比=3.27，95%可信区间：1.63-6.56)和复发风险(风险比=2.53，95%可信区间：1.41-4.54)，这些关联仍然存在于多因素分析中。这些结果表明，rs314276改变了RNA二级结构，从而影响了基因的表达，并且LIN-28B是一个与肿瘤干细胞相关的标记物，可能是治疗卵巢癌的药物靶点。
Several single-nucleotide polymorphisms (SNPs) of the stem cell-associated gene lin-28B have been identified in association with ovarian cancer and ovarian cancer-related risk factors. However, whether these SNPs are functional or might be potential biomarkers for ovarian cancer prognosis remains unknown. The purposes of this study were to investigate the functional relevance of the identified lin-28B SNPs, as well as the associations of genotype and phenotype with epithelial ovarian cancer (EOC) survival. We analyzed five SNPs and mRNA levels of lin-28B in 211 primary EOC tissues using Taqman (R) SNP genotyping assays and SYBR green-based real-time PCR, respectively. The RNA secondary structures at the region of a genome-wide association-identified intronic rs314276 were analyzed theoretically with mfold and experimentally with circular dichroism spectroscopy. We found that rs314276 was a cis-acting expression quantitative trait locus (eQTL) in both additive and dominant models, while rs7759938 and rs314277 were significant or of borderline significance in dominant models only. The rs314276 variant significantly affects RNA secondary structure. No SNPs alone were associated with patient survival. However, we found that among patients initially responding to chemotherapy, those with higher lin-28B expression had higher mortality risk (hazard ratio =3.27, 95% confidence interval: 1.63-6.56) and relapse risk (hazard ratio = 2.53, 95% confidence interval: 1.41-4.54) than those with lower expression, and these associations remained in multivariate analyses. These results suggest that rs314276 alters RNA secondary structure and thereby influences gene expression, and that lin-28B is a cancer stem cell-associated marker, which may be a pharmaceutical target in the management of EOC.