Godfrey Ashley C, Xu Zongli, Weinberg Clarice R, Getts Robert C, Wade Paul A, DeRoo Lisa A, Sandler Dale P, Taylor Jack A
Breast Cancer Res. 2013 May 24;15(3):R42. doi: 10.1186/bcr3428.
MicroRNAs (miRNAs) are small, non-coding, single-stranded RNAs between 18-22 nucleotides long that regulate gene expression. Expression of miRNAs is altered in tumor compared to normal tissue; there is some evidence that these changes may be reflected in the serum of cancer cases compared to healthy individuals. This has yet to be examined in a prospective study where samples are collected before diagnosis.
We used Affymetrix arrays to examine serum miRNA expression profiles in 410 participants in the Sister Study, a prospective cohort study of 50,884 women. All women in the cohort had never been diagnosed with breast cancer at the time of enrollment. We compared global miRNA expression patterns in 205 women who subsequently developed breast cancer and 205 women who remained breast cancer-free. In addition within the case group we examined the association of miRNA expression in serum with different tumor characteristics, including hormone status (ER, PR, and HER-2) and lymph node status.
Overall, 414 of 1,105 of the human miRNAs on the chip were expressed above background levels in 50 or more women. When the average expression among controls was compared to cases using conditional logistic regression, 21 miRNAs were found to be differentially expressed (P≤.05). Using qRT-PCR on a small, independent sample of 5 cases and 5 controls we verified overexpression of the 3 highest expressing miRNAs among cases, miR-18a, miR-181a, and miR-222; the differences were not statistically significant in this small set. The 21 differentially expressed miRNAs are known to target at least 82 genes; using the gene list for pathway analysis we found enrichment of genes involved in cancer-related processes. In a separate case-case analyses restricted to the 21 miRNAs, we found 7 miRNAs with differential expression for women whose breast tumors differed by HER-2 expression, and 10 miRNAs with differential expression by nodal status.
miRNA levels in serum show a number of small differences between women who later develop cancer versus those who remain cancer-free.
微小RNA（miRNA）是长度为18 - 22个核苷酸的小型非编码单链RNA，可调节基因表达。与正常组织相比，肿瘤中miRNA的表达会发生改变；有证据表明，与健康个体相比，癌症患者血清中的这些变化可能会有所体现。但这一点尚未在前瞻性研究中得到验证，因为前瞻性研究需要在诊断前采集样本。
我们使用Affymetrix芯片检测了“姐妹研究”中410名参与者的血清miRNA表达谱，该研究是一项针对50,884名女性的前瞻性队列研究。队列中的所有女性在入组时均未被诊断出患有乳腺癌。我们比较了205名随后患乳腺癌的女性和205名未患乳腺癌的女性的整体miRNA表达模式。此外，在病例组中，我们研究了血清中miRNA表达与不同肿瘤特征之间的关联，包括激素状态（雌激素受体、孕激素受体和人表皮生长因子受体2）和淋巴结状态。
总体而言，芯片上1105个人类miRNA中的414个在50名或更多女性中的表达高于背景水平。当使用条件逻辑回归将对照组的平均表达与病例组进行比较时，发现有21个miRNA存在差异表达（P≤0.05）。我们在一个由5例病例和5例对照组成的小型独立样本上使用定量逆转录聚合酶链反应（qRT-PCR），验证了病例组中表达最高的3个miRNA，即miR-18a、miR-181a和miR-222的过表达情况；在这个小样本中，差异无统计学意义。已知这21个差异表达的miRNA至少靶向82个基因；使用基因列表进行通路分析时，我们发现参与癌症相关过程的基因出现富集。在一项单独的仅限于这21个miRNA的病例-病例分析中，我们发现对于乳腺肿瘤因HER-2表达不同的女性，有7个miRNA存在差异表达，对于因淋巴结状态不同的女性，有10个miRNA存在差异表达。
血清中的miRNA水平显示，后来患癌的女性与未患癌的女性之间存在一些细微差异。
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