SYK allelic loss and the role of Syk-regulated genes in breast cancer survival.
SYK allelic loss and the role of Syk-regulated genes in breast cancer survival.
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DOI：
10.1371/journal.pone.0087610
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Mueller SC
中科院分区：
文献类型：
--
作者：
Blancato J;Graves A;Rashidi B;Moroni M;Tchobe L;Ozdemirli M;Kallakury B;Makambi KH;Marian C;Mueller SC
SYK（一种非受体酪氨酸激酶）的杂合性缺失导致小鼠乳腺肿瘤形成，其中Syk蛋白水平降低约一半; SYK mRNA的缺失与体外模型中的侵袭性细胞行为相关; SYK缺失与患者的远处转移相关。在这里，分别使用荧光原位杂交和焦磷酸测序在乳腺导管原位癌（DCIS）中探索了SYK基因的等位基因丢失，并使用来自癌症基因组图谱（TCGA）的基因组数据在浸润性导管癌（IDC）中探索了SYK基因的等位基因丢失。在存在相邻IDC的DCIS病例亚组中存在等位基因丢失。SYK拷贝数丢失在1002例乳腺癌病例中约占26%，在IDC病例中约占30%。定量免疫荧光显示Syk蛋白在浸润免疫细胞中比上皮细胞高6倍。这种差异扭曲了提取物中肿瘤细胞的mRNA和蛋白质水平。根据升高的免疫特异性mRNA估计，1002例IDC病例中有20%含有升高的免疫细胞浸润。在没有免疫细胞浸润的情况下，SYK拷贝数的丢失与SYK mRNA的显着减少有关。在这里，我们定义了一个55个基因集组成的Syk相互作用，运动和入侵相关的基因。我们发现IDC和Luminal A+B病例的总生存期显著降低，其中这55个基因的拷贝数和突变受到影响（Kaplan-Meier，对数秩检验p值分别为0.007141和0.001198）。我们的结论是，减少Syk的表达和基因组不稳定的贡献拷贝数和突变的55 Syk相互作用的基因显着有助于较差的整体患者生存。需要更仔细地研究Syk相互作用的运动和侵袭基因的作用及其与转移性疾病和患者结局的预后和/或因果关系。
Heterozygotic loss of SYK, a non-receptor tyrosine kinase, gives rise to mouse mammary tumor formation where Syk protein levels are reduced by about half; loss of SYK mRNA is correlated with invasive cell behavior in in vitro models; and SYK loss has been correlated with distant metastases in patients. Here, allelic loss of the SYK gene was explored in breast ductal carcinoma in situ (DCIS) using fluorescence in situ hybridization and pyrosequencing, respectively, and in infiltrating ductal carcinoma (IDC) using genomic data from The Cancer Genome Atlas (TCGA). Allelic loss was present in a subset of DCIS cases where adjacent IDC was present. SYK copy number loss was found in about 26% of 1002 total breast cancer cases and 30% of IDC cases. Quantitative immunofluorescence revealed Syk protein to be six-fold higher in infiltrating immune cells compared with epithelial cells. This difference distorted tumor cell mRNA and protein levels in extracts. 20% of 1002 IDC cases contained elevated immune cell infiltration as estimated by elevated immune-specific mRNAs. In cases without immune cell infiltration, loss of SYK copy number was associated with a significant reduction of SYK mRNA. Here we define a 55 Gene Set consisting of Syk interacting, motility- and invasion-related genes. We found that overall survival was significantly reduced in IDC and Luminal A+B cases where copy number and mutations of these 55 genes were affected (Kaplan-Meier, Logrank test p-value 0.007141 and Logrank test p-value 0.001198, respectively). We conclude that reduction in Syk expression and contributions of genomic instability to copy number and mutations in the 55 Syk interacting genes significantly contribute to poorer overall patient survival. A closer examination of the role of Syk interacting motility and invasion genes and their prognostic and/or causative association with metastatic disease and patient outcome is warranted.
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