Translational Research Unit, Albacete University Hospital, and CIBERONC, Albacete, Spain.
Centro Regional de Investigaciones Biomédicas, Universidad de Castilla La Mancha, Albacete, Spain.
PLoS One. 2019 Apr 16;14(4):e0209134. doi: 10.1371/journal.pone.0209134. eCollection 2019.
Epigenetic regulating proteins like histone methyltransferases produce variations in several functions, some of them associated with the generation of oncogenic processes. Mutations of genes involved in these functions have been recently associated with cancer, and strategies to modulate their activity are currently in clinical development.
By using data extracted from the METABRIC study, we searched for mutated genes linked with detrimental outcome in invasive breast carcinoma (n = 772). Then, we used downstream signatures for each mutated gene to associate that signature with clinical prognosis using the online tool "Genotype-2-Outcome" (http://www.g-2-o.com). Next, we performed functional annotation analyses to classify genes by functions, and focused on those associated with the epigenetic machinery.
We identified KMT2D, SETD1A and SETD2, included in the lysine methyltransferase activity function, as linked with poor prognosis in invasive breast cancer. KMT2D which codes for a histone methyltransferase that acts as a transcriptional regulator was mutated in 6% of triple negative breast tumors and found to be linked to poor survival. Genes regulated by KMT2D included RAC3, KRT23, or KRT14, among others, which are involved in cell communication and signal transduction. Finally, low expression of KMT2D at the transcriptomic level, which mirror what happens when KMT2D is mutated and functionally inactive, confirmed its prognostic value.
In the present work, we describe epigenetic modulating genes which are found to be mutated in breast cancer. We identify the histone methyltransferase KMT2D, which is mutated in 6% of triple negative tumors and linked with poor survival.
组蛋白甲基转移酶等表观遗传调节蛋白在多种功能上产生变异，其中一些与致癌过程的产生有关。最近，与这些功能相关的基因发生突变与癌症有关，目前正在临床开发调节其活性的策略。
我们使用从 METABRIC 研究中提取的数据，搜索与浸润性乳腺癌（n=772）不良结局相关的突变基因。然后，我们使用每个突变基因的下游特征，使用在线工具“基因型-2-结果”（http://www.g-2-o.com）将该特征与临床预后相关联。接下来，我们进行功能注释分析，按功能对基因进行分类，并重点关注与表观遗传机制相关的基因。
我们确定了 KMT2D、SETD1A 和 SETD2，它们都包含在赖氨酸甲基转移酶活性功能中，与浸润性乳腺癌的不良预后相关。编码组蛋白甲基转移酶的 KMT2D 作为转录调节剂，在三阴性乳腺癌中发生突变的比例为 6%，并发现与不良生存相关。KMT2D 调节的基因包括 RAC3、KRT23 和 KRT14 等，它们参与细胞通讯和信号转导。最后，在转录组水平上 KMT2D 的低表达，反映了 KMT2D 发生突变和功能失活时的情况，证实了其预后价值。
在本工作中，我们描述了在乳腺癌中发现发生突变的表观遗传调节基因。我们确定了组蛋白甲基转移酶 KMT2D，它在 6%的三阴性肿瘤中发生突变，并与不良生存相关。
