Department of Surgery, Teikyo University School of Medicine, Itabashi-ku, Tokyo 173-8605, Japan.
Eur J Cancer. 2011 Sep;47(13):1946-54. doi: 10.1016/j.ejca.2011.03.029. Epub 2011 Apr 29.
KRAS mutation is an important predictive marker in determining resistance to anti-Epidermal Growth Factor Receptor (EGFR) antibody therapies. In order to clarify whether not only KRAS related signalling pathways but also other signalling pathways are altered in patients with colorectal cancers (CRCs) with KRAS mutations, we examined the differences in the gene expression signatures between CRCs with and without KRAS mutation.
One-hundred and thirteen patients who underwent a surgical resection of a primary CRC were examined. KRAS mutational status was determined using the Peptide Nucleic Acid (PNA)-clamp real-time polymerase chain reaction (PCR) TaqMan assay. Gene expression profiles were compared between CRCs with and without KRAS mutation using the Human Genome GeneChip array U133.
Among 113 CRCs, KRAS mutations were present in 35 tumours (31%). We identified 30 genes (probes) that were differentially expressed between CRCs with and without KRAS mutation (False Discovery Rate (FDR), p<0.01), by which we were able to predict the KRAS status with an accuracy of 90.3%. Thirty discriminating genes included TC21, paired-like homeodomain 1 (PITX1), Sprouty-2, dickkopf homologue 4 (DKK-4), SET and MYND domain containing 3 (SMYD3), mitogen-activated protein kinase kinase kinase 14 (MAP3K14) and c-mer Proto-oncogene tyrosine kinase (MerTK). These genes were related to not only KRAS related signalling pathway but also to other signalling pathways, such as the Wnt-signalling pathway, the NF-kappa B activation pathway and the TGF-beta signalling pathway.
KRAS mutant CRCs exhibited a distinct gene expression signature different from wild-type KRAS CRCs. Using human CRC samples, we were able to show that there is crosstalk between the KRAS-mediated pathway and other signalling pathways. These results are necessary to be taken into account in establishing chemotherapeutic strategies for patients with anti-EGFR-refractory KRAS mutant CRCs.
KRAS 突变是预测抗表皮生长因子受体（EGFR）抗体治疗耐药的重要标志物。为了阐明 KRAS 突变的结直肠癌（CRC）患者不仅 KRAS 相关信号通路发生改变，其他信号通路是否也发生改变，我们检测了 KRAS 突变型和野生型 CRC 之间的基因表达谱差异。
对 113 例接受原发性 CRC 手术切除的患者进行了检查。采用肽核酸（PNA）-夹实时聚合酶链反应（PCR）TaqMan 检测法确定 KRAS 突变状态。使用人类基因组基因芯片 U133 比较 KRAS 突变型和野生型 CRC 之间的基因表达谱。
在 113 例 CRC 中，35 例（31%）肿瘤存在 KRAS 突变。我们鉴定出 30 个在 KRAS 突变型和野生型 CRC 之间差异表达的基因（探针）（错误发现率（FDR），p<0.01），由此我们能够以 90.3%的准确率预测 KRAS 状态。30 个有区别的基因包括 TC21、同源框基因 1（PITX1）、Sprouty-2、Dickkopf 同源物 4（DKK-4）、SET 和 MYND 结构域包含 3（SMYD3）、丝裂原激活蛋白激酶激酶激酶 14（MAP3K14）和 c-Mer 原癌基因酪氨酸激酶（MerTK）。这些基因不仅与 KRAS 相关信号通路有关，还与其他信号通路有关，如 Wnt 信号通路、NF-κB 激活通路和 TGF-β信号通路。
KRAS 突变型 CRC 表现出与野生型 KRAS CRC 不同的独特基因表达谱。使用人类 CRC 样本，我们能够证明 KRAS 介导的通路与其他信号通路之间存在串扰。这些结果对于制定抗 EGFR 耐药的 KRAS 突变型 CRC 患者的化疗策略是必要的。
