Department of General Surgery, the Affiliated Tumor Hospital of Zhengzhou University, Zhengzhou 450008, Henan Province, China.
Department of Pharmacy, The Second Affiliated Hospital of Xinxiang Medical University, Xinxiang 453002, Henan Province, China.
World J Gastroenterol. 2019 Feb 21;25(7):808-823. doi: 10.3748/wjg.v25.i7.808.
The RAS/RAF/MEK/ERK and PI3K/AKT/mTOR signaling pathways all belong to mitogen-activated protein kinase (MAPK) signaling pathways, Mutations in any one of the upstream genes (such as the gene or the gene) may be transmitted to the protein through transcription or translation, resulting in abnormal activation of the signaling pathway. This study investigated the relationship between the gene mutation and the clinicopathological features and prognosis of colorectal cancer (CRC), and the effect of mutations on its associated proteins in CRC, with an aim to clarify the cause of tumor progression and drug resistance caused by mutation of the gene.
To investigate the gene and RAS pathway signaling molecules in CRC and to analyze their relationship with clinicopathological features and prognosis.
Colorectal cancer tissue specimens from 196 patients were analyzed for mutations using quantitative polymerase chain reaction and for KRAS, BRAF, MEK, and ERK protein expression levels using immunohistochemistry of tumor microarrays. To analyze differences of RAS pathway signaling molecule expression levels in different gene status, the relationships between these parameters and clinicopathological features, 4-year progression-free survival, and overall survival were analyzed by independent sample test, Kaplan-Meier plots, and the log-rank test. Predictors of overall and disease-free survival were assessed using a Cox proportional hazards model.
Of the 196 patients, 62 (32%) carried mutations in codon 12 (53/62) or codon 13 (9/62) in exon 2 of the gene. KRAS, BRAF, ERK, and MEK protein expression was detected in 71.4%, 78.8%, 64.3%, and 50.8% of CRC tissues, respectively. There were no significant differences between mutation status and KRAS, BRAF, MEK, or ERK protein levels. Positive expression of KRAS and ERK was associated with poor tumor differentiation, and KRAS expression was also associated with age < 56 years. MEK expression was significantly associated with distant metastasis ( < 0.05). The 4-year progression-free survival rate, but not overall survival rate, was significantly higher in patients with KRAS-negative tumors than in those with KRAS-positive tumors ( < 0.05), whereas BRAF, MEK, and ERK expression was unrelated to survival. Multivariate analysis showed that only the expression of KRAS protein was a risk factor for tumor recurrence ( < 0.05). No other clinicopathological factors correlated with KRAS, BRAF, MEK, or ERK expression.
gene mutations do not affect downstream protein expression in CRC. KRAS protein is associated with poor tumor differentiation, older age, and a risk of tumor recurrence.
RAS/RAF/MEK/ERK 和 PI3K/AKT/mTOR 信号通路均属于丝裂原活化蛋白激酶（MAPK）信号通路，上游基因（如 KRAS 基因或 NRAS 基因）的任何一个基因突变都可能通过转录或翻译将信号传递至蛋白，导致信号通路异常激活。本研究旨在探讨 CRC 中基因的突变与临床病理特征和预后的关系，以及基因的突变对 CRC 相关蛋白的影响，以期阐明基因突变导致肿瘤进展和耐药的原因。
探讨 CRC 中基因和 RAS 通路信号分子，并分析其与临床病理特征和预后的关系。
采用实时定量聚合酶链反应检测 196 例 CRC 组织标本中基因的突变情况，采用肿瘤微阵列免疫组化检测 KRAS、BRAF、MEK 和 ERK 蛋白的表达水平。采用独立样本 t 检验、Kaplan-Meier 图和对数秩检验分析不同基因状态下 RAS 通路信号分子表达水平的差异，分析这些参数与临床病理特征、4 年无进展生存期和总生存期的关系。采用 Cox 比例风险模型评估总生存期和无病生存期的预测因素。
在 196 例患者中，有 62 例（32%）携带基因外显子 2 中密码子 12（53/62）或密码子 13（9/62）的突变。在 CRC 组织中，KRAS、BRAF、ERK 和 MEK 蛋白的表达率分别为 71.4%、78.8%、64.3%和 50.8%。基因突变状态与 KRAS、BRAF、MEK 或 ERK 蛋白水平之间无显著差异。KRAS 和 ERK 的阳性表达与肿瘤分化不良有关，KRAS 的表达还与年龄<56 岁有关。MEK 的表达与远处转移显著相关（<0.05）。KRAS 阴性肿瘤患者的 4 年无进展生存率显著高于 KRAS 阳性肿瘤患者（<0.05），而 BRAF、MEK 和 ERK 的表达与生存无关。多因素分析显示，只有 KRAS 蛋白的表达是肿瘤复发的危险因素（<0.05）。其他临床病理因素与 KRAS、BRAF、MEK 或 ERK 的表达均无相关性。
基因的突变不影响 CRC 下游蛋白的表达。KRAS 蛋白与肿瘤分化不良、年龄较大和肿瘤复发风险有关。
