Clinical Implications of NRAS Overexpression in Resectable Pancreatic Adenocarcinoma Patients
Clinical Implications of NRAS Overexpression in Resectable Pancreatic Adenocarcinoma Patients
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DOI：
10.1007/s12253-017-0341-0
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发表时间：
2019-01-01
影响因子：
2.8
通讯作者：
Garcia-Foncillas, Jesus
中科院分区：
文献类型：
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作者：
Martinez-Useros, Javier;Li, Weiyao;Garcia-Foncillas, Jesus
胰腺导管腺癌(PDAC)是最致命的癌症之一，其发病率在全球范围内呈上升趋势。虽然手术切除可以提高存活率，但在早期发现时，这种类型的癌症通常是无症状的，只有在转移后才会显现出来。辅助治疗不能提高存活率，因此术后缺乏预测和预后的生物标志物来预测治疗反应和存活率。丝裂原活化蛋白激酶和磷脂酰肌醇3-激酶信号通路在癌症的发生发展中起着关键作用。特别是，激活的RAS蛋白通过对下游效应分子RAF-MEK-ERK和PI3K-AKT的结构性刺激促进细胞增殖。NRAS的突变状态在几种类型的癌症中是必需的，如结直肠癌或皮肤黑色素瘤。然而，该基因在PDAC患者中的突变非常罕见，临床上通常不对此类肿瘤进行NRAS检测。在这项研究中，我们分析了NRAS蛋白表达与来自单一中心的同质胰腺导管腺癌患者的无进展生存期和总生存期的关系。有趣的是，我们发现高表达的患者不仅比低表达的患者有更长的无进展生存期(分别为22个月和9个月)(P=0.013)，而且总的生存期也更长(分别为43个月和19个月)(P=0.020)。这些结果证实了NRAS的表达可以用来区分患者的预后。比例风险模型显示NRAS的表达和分化程度是预测患者预后的病理变量。
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal forms of cancer, and its incidence is rising worldwide. Although survival can be improved by surgical resection, when detected at an early stage, this type of cancer is usually asymptomatic, and disease becomes only apparent after metastasis. Adjuvant treatment does not improve survival, thus after surgery there is a lack of predictive and prognosis biomarkers to predict treatment response and survival. The mitogen-activated protein-kinase and phosphoinositide 3-kinase signalling pathways play a crucial role in cancer development and progression. Especially, activated RAS proteins promote cell proliferation through constitutive stimulation of the downstream effectors RAF-MEK-ERK and PI3K-AKT. Mutational status of NRAS is required in several types of cancer like colorectal or cutaneous melanoma. However, mutations in this gene are very scarce in PDAC patients, and NRAS determination is not usually performed in clinical practice for this kind of tumor. In this study, we analyse the association between NRAS protein expression and progression-free survival and overall survival of an homogenous cohort of pancreatic ductal adenocarcinoma patients from a single-centre. Interestingly, we found that patients with high expression not only showed longer progression-free survival than those patients with low expression (22 versus 9 months, respectively) (P = 0.013), but also longer overall survival (43 versus 19 months, respectively) (P = 0.020). These results confirm NRAS expression could be used to differentiate patients according to their prognosis. Proportional hazard model revealed NRAS expression together with grade of differentiation as pathological variables to predict patient's outcome.