晚期非小细胞肺癌患者KRAS基因状态与一线化疗疗效关系探讨

目的 鼠类肉瘤病毒癌基因(kirsten rat sarcoma viral oncogene,KRAS)是非小细胞肺癌(non-small cell lung cancer,NSCLC)的重要驱动基因之一,KRAS基因状态在晚期NSCLC患者一线化疗疗效中的预测作用尚未明确.本研究旨在探讨晚期NSCLC患者KRAS基因状态和一线化疗疗效的关系.方法 回顾性分析郑州大学第一附属医院2014-07-10-2015-12-01收治经组织病理学确诊的205例表皮生长因子受体(epidermal growth factor receptor,EGFR)阴性的晚期NSCLC患者临床资料.随访至2015-12-31,排除随访丢失的患者,185例患者纳入本研究.分析KRAS基因状态、临床特征、化疗疗效及无疾病进展生存期(progression-free survival,PFS)之间的关系.结果 185例患者均进行了KRAS基因检测,KRAS基因突变患者44例(23.8％),野生型为141例(76.2％).KRAS基因突变类型分别为G12D(36.4％)、G12A(25.0％)、G12C(15.9％)、G12V(13.6％)、G12R(6.8％)和G13D(2.3％).全部患者均接受一线铂类为基础的化疗,客观缓解率(objective response rate,ORR)为24.3％,疾病控制率(disease control rat,DCR)为62.2％.KRAS野生型患者的DCR为63.8％,略高于突变型患者的56.8％,差异无统计学意义,x2 =0.701,P=0.477.KRAS突变患者培美曲塞化疗组中男性的ORR为52.2％,高于女性的12.5％,差异有统计学意义,x2=6.454,P=0.011;男性的DCR为82.6％,明显高于女性的31.2％,差异有统计学意义,x2=10.516,P=0.001.KRAS基因野生型患者的中位PFS为4.3个月,显著长于突变组患者的3.7个月,差异有统计学意义,x2 =21.982,P＜0.01;而KRAS各突变亚型之间的PFS相比较,差异无统计学意义,x2 =5.110,P=0.403.Cox回归多因素分析显示,KRAS基因突变是影响PFS的预后因素,HR=2.152,95％CI:1.513～3.062,P＜0.01.结论 KRAS突变是晚期NSCLC患者一线化疗PFS的负性预后因素,KRAS突变患者中男性对以培美曲塞为基础的化疗反应更好.     

754例Ⅰ期-Ⅲa期可手术切除非小细胞肺癌患者EGFR和KRAS基因突变状态及其临床意义

背景与目的 表皮生长因子受体(epidermal growth factor receptor,EGFR)和KRAS基因是非小细胞肺癌(non-small cell lung cancer,NSCLC)重要的分子靶点,但目前研究主要集中在晚期NSCLC组织和血浆标本的EGFR检测,早期NSCLC组织样本中EGFR和KRAS突变特征尚不清楚.本研究将探讨Ⅰ期-Ⅲa期NSCLC EGFR和KRAS基因突变与相关临床病理特征的关系.方法 采用突变扩增系统(amplification refractory mutation system,ARMS)PCR方法检测北京协和医院病理科提供的754例Ⅰ期-Ⅲa期NSCLC组织样本的EGFR和KRAS基因突变状况,分析基因突变率及其与临床病理特征的关系.结果 EGFR和KRAS基因热点突变的突变率分别为34.5％和13.1％,其中有3例样本具有EGFR和KRAS基因的双突变.EGFR基因在女性中的突变率高于男性(39.5％vs 29.4％,P=0.076),在腺癌中的突变率(38.7％)高于鳞癌、腺鳞癌、大细胞癌(P＜0.01),但仍明显低于其他研究报道的亚裔晚期腺癌突变率(-50％).KRAS基因突变在男性中的突变率高于女性(16.6％vs 9％,P=0.048),且在腺癌中的突变率也高于其他类型,但差异不显著(P=0.268).与KRAS基因突变阳性组相比,EGFR基因突变阳性组在年龄分布上有年轻化的趋势(P=0.031,5),在性别分布上有显著性差异(P＜0.01).结论 Ⅰ期-Ⅲa期NSCLC EGFR基因突变率较晚期患者低,且EGFR和KRAS基因双突变的发生率为0.9％.     

结直肠癌患者KRAS和BRAF基因突变检测及其临床意义

目的探讨结直肠癌患者组织中KRAS和BRAF基因突变情况,分析突变与临床病理特征的关系。方法应用荧光PCR-优化寡核苷酸探针法检测304例结直肠癌石蜡包埋标本中KRAS基因2号外显子的12和13密码子、BRAF基因的15号外显子的突变情况,分析KRAS和BRAF基因突变与临床病理特征的关系。结果 KRAS和BRAF基因在结直肠癌的突变率分别为38.8%(118/304)和4.3%(13/304)。KRAS基因突变阳性标本中12密码子的突变率为78.0%,其中p.G12D发生率最高,占总突变的45.3%;13密码子的突变率为22.0%。高年龄组(≥60岁)患者的KRAS基因突变率为47.2%(58/123),高于低年龄组(<60岁)的33.1%(60/181),差异有统计学意义(P<0.05)。转移性结直肠癌患者19例,其KRAS基因突变率为36.8%(7/19),与285例原发性结直肠癌患者的突变率(38.9%,111/285)差异无统计学意义(P>0.05)。BRAF基因在结肠、低分化、黏液腺癌患者中的突变率明显高于直肠、中或高分化和管状腺癌的患者。结论结直肠癌患者中KRAS基因突变的发生率较高,与年龄相关,而与性别、部位、病理类型和分化程度不相关。BRAF基因突变与肿瘤部位、病理类型和分化程度有关。原发性与转移性结直肠癌患者KRAS基因突变率无明显差异。     

非小细胞肺癌原发灶和转移淋巴结EGFR、KRAS和MET基因状态比较

目的:比较配对的原发肺癌灶和转移淋巴结EGFR、KRAS和MET基因状态,探讨NSCLC原发灶和转移淋巴结基因变化规律并指导临床实践。方法:22例手术切除的Ⅲa期非小细胞肺癌,术前未经靶向和化学治疗,获取配对的原发灶和N2站转移淋巴结。采用直接测序法检测EGFR外显子19-21,KRAS密码子12和13突变,实时定量PCR检测MET基因拷贝数。结果:原发灶和N2转移淋巴结中EGFR基因突变率分别为7/22例(31.82%)和6/22例(27.27%),EGFR基因型一致率达95.45%。KRAS基因突变率分别为2/22例(9.09%)和1/22例(4.55%)。转移淋巴结MET基因拷贝数(1.54±0.71)显著高于原发灶(1.19±0.41),P=0.038。EGFR 19和21基因突变与原发灶(P=0.24)、转移灶(P=0.97)的MET基因拷贝数以及原发灶和转移灶MET基因拷贝数变化(P=0.69)之间都无相关性,P>0.05。不同的EGFR基因状态和MET基因拷贝数其1年无病生存无显著差异(P>0.05)。结论:肺癌原发灶和相应转移淋巴结中EGFR基因突变较稳定;EGFR敏感基因突变与MET基因拷贝数可能无关;而未经EGFR-TKI治疗的肺癌患者其MET基因拷贝数在淋巴结转移时即已开始出现明显增高。     

肺腺癌患者EGFR和KRAS基因突变与预后的相关性研究

目的 探讨肺腺癌患者表皮生长因子受体(EGFR)和KRAS基因突变与预后的相关性.方法 选取134例肺腺癌患者的肺腺癌组织标本,应用探针扩增阻滞突变系统在PCR仪上进行EGFR和KRAS基因突变检测,分析EGFR和KRAS基因突变与肺腺癌患者临床病理特征及预后的关系.结果 134例患者中,EGFR基因突变53例,突变率为39.55%,KRAS基因突变6例,突变率为4.48%.肺腺癌患者EGFR基因突变率与年龄、吸烟史有关(P﹤0.01).EGFR基因突变型患者的KRAS基因突变率低于EGFR基因野生型患者(P﹤0.05).EGFR基因突变型患者的无进展生存期(PFS)长于EGFR基因野生型患者(P﹤0.05),KRAS基因野生型患者的PFS长于KRAS基因突变型患者(P﹤0.05).结论 EGFR基因突变的肺腺癌患者KRAS基因更倾向于野生型,EGFR基因突变型或KRAS基因野生型的肺腺癌患者PFS更长.     

胃癌中hMSH2表达缺失对EGFR及KRAS基因突变影响的研究

目的:探讨胃癌中hMSH2表达缺失对EGFR和KRAS基因突变的影响.方法:收集大连地区胃癌标本63例,所有患者均未经放疗或化疗.应用免疫组织化学方法检测63例胃癌标本和38例癌旁组织的hM-SH-2、EGFR和KRAS蛋白的表达情况;应用HRM技术检测其中58例胃癌标本的EGFR基因19-21外显子和KRAS基因2外显子的突变情况,筛选出的阳性标本应用DNA测序证实.结果:hMSH2表达缺失率在胃癌组为34.9％,显著低于癌旁组的60.5％(P=0.012);在Ⅲ-Ⅳ期胃癌组为47.4％,显著高于Ⅰ-Ⅱ期胃癌组的16.0％ (P =0.011).58例胃癌标本中,hMSH2表达缺失组的EGFR突变率为10.5％,高于hMSH2表达组的2.6％ (P=0.513);hMSH2表达缺失组的KRAS突变率为15.8％,高于hMSH2表达组的7.7％(P =0.623).EGFR蛋白表达率在胃癌组为47.6％,显著高于癌旁组的26.3％ (P =0.034);在淋巴结转移组为57.4％,显著高于无淋巴结转移组的18.8％ (P =0.007);在Ⅲ-Ⅳ期胃癌组为57.9％,显著高于Ⅰ-Ⅱ期胃癌组的32.0％ (P =0.044).KRAS蛋白表达率在胃癌组为63.5％,显著高于癌旁组的36.8％(P=0.009);在Ⅲ-Ⅳ期胃癌组为73.7％,显著高于Ⅰ-Ⅱ期胃癌组的48.0％(p=0.038).结论:hMSH2表达缺失的胃癌组织可能更易携带EGFR及KRAS基因突变;hMSH2、EGFR和KRAS蛋白表达的增加可能早于胃癌的发生;hMSH2表达缺失、EGFR和KRAS蛋白表达增加在胃癌的进展中发挥作用.     

高分辨率熔解曲线技术检测结直肠癌患者KRAS基因突变

目的探讨高分辨率熔解曲线技术(HRM)检测结直肠癌患者KRAS基因突变的可行性及其临床意义。方法采用HRM技术检测60例结直肠癌患者石蜡包埋组织标本KRAS基因2号外显子12和13位密码子突变,并与Sanger测序法检测结果进行对比分析。结果 HRM法检测结直肠癌患者KRAS基因2号外显子12和13位密码子突变检出率为36.67%(22/60),Sanger测序法检测突变检出率为33.33%(20/60)。HRM法检测突变检出率高于Sanger测序法,HRM法检测敏感性为100%,特异性为95.24%。结论 HRM法检测KRAS基因突变,灵敏度高,敏感性和特异性好,具有操作简便、节约时间、成本低的特点,方法可行。     

肺腺癌EGFR、KRAS基因突变、ALK融合蛋白状态分析

目的 分析肺腺癌中EGFR、KRAS、ALK三种肿瘤驱动基因的突变状态及与其临床病理特征、肿瘤分期的关系.方法 85例肺腺癌EGFR,KRAS基因突变采用ARMS法检测,ALK融合蛋白用特异性抗ALK单克隆抗体(克隆号:D5F3)采取免疫组织化学法检测.结果 EGFR,KRAS,和ALK融合蛋白检测阳性率分别是62％,15％,和14％.EGFR基因突变更常见于女性.KRAS基因突变更常见于男性及有吸烟史患者.ALK融合蛋白更常见于年轻及肿瘤分期Ⅲ/Ⅳ患者.检测中发现了8例双突变病例.结论 结果 进一步证实了EGFR、KRAS基因突变与ALK融合蛋白并非完全互斥.对于肺腺癌患者进行全面的基因检测非常重要,在选择靶向治疗时更应考虑到多种变异同时存在的情况.     

结直肠癌中KRAS基因突变及其检测方法概述

结直肠癌（Colorectal Cancer,CRC）是世界上发病率最高的恶性肿瘤之一.CRC的发生与细胞的跨膜信号转导系统功能异常有关,目前已经明确Ras/Raf/MAPK级联反应通路在其中起到很重要的作用.在CRC中,KRAS基因突变十分常见,KRAS基因的突变使信号转导通路下游各种基因的激活不再依赖于表皮生长因子受体（Epidermal Growth Factor Receptor,EGFR）的启动,这对CRC的发生、发展、治疗与预后起着非常重要的作用.因此,在临床工作中,检测KRAS基因突变情况显得尤为重要,这也对检测技术及其准确性提出了更高的要求.本文对KRAS在CRC中的作用、机制及其突变的概率、检测方法做一简要综述.     

COLD-PCR-HRM 检测结直肠癌患者外周血KRAS基因突变

目的  评价COLD-PCR-HRM 检测结直肠癌患者外周血KRAS 基因突变的临床应用价值。方法  将已知突变型 KRAS 组织DNA 与野生型DNA 做系列稀释,突变DNA 所占比例分别为50%、25%、10%、5%、3%、2% 和 1%。分别应 用常规PCR-HRM 法和COLD-PCR-HRM 法对不同比例KRAS 突变DNA 样本进行检测,验证两种检测方法的灵敏度;同 时应用 COLD-PCR-HRM 法对 62 例外周血和肿瘤组织配对样本进行一致性验证。结果  PCR-HRM 法最低检测浓度为 3%; COLD-PCR-HRM 法最低检测浓度为1%,两种方法的检测灵敏度均明显高于直接测序法（P ＜ 0.05）。应用COLD-PCRHRM 法检测两种样本中KRAS 基因突变状态,其中血清样本中检测出13 例突变（突变率21.0%,13/62）,组织中检测出 12 例突变（突变率 19.4%,12/62）,两种标本同时存在突变的有 9 例,以组织中检测的 KRAS 状态为准,两者突变一致性 为 75.0%（9/12）。KRAS 基因突变在组织与外周血中存在一致性（κ=0.649;P ＜ 0.001）。结论  COLD-PCR 结合 HRM 明 显提高了 KRAS 突变检测灵敏度,为其应用于低丰度突变样本检测提供了有利条件。     

Clinicopathological features of lung adenocarcinoma with KRAS mutations

BACKGROUND:

KRAS and epidermal growth factor receptor (EGFR) mutations are thought to play an important role in the carcinogenesis of lung adenocarcinoma. However, clinicopathological findings of KRAS mutated adenocarcinoma cases have not yet been fully clarified. The authors analyzed the relationship between the KRAS mutation and corresponding clinicopathological findings, focusing on nonmucinous and mucinous bronchioloalveolar elements.

METHODS:

EGFR and KRAS mutations were detected in DNA samples extracted from 182 surgically resected tissues of lung adenocarcinomas by the Smart Amplification Process. The relations between gene mutation status and clinicopathological features were analyzed. All adenocarcinoma cases were divided into bronchioloalveolar carcinoma (BAC), adenocarcinoma with bronchioloalveolar features, and adenocarcinoma without BAC components (non‐BAC). BAC/adenocarcinoma with bronchioloalveolar features tumors were further assessed for the presence of mucinous features.

RESULTS:

EGFR and KRAS mutations were found in 76 and 30 cases, respectively. In the KRAS mutant group, BAC/adenocarcinoma with bronchioloalveolar features was found in 22 cases, which included 10 nonmucinous and 12 mucinous tumors. Of 19 cases with mucinous BAC/adenocarcinoma with bronchioloalveolar features, KRAS mutations were detected in 12, but no EGFR mutation was detected. In the KRAS mutant group, BAC/adenocarcinoma with bronchioloalveolar features had significantly earlier pathological stages and more favorable prognoses than did non‐BAC. Mucinous BAC/adenocarcinoma with bronchioloalveolar features showed less smoking history than did nonmucinous BAC/adenocarcinoma with bronchioloalveolar features and non‐BAC. Furthermore, transversion type KRAS mutations were more common in non‐BAC.

CONCLUSIONS:

KRAS mutated adenocarcinomas can be divided into BAC/adenocarcinoma with bronchioloalveolar features and non‐BAC types. Non‐BAC adenocarcinoma is related to smoking history and has a poor prognosis. BAC/adenocarcinoma with bronchioloalveolar features adenocarcinoma, however, has a more favorable prognosis, and mucinous BAC/adenocarcinoma with bronchioloalveolar features has little relationship to smoking history. Cancer 2011;. © 2011 American Cancer Society.     

KRAS and BRAF mutations are prognostic biomarkers in patients undergoing lung metastasectomy of colorectal cancer

Background:

We evaluated KRAS (mKRAS (mutant KRAS)) and BRAF (mBRAF (mutant BRAF)) mutations to determine their prognostic potential in assessing patients with colorectal cancer (CRC) for lung metastasectomy.

Methods:

Data were reviewed from 180 patients with a diagnosis of CRC who underwent a lung metastasectomy between January 1998 and December 2011.

Results:

Molecular analysis revealed mKRAS in 93 patients (51.7%), mBRAF in 19 patients (10.6%). In univariate analyses, overall survival (OS) was influenced by thoracic nodal status (median OS: 98 months for pN−, 27 months for pN+, P<0.0001), multiple thoracic metastases (75 months vs 101 months, P=0.008) or a history of liver metastases (94 months vs 101 months, P=0.04). mBRAF had a significantly worse OS than mKRAS and wild type (WT) (P<0.0001). The 5-year OS was 0% for mBRAF, 44% for mKRAS and 100% for WT, with corresponding median OS of 15, 55 and 98 months, respectively (P<0.0001). In multivariate analysis, WT BRAF (HR: 0.005 (95% CI: 0.001–0.02), P<0.0001) and WT KRAS (HR: 0.04 (95% CI: 0.02–0.1), P<0.0001) had a significant impact on OS.

Conclusions:

mKRAS and mBRAF seem to be prognostic factors in patients with CRC who undergo lung metastasectomy. Further studies are necessary.     

High mesothelin expression in advanced lung adenocarcinoma is associated with KRAS mutations and a poor prognosis

Mesothelin is a cell surface glycoprotein which is highly expressed in several epithelial cancers and may have a role in cell adhesion and metastases. In this study, we used prospectively obtained clinical and pathological data to characterize mesothelin expression in advanced lung adenocarcinoma. Tissue was obtained from patients who underwent molecular profiling of potentially actionable genes on a trial of molecular profiling and targeted therapies in advanced thoracic malignancies. We immunohistochemically evaluated the intensity, and the percentage of cells expressing mesothelin in 93 advanced lung adenocarcinomas. The evaluation was blinded for molecular data and outcome. Mutations of EGFR, KRAS, BRAF, AKT1, PIK3CA and HER2 were assessed by pyrosequencing; HER2 amplification and ALK translocation were assessed by fluorescence in situ hybridization. 53% of advanced lung adenocarcinomas expressed mesothelin to some degree; high mesothelin expression, defined as mesothelin positivity in more than 25% of cells, was found in 24% of patients. High mesothelin expression was associated with inferior survival (median 18.2 months vs. 32.9 months; P = 0.014). High mesothelin expression was strongly associated with mutant KRAS (P < 0.0001) and wild-type EGFR (P = 0.002). Our results provide strong rationale to explore anti-mesothelin targeted therapies in advanced lung adenocarcinoma especially in the KRAS-mutant subgroup.     

The genetics and biology of KRAS in lung cancer

Mutational activation of KRAS is a common oncogenic event in lung cancer and other epithelial cancer types.Efforts to develop therapies that counteract the oncogenic effects of mutant KRAS have been largely unsuccessful,and cancers driven by mutant KRAS remain among the most refractory to available treatments.Studies undertaken over the past decades have produced a wealth of information regarding the clinical relevance of KRAS mutations in lung cancer.Mutant Kras-driven mouse models of cancer,together with cellular and molecular studies,have provided a deeper appreciation for the complex functions of KRAS in tumorigenesis.However,a much more thorough understanding of these complexities is needed before clinically effective therapies targeting mutant KRAS-driven cancers can be achieved.     

Association of KRAS and EGFR mutations with survival in patients with advanced lung adenocarcinomas

BACKGROUND:

Lung adenocarcinomas can be distinguished by identifying mutated driver oncogenes, including epidermal growth factor receptor (EGFR) and KRAS. Mutations in EGFR are associated with both improved survival as well as response to treatment with erlotinib and gefitinib. However, the prognostic significance of KRAS has not been evaluated in large numbers of patients and remains controversial. For the current report, the authors examined the association of EGFR and KRAS mutations with survival among patients with advanced lung adenocarcinomas.

METHODS:

Data were analyzed from patients with advanced lung adenocarcinomas who had known EGFR and KRAS mutation status evaluated between 2002 and 2009. The collected clinical variables included age, sex, Karnofsky performance status, smoking history, and treatment history. Overall survival from the diagnosis of advanced disease was analyzed using Kaplan‐Meier and Cox proportional hazard methods.

RESULTS:

In total, 1036 patients were evaluated, including 610 women (59%) and 344 never‐smokers (33%). The median patient age was 65 years (range, 25‐92 years), and the majority of patients (81%) had a Karnofsky performance status ≥80%. In multivariate analysis, EGFR mutations were associated with longer overall survival (hazard ratio, 0.6; P < .001), and KRAS mutations were associated with shorter survival (hazard ratio, 1.21; P = .048).

CONCLUSIONS:

KRAS mutations predicted shorter survival for patients with advanced lung adenocarcinomas. The presence of EGFR and KRAS mutations define distinct subsets of patients with lung adenocarcinomas and should be determined in patients when they are diagnosed with advanced disease. Clinical trial reports should include EGFR and KRAS mutation status along with other prognostic factors. Cancer 2013. © 2012 American Cancer Society.     

Subtype-specific KRAS mutations in advanced lung adenocarcinoma: A retrospective study of patients treated with platinum-based chemotherapy

BackgroundPlatinum-based chemotherapy is the most common treatment in advanced-stage lung adenocarcinoma. Because the clinical significance of KRAS mutational status in this setting has not yet been clearly determined, a mutation subtype-specific analysis was performed in the so far largest cohort of Caucasian patients with KRAS mutant advanced-stage lung adenocarcinoma treated with platinum-based chemotherapy.Methods505 Caucasian stage III–IV lung adenocarcinoma patients with known amino acid substitution-specific KRAS mutational status and treated with platinum-based chemotherapy were included. The correlations of subtype-specific KRAS mutations with smoking status, progression-free and overall survival (PFS and OS, respectively) and therapeutic response were analysed.ResultsAmong 338 KRAS wild-type, 147 codon 12 mutant and 20 codon 13 mutant patients, there were no mutation-related significant differences in PFS or OS (P values were 0.534 and 0.917, respectively). Eastern Cooperative Oncology Group (ECOG) status and clinical stage were significant independent prognostic factors. KRAS mutation showed a significant correlation with smoking status (P = 0.018). Importantly, however, G12V KRAS mutant patients were significantly more frequent among never-smokers than all other codon 12 KRAS mutant (G12x) subtypes (P = 0.016). Furthermore, this subgroup tended to have a higher response rate (66% versus 47%; P = 0.077). A modestly longer median PFS was also found in the G12V mutant cohort (233 days; versus 175 days in the G12x group; P = 0.145).ConclusionsWhile KRAS mutation status per se is neither prognostic nor predictive in stage III–IV lung adenocarcinoma, subtype-specific analysis may indeed identify clinically relevant subgroups of patients that may ultimately influence treatment decisions.     

Differential gene expression signatures between colorectal cancers with and without KRAS mutations: crosstalk between the KRAS pathway and other signalling pathways

Purpose

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.

Patients and methods

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.

Results

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.

Conclusions

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.