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1.
背景与目的:随着西妥昔单抗联合化疗在转移性结直肠癌患者中的不断应用,预测其治疗疗效的研究也越来越深入。本文旨在探讨转移性结直肠癌患者肿瘤组织中K—ras基因表达状态(野生型或突变型)及其与西妥昔单抗联合化疗疗效之间的关系。方法:2006年3月02008年6月期间应用西妥昔单抗联合化疗治疗转移性结直肠癌27例。采用聚合酶链反应(PCR)技术和直接测序法检测肿瘤组织中K-ras基因表达状态。分析K—ras基因表达状态与西妥昔单抗联合化疗疗效之间的关系。结果:全组27例患者中,K-ras野生型15例(55.6%),K—FaS突变型12例(44.4%)。在K—FaS野生型中,西妥昔单抗联合化疗的总有效率(ORR)为66.7%,其中cR2例(13.3%),PR 8例(53.3%),中位无进展生存期(PFS)8个月。在K—ras突变型中,总有效率为25.0%,PR3例(25.0%),中位PFS4个月。在K—ras野生型转移性结直肠癌患者中应用西妥昔单抗联合化疗的疗效明显优于K—ras突变型患者。结论:K-ras野生型是西妥昔单抗联合化疗疗效良好的预测指标。在西妥昔单抗联合化疗前明确患者的K—ras基因状态有助于选择合适的患者,获得最佳疗效。  相似文献   

2.
目的:构建靶向Kras的siRNA,研究Kras siRNA对Kras基因突变型肺癌细胞A549及Kras野生型小细胞肺癌细胞NCIH446生长和迁移的抑制作用。方法:设计并人工合成4条Kras siRNA(针对野生型Kras基因的Kras siRNA1~ Kras siRNA3;针对突变型Kras 基因的Kras siRNA4),并分别转入A549和NCIH446细胞。RTPCR和Western blotting检测不同Kras siRNA对Kras mRNA和蛋白表达的影响,MTT法检测不同Kras siRNA对A549和NCIH446细胞增殖的抑制作用,Transwell实验和Hoechst 33258染色检测Kras siRNA对细胞迁移和凋亡的影响。结果:靶向突变型Kras的Kras siRNA4能特异性抑制A549细胞中Kras的表达,但对Nras和Hras的表达没有影响。Kras siRNA4抑制A549细胞的增殖,但不影响含野生型Kras基因的NCIH446细胞的增殖。Kras siRNA4还能诱导A549细胞凋亡、抑制A549细胞迁移。结论: 针对突变型Kras基因的siRNA可特异性抑制Kras突变型肺癌细胞的增殖和迁移,并诱导该细胞凋亡,Kras siRNA可望用于Kras突变型肿瘤特别是肺癌的个体化治疗。  相似文献   

3.
俞悦  周爱萍 《中国肿瘤临床》2017,44(11):517-521
抗表皮生长因子受体(epidermal growth factor receptor,EGFR)抗体的应用是转移性结直肠癌治疗进展中的里程碑。抗EGFR单抗和其他靶向药物的出现使转移性结直肠癌患者的中位总生存期从6个月提高至将近30个月,显著改善转移性结直肠癌患者的生存质量及预后。目前KRAS和NRAS被公认为是抗EGFR治疗原发耐药的结直肠癌患者疗效预测标志物,用于抗EGFR治疗的转移性结直结癌患者筛选。除了RAS,其他分子改变也可能影响抗EGFR的疗效。即使是抗EGFR治疗有效的患者也会在13~18个月间产生获得性耐药。本文将对目前已知的抗EGFR治疗耐药机制进行综述,并展望可能的逆转耐药策略,以期为转移性结直肠癌患者精准分子靶向治疗提供依据和指导。   相似文献   

4.
K-ras基因在肿瘤中的研究与展望   总被引:1,自引:0,他引:1  
通过对人类基因组序列的鉴定,人们发现基凶的突变可以导致各种不同的肿瘤,比如p53、EGFR等。在肿瘤基因中,ras基冈的突变可以说和人类肿瘤的关系非常密切,其中ras家族中K—ras基因又因为其高突变率而成为了ras基因研究的1个热点。下面就K—ras基因及该基因在一些肿瘤中的研究及应用情况综述如下。  相似文献   

5.
目的 探索p5 3、k ras基因同时突变对直肠癌的恶性行为升级的作用及其临床意义。方法 用PCR SSCP方法检测直肠癌细胞p5 3、K ras基因突变 ,分析该基因突变与临床病理因素及预后的关系。结果 直肠癌细胞p5 3、K ras基因突变与临床病理因素无关 ,生存率也无统计学差异。结论 直肠癌细胞p5 3、K ras基因突变对癌细胞恶性生物学行为升级无明显的促进作用 ,p5 3、K ras基因同时突变也无协同促癌作用 ,也不影响病人的预后。  相似文献   

6.
目的:通过对结直肠癌上皮生长因子受体(epidermal growth factor receptor,EGFR)基因的表达及其在体细胞突变的研究,探讨EGFR基因的表达与临床病理特征的关系。方法:收集解放军总医院病理科2004~2006年手术治疗的675例结直肠癌患者的临床及病理资料,采用免疫组织化学法检测结直肠癌组织中EGFR基因的表达并探讨其与患者临床病理特征的关系。在上述病例中随机选取25例,其中5例经免疫组织化学染色显示EGFR表达呈强阳性,提取这25例石蜡组织DNA,进行PCR扩增并测序从而分析在结直肠癌中EGFR基因的突变情况。结果:免疫组化结果显示EGFR基因的阳性率为21.33%(144/675)。EGFR基因的表达与结直肠癌的肿瘤直径(Χ^2=0.0204,P=0。8836)、肠壁浸润深度(Χ^2=1.1286,P=0.2881)、淋巴结转移情况(Χ^2=0.0708,P=0.7902)及肿瘤的病理分期(Χ^2=5.3691,P=0.1467)无关,但与肿瘤的分化程度(Χ^2=5.7793,P=0.0162)、腹腔及远处转移情况(Χ^2=4.3983,P=0.0360)密切相关。25例结直肠癌中有1例显示EGFR基因存在错义突变,有5例显示同义突变。结论:EGFR基因的表达与结直肠癌的分化程度及远处转移有关,可辅助判断患者的预后和转移情况以及指导临床治疗。EGFR基因在结直肠癌的突变可能为低频率事件。  相似文献   

7.
谭清和  陈佳 《临床肿瘤学杂志》2011,16(12):1146-1149
目的 结直肠癌经典化疗方案是以氟尿嘧啶为主的联合化疗.近年来,抗表皮生长因子受体(EGFR)的靶向治疗被广泛讨论,且在结直肠癌的治疗中取得一定疗效.目前,对抗EGFR靶向治疗的疗效研究已经涉及到相关基因的表达状态,如既往探讨较多的K-Ras基因表达,新近又发现BRAF基因的突变在结直肠癌的发展以及抗EGFR靶向药物的疗...  相似文献   

8.
目前,在肿瘤的治疗中EGFR信号通路成为重要的靶点,尤其在转移性结直肠癌(mCRC)的治疗中.EGFR单克隆抗体(mAbs)包括西妥昔单抗和帕尼单抗,抗EGFR mAbs联合传统的化疗在很大程度上改善了mCRC患者的无进展生存期(PFS)和总生存期(OS).然而,抗EGFR mAbs仅仅对KRAS野生型的mCRC患者有效,说明还有其他方面的因素影响着抗EGFR mAbs的疗效.研究表明,在结直肠癌中KRAS野生型(WT)的患者常伴有BRAF、PIK3A、NRAS突变和PTEN缺失,这些分子基因状态的改变可能与抗EGFR单克隆抗体靶向治疗抵抗性相关.因此检测患者对抗EGFR mAbs靶向治疗的相关生物标记物,可以对mCRC患者个体化治疗提供依据.  相似文献   

9.
 PIK3CA基因编码蛋白激酶PI3K的p100α亚单位,参与PI3K的合成,通过下游PI3K/AKT通路发挥其生物学效应。多种肿瘤组织中可检测到PIK3CA基因突变,突变的PIK3CA异常激活PI3K-AKT信号通路,导致细胞周期异常、细胞黏附性下降、细胞凋亡下调及新生血管形成等,促进肿瘤发生发展。研究表明PIK3CA与结直肠癌的发生、发展、分化、转移及耐药密切相关,有望在结直肠癌的早期诊断、基因筛查、治疗方案制定、复发随访等方面提供一定的临床证据。  相似文献   

10.
周政涛  王金万 《癌症进展》2005,3(5):461-466,518
结直肠癌的发病率和死亡率均较高各种生长因子、生长因子抑制剂、生长因子受体在结直肠癌细胞的增殖、发展中起着重要的作用.65%~70%的结直肠癌中存在表皮生长因子受体邋(EGFR)的表达.多个研究显示,EGFR在细胞内信号传导过程中具有重要作用,EGFR的表达与结直肠癌的病情进展、预后密切相关,针对EGFR信号传导通路的治疗药物可抑制细胞的增殖,这些药物包括抗EGFR单克隆抗体、酪氨酸激酶抑制剂等,本文综述了这些表皮生长因子受体抑制剂在大肠癌治疗中的应用.  相似文献   

11.
  目的 探讨K-ras基因突变在大肠癌诊断中的意义。方法 该院2005年5月至2006年7月住院患者经肠镜确诊的36例大肠癌患者和24例大肠良性疾病患者,24例正常健康体检患者对照组。通过改良酚-氯仿抽提法提取患者粪便中DNA,PCR-RFLP方法检测K-ras基因第一外显子12密码子的突变。结果 大肠癌患者粪便中K-ras突变率为77.8 %,大肠良性疾病者为25.0 %,正常对照组为8.3 %。结论 检测粪便中K-ras基因可以提高大肠癌的诊断。  相似文献   

12.
A distinct genetic pathway may be involved in the development of polypoid and flat colorectal cancers, two morphologically different cancer subtypes. The present study was undertaken to clarify whether different combinations of some genetic alterations commonly involved (such as K-ras and p53 gene mutations) may exist between polypoid and flat types. In addition, to investigate any different proliferative behavior between the two distinct types of colorectal cancer, we tested the enzymatic activity of ornithine decarboxylase (ODC). A total of 29 polypoid type and 21 flat type colorectal cancers were selected for this study. We investigated K-ras and p53 mutations by polymerase chain reaction followed by restriction fragment length polymorphism (PCR-RFLP) and single strand conformational polymorphism (PCR-SSCP) analysis, respectively. A radiometric method was used to evaluate ODC activity. K-ras and p53 gene mutations were present in 30 and 48% of cases, respectively. A significant association between the p53 mutation and the flat type of colorectal cancer was detected; on the contrary, no significant difference in frequency of K-ras mutation between polypoid and flat type colorectal cancer was found. A statistically significant difference in ODC activity levels was observed between polypoid and flat types. Moreover, we found that ODC activity was significantly higher in neoplastic tissue than in surrounding normal mucosa in polypoid type colorectal cancer. Different mutation patterns and proliferative behavior were observed in polypoid and flat colorectal malignant tumors. Further studies will be required to ascertain whether the distinct growth appearance of colorectal cancer can affect the outcome and prognosis of patients with this type of malignant disease.  相似文献   

13.
Mutation of the Kirsten ras (K-ras) gene is one of most common alterations in solid tumors including lung and colorectal cancers. We developed new enriched PCR-RFLP assay to detect mutations of K-ras codon 61 at the 1st and 2nd letters and non-enriched PCR-RFLP assay to detect the 3rd letter mutation. One mutant allele among 10(3) wild-type alleles was detected by enriched PCR-RFLP assay, while one mutant in 10 wild-type alleles was detected by non-enriched PCR-RFLP assay for codon 61 3rd letter. We then examined K-ras codon 12, 13 and 61 mutations in lung and colorectal cancers using these assays. K-ras codon 12 mutation was detected in 10 of 109 (9%) lung cancer and 19 of 83 (23%) colorectal cancer cases. K-ras codon 13 mutation was detected in 2 of 83 (2%) colorectal and 0 of 109 NSCLC cases, respectively. There was no K-ras codon 61 mutation in either type of cancer. Our results demonstrate that enriched PCR-RFLP is a sensitive assay to detect K-ras codon 61 mutation, however, it was extremely rare in lung and colorectal cancers, suggesting organ-specific pathways in mutagenesis of the ras gene family.  相似文献   

14.
Genetic alterations and their association with clinicopathological features in colorectal mucinous carcinoma (MC) remain unknown. In particular, little is known about the mutational status of the BRAF gene, which is activated by oncogenic Ras. This study aimed to evaluate the status of BRAF together with K-ras, p53 and mismatch-repair deficiency to clarify their association with tumorigenesis of colorectal MC. BRAF and K-ras mutations were determined in 43 colorectal MCs by direct sequencing. p53 alteration was investigated immunohistochemically. The status of mismatch-repair deficiency was assessed by microsatellite analyses and immunohistochemistry for hMLH1. We also examined the association between these molecular alterations and clinicopathological features including histological configuration. BRAF mutation was detected in 4 (9.3%) tumors and was located at codon 599 of exon 15 in all cases. K-ras mutation was detected in 13 tumors (30.2%). No BRAF and K-ras mutations were identified simultaneously in the same tumor. The incidence of mismatch-repair deficiency tended to be higher in MC with BRAF mutation than without. In terms of histological configuration, we classified the cases according to growth type by tumor edge morphology. All MCs with BRAF mutation and 9 of 13 MCs (69.2%) with K-ras mutation were classified as polypoid type. BRAF and K-ras mutation did not affect patient prognosis, but non polypoid type was significantly more aggressive than polypoid type. Our findings indicate that BRAF mutation plays an important role in the tumorigenesis of colorectal MC and in tumor edge morphology, similar to K-ras mutation.  相似文献   

15.
 【摘要】 目的:研究结直肠癌组织中K-ras基因的突变情况与临床病理特性之间的相关性。 目的 研究结直肠癌组织中K-ras基因的突变情况与临床病理特性之间的相关性。方法 采用直接测序法对90例结直肠癌石蜡标本进行K-ras基因突变检测,并对K-ras基因的突变情况及其与结直肠癌患者临床病理特征的关系进行统计学分析。结果 90例结直肠癌患者组织中,K-ras基因12、13密码子总突变者31例,总突变率为34.4 %。12密码子单突变21例,突变率为23.3 %;双突变1例。13密码子突变者9例,突变率为10.0 %。结直肠癌K-ras基因突变率与肿瘤部位有明显相关性(P=0.042)。12密码子单突变和13密码子突变与临床病理参数均无明显相关性(P>0.05)。结论 不同肿瘤部位患者的K-ras基因突变率存在明显不同。  相似文献   

16.
Using an in vitro amplification step (polymerase chain reaction) followed by oligonucleotide dot blot analysis, DNA samples from 29 familial polyposis coli patients (75 polyp-derived and 26 'normal' colon samples with no epithelial atypia) were screened for the presence of K-, N-, and H-ras mutations. Only 5 polyps contained ras mutations (7%)--all in K-ras codon 12. In each case 'normal' colon DNA was available and found to be negative in this assay. We also report the detection of K-ras codon 12 mutations in a stably non-tumorigenic immortal adenoma-derived cell line, PC/AA, and in a tumorigenic colorectal carcinoma cell line, PC/JW. Both epithelial cell lines were derived from different FPC patients. An activated K-ras gene was also found in cell line S/AN, isolated from a sporadic villous adenoma. These results provide further evidence that there are common molecular events involved in sporadic and hereditary colorectal carcinogenesis and that K-ras mutations can precede the development of malignancy. To our knowledge PC/AA is the first reported example of a human cell line bearing a mutant ras gene that is not tumorigenic and shows that the presence of an activated ras gene even in an immortal human cell line is insufficient for malignancy.  相似文献   

17.
Material from paraffin sections of 109 human colorectal carcinomas, mostly obtained at autopsy, was analyzed for the presence of K-ras point mutations at codon 12, position 2. Mutations at this position were found in 23 cases (21.1%). Aneuploid colorectal carcinomas showed a significantly higher prevalence of K-ras point mutations than diploid tumors, suggesting an involvement of ras mutations in the development of aneuploidy. No differences in the prevalence of K-ras mutations were observed with respect to the patients' age, sex and tumor type. In metastases, the type of ras gene mutation was always identical to that of the respective primary tumor. Mutations were not found in metastases from primary tumors devoid of ras mutations. This renders a clonal selection of K-ras mutated cells from a wild-type primary tumor during the metastatic process unlikely. However, nearly twice as many ras gene mutations were seen in metastatic than in non-metastatic primary tumors.  相似文献   

18.
19.
K-ras gene mutations in adenomas and carcinomas of the colon.   总被引:3,自引:0,他引:3  
DNA extracted from 29 colorectal carcinomas and 40 sporadic adenomas was amplified by the polymerase chain reaction (PCR) and analysed for the presence of K-ras gene mutations at codon 12 using a panel of synthetic oligonucleotide probes specific for normal and mutated sequences. The presence of mutations was correlated with various histopathological and clinical data. Ten carcinomas (34.5%) and 14 sporadic adenomas (35%) showed K-ras mutations at codon 12. In the carcinoma group, no apparent correlation was found between the presence of mutant oncogenes and the degree of histological differentiation, Dukes' staging or the development of distant metastasis. In the adenoma group, the frequency of mutations increased with the size of the adenoma and the severity of the dysplastic changes. This study confirms that ras gene mutations are common and early events in colon carcinogenesis. They appear to give a selective growth advantage to those polyps with mutations which leads to their increase in size and thus possibly prepare the ground for malignant transformation.  相似文献   

20.
To understand the role of BRAF dysfunction in the carcinogenesis and progression/development of colorectal tumors, the authors investigated genetic alterations in the BRAF gene in human colorectal neoplasms as well as the effects of an RAS inhibitor in BRAF-mutant cells. Seven colon cancer cell lines and 116 colorectal tumors (34 adenomas and 82 adenocarcinomas) were analyzed. Genetic alterations in the BRAF and K-ras genes were examined using polymerase chain reaction-single strand conformation polymorphism and direct sequencing analyses. The growth-inhibitory and apoptosis-inducing effects of the FTI-277 RAS inhibitor in colon cancer cell lines were analyzed as well. An immunohistochemical study was also performed to investigate the correlations between the clinicopathologic parameters involved in the Ki-67 labeling index and the number of apoptotic bodies in tumor cells. FTI-277 did not suppress the proliferation of BRAF-mutant cells (WiDr and TCO), but remarkably inhibited the growth of K-ras mutant cells (LoVo). Interestingly, LoVo cells underwent apoptosis by FTI-277 in a dose-dependent manner, whereas WiDr cells were resistant to this agent. In tumor samples, BRAF mutations were found in 1 (3.0%) of 33 adenomas and 6 (7.2%) of 83 adenocarcinomas. No tumor exhibited mutations in both the BRAF and K-ras genes. Neither BRAF nor K-ras mutations correlated with the Ki-67 labeling index immunohistochemically. However, the number of apoptotic bodies was significantly decreased in the BRAF-mutant tumors. Mutation in the BRAF gene may contribute to colorectal carcinogenesis by upregulating the antiapoptotic role of the RAS/RAF/MEK/ERK pathway.  相似文献   

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