EGFR蛋白表达与EGFR基因突变在宫颈癌中的临床意义
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摘要
目的：
1.研究宫颈癌中表皮生长因子受体蛋白(Epidermal growth factor receptor, EGFR)的表达情况,并探讨宫颈癌中EGFR蛋白表达与临床病理特征的关系。
2.分析宫颈癌病理组织中EGFR常见基因突变的发生率和突变类型,为临床针对EGFR的靶向治疗提供基因检测方法和实验依据。
3.探讨EGFR蛋白表达与EGFR基因突变的相关性。
方法：
1.选取77例宫颈病理石蜡组织为样本,采用免疫组织化学法检测组织中的EGFR蛋白表达情况。
2.选取86例宫颈癌患者的病理石蜡组织为样本,采用酚氯仿法抽提基因组DNA,分别运用聚合酶链反应(Polymerase chain reaction, PCR)技术及聚合酶链反应-限制性片段长度多态(Polymerase chain reaction-Restriction Fragment Length Polymophism, PCR-RLFP)技术对石蜡组织中的EGFR外显子19及21中常见基因突变进行分析,阳性结果再进行DNA直接测序验证。
结果：
1. EGFR蛋白在正常宫颈组织、宫颈原位癌及宫颈浸润癌组织中的阳性表达率分别为0,42.9%(6/14),76.7%(33/43),三组间差异具有显著性意义(χ2=32.581,P<0.01),且两两间比较差异均具有显著性(P<0.01)。宫颈浸润癌EGFR蛋白表达与临床分期有关,随着临床分期的进展,EGFR的阳性表达率逐渐升高(P<0.01),与病理类型、年龄及病理分级无关(P>0.05)。
2.经PCR, PCR-RLFP方法检测及DNA测序验证,宫颈癌中未检测到EGFR基因外显子19的缺失突变和外显子21的错义突变。
结论：
1. EGFR蛋白表达率随着宫颈组织恶性程度升高而升高,与临床分期有关,与病理分级、组织学分型及年龄无关。
2.宫颈癌中EGFR基因外显子19及外显子21未检测到突变。
3. EGFR蛋白高表达与EGFR基因第19、21外显子突变无关,可能与EGFR基因中其它突变相关。
Objective:
1. To investigate the expression of epidermal growth factor receptor (EGFR) and interrelation with some factors in the specimens.
2. To analyze the incidence and profiles of EGFR mutation in cervical cancer, which provide gene detection methods and theoretical basis for the targeted treatment of cervical cancer.
3. To investigate the relationship between the expression of EGFR and the immutation of EGFR.
Methods:
1. Paraffin-embedded tumor tissue samples were obtained from 77 patients with cervical cancer. The EGFR protein expression were detected by immunohisto-chemical (IHC) method.
2. Paraffin-embedded tumor tissue samples were obtained from 86 patients with cervical cancer. The deletion mutation in EGFR exon 19 were detected by PCR and the point mutation in EGFR exon 21 was detected by PCR-RLFP. The positive mutation of EGFR gene were detected by DNA sequencing.
Results:
1. The positive expression rate of EGFR was zero in normal cervix,42.9%(6/14) in preinvasive cervical carcinoma,76.7%(33/43) in invasive cervical cancer. The expression rate of EGFR protein was significantly correlated among the three groups and between each of them, with the progress of clinical stage, EGFR positive expression tatio increased (P<0.01). In invasive cervical cancer, The expression rate of EGFR protein was significantly correlated with the clinical stage(P<0.01), but had no relation with histological grade,age or pathological type(P>0.05).
2. No EGFR gene mutation were detected in exons 19 and 21 of cervical cancer samples by PCR, PCR-RLFP and DNA sequencing method.
Conclusions:
1. There was an over-expression of EGFR in cervical cancer.The rate of EGFR protein expression related to the clinical stage, but had no relation to the age, histological grade or hitologic type.
2. There was no EGFR mutation in exon 19 and 21 in cervical cancer.
3. The abnormal expression of EGFR protein had no relation to EGFR mutations, while maybe relate to other EGFR mutations in cervical cancer.
1.研究宫颈癌中表皮生长因子受体蛋白(Epidermal growth factor receptor, EGFR)的表达情况,并探讨宫颈癌中EGFR蛋白表达与临床病理特征的关系。
2.分析宫颈癌病理组织中EGFR常见基因突变的发生率和突变类型,为临床针对EGFR的靶向治疗提供基因检测方法和实验依据。
3.探讨EGFR蛋白表达与EGFR基因突变的相关性。
方法：
1.选取77例宫颈病理石蜡组织为样本,采用免疫组织化学法检测组织中的EGFR蛋白表达情况。
2.选取86例宫颈癌患者的病理石蜡组织为样本,采用酚氯仿法抽提基因组DNA,分别运用聚合酶链反应(Polymerase chain reaction, PCR)技术及聚合酶链反应-限制性片段长度多态(Polymerase chain reaction-Restriction Fragment Length Polymophism, PCR-RLFP)技术对石蜡组织中的EGFR外显子19及21中常见基因突变进行分析,阳性结果再进行DNA直接测序验证。
结果：
1. EGFR蛋白在正常宫颈组织、宫颈原位癌及宫颈浸润癌组织中的阳性表达率分别为0,42.9%(6/14),76.7%(33/43),三组间差异具有显著性意义(χ2=32.581,P<0.01),且两两间比较差异均具有显著性(P<0.01)。宫颈浸润癌EGFR蛋白表达与临床分期有关,随着临床分期的进展,EGFR的阳性表达率逐渐升高(P<0.01),与病理类型、年龄及病理分级无关(P>0.05)。
2.经PCR, PCR-RLFP方法检测及DNA测序验证,宫颈癌中未检测到EGFR基因外显子19的缺失突变和外显子21的错义突变。
结论：
1. EGFR蛋白表达率随着宫颈组织恶性程度升高而升高,与临床分期有关,与病理分级、组织学分型及年龄无关。
2.宫颈癌中EGFR基因外显子19及外显子21未检测到突变。
3. EGFR蛋白高表达与EGFR基因第19、21外显子突变无关,可能与EGFR基因中其它突变相关。
Objective:
1. To investigate the expression of epidermal growth factor receptor (EGFR) and interrelation with some factors in the specimens.
2. To analyze the incidence and profiles of EGFR mutation in cervical cancer, which provide gene detection methods and theoretical basis for the targeted treatment of cervical cancer.
3. To investigate the relationship between the expression of EGFR and the immutation of EGFR.
Methods:
1. Paraffin-embedded tumor tissue samples were obtained from 77 patients with cervical cancer. The EGFR protein expression were detected by immunohisto-chemical (IHC) method.
2. Paraffin-embedded tumor tissue samples were obtained from 86 patients with cervical cancer. The deletion mutation in EGFR exon 19 were detected by PCR and the point mutation in EGFR exon 21 was detected by PCR-RLFP. The positive mutation of EGFR gene were detected by DNA sequencing.
Results:
1. The positive expression rate of EGFR was zero in normal cervix,42.9%(6/14) in preinvasive cervical carcinoma,76.7%(33/43) in invasive cervical cancer. The expression rate of EGFR protein was significantly correlated among the three groups and between each of them, with the progress of clinical stage, EGFR positive expression tatio increased (P<0.01). In invasive cervical cancer, The expression rate of EGFR protein was significantly correlated with the clinical stage(P<0.01), but had no relation with histological grade,age or pathological type(P>0.05).
2. No EGFR gene mutation were detected in exons 19 and 21 of cervical cancer samples by PCR, PCR-RLFP and DNA sequencing method.
Conclusions:
1. There was an over-expression of EGFR in cervical cancer.The rate of EGFR protein expression related to the clinical stage, but had no relation to the age, histological grade or hitologic type.
2. There was no EGFR mutation in exon 19 and 21 in cervical cancer.
3. The abnormal expression of EGFR protein had no relation to EGFR mutations, while maybe relate to other EGFR mutations in cervical cancer.
引文
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[1]Ratushny V, Astsaturov I, Burtness BA, Golemis EA, Silverman JS. Targeting EGFR resistance networks in head and neck cancer [J]. Cell Signal,2009,21(8):1255-1268.
[2]Kim SJ, Rabbani ZN, Dong F, Vollmer RT, Schreiber EG, Dewhirst MW, et al. Phosphorylated epidermal growth factor receptor and cyclooxygenase-2 expression in localized non-small cell lung cancer [J]. Medical Oncology,2010,27(1):91-97.
[3]Matkovic B, Juretic A, Separovic V, Novosel 1, Separovic R, Gamulin M, et al. Immunohistochemical analysis of ER, PR, HER-2, CK 5/6, p63 and EGFR antigen expression in medullary breast cancer [J]. Tumori,2008,94(6):838-844.
[4]Molaei M, Pejhan S, Nayer BN, Moradi A, Ghiasi S, Zali MR. Human epidermal growth factor receptor-2 family in colorectal adenocarcinoma:correlation with survival and clinicopathological findings [J]. Eur J Gastroenterol Hepatol,2009,21(3):289-293.
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[29]于晓红,李隆玉,魏宝秀等CD44V6、EGFR在宫颈上皮内瘤变及宫颈鳞癌中的表达与意义.实用癌症杂志,2005,20(5)：472-474.
[30]田琦,吕胜军,王佳铭.皮生长因子受体在宫颈癌中的表达及意义.实用肿瘤学杂志,2000,14(2)：86-87.
[31]Bellone S, Frera G, Landolfi G, et al. Overexpression of epidermal growth factor type-1 receptor (EGF-R1) in cervical cancer:Implications for Cetuximab-mediated therapy in recurrent/metastatic disease [J]. Int J Gynecol Oncol.2007,106 (3):513-520.
[32]Kim JW, Kim YT, Kim DK, et al.Expression of epidermal growth factor receptor in carcinomal of the cervix [J]. Gynecol Oncol.1996,60 (2):283-287.
[33]宋作林,彭芝兰,姚先莹EGFR在宫颈癌及淋巴结转移灶中的表达.中国航天医药杂[J].2004,6(2)：25-28.
[34]Leung T W, Cheung A N, Cheng D K, etal. Expressions of c-erbB-2, epidermal growth factor receptor and pan-ras proto-on-cogenes in adenocarcinoma of the cervix:correlation with clinical prognosis [J]. Oncol Rep,2001,8 (5):1159-1164.
[35]Herbst RS. Review of epidermal growth factor receptor biology [J]. Int J Radiat Oncol Biol Phys,2004,59(Suppl 2):21-26.
[36]Herbst R, Shin DM.Monoclonal antibodies to target epidermal growth factor receptor-positive tumors:a new paradigm for cancer therapy [J]. Cancer,2002,94(5):1593-1611.
[37]Kim HG,Kassis J,Souto JC,et al. ECF receptor signaling in prostste, morphogenesis and tamorigemesis[J]. Histol Histopathol,1999,14(4):1175-1182.
[38]Arias-Pulido H, Joste N, Chavez A, et.al. Absence of epidermal growth factor receptor mutations in cervical cancer [J].Int J Gynecol Cancer,2008,18 (4):749-754.
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