Ⅰ、Ⅱ型子宫内膜癌的临床病理和表观遗传学及Her-2基因异常的研究
|
摘要
子宫内膜癌为女性生殖道常见三大恶性肿瘤之一,根据其临床特征与生物学行为特点可分为Ⅰ、Ⅱ两种类型:Ⅰ型即为雌激素相关的子宫内膜样腺癌,Ⅱ型为非雌激素相关,包括子宫内膜浆液性乳头状癌(Uterine Papillary SerousCarcinoma,UPSC)、透明细胞癌等类型。Ⅰ、Ⅱ两型不仅有不同的临床病理特征,近年来研究还发现两型子宫内膜癌有不同的分子发生机制。但其中仍有很多机制未明,需要进一步深入研究,并探讨Ⅱ型子宫内膜癌疾病快速进展的分子机制。本研究共分为三个部分:
第一部分Ⅰ、Ⅱ型子宫内膜癌不同的临床病理特征分析
目的:分析比较Ⅰ、Ⅱ型子宫内膜癌不同的临床病理特征及预后因素。
方法:回顾性分析1996年1月至2006年12月11年间我院收治的563例子宫内膜癌,并进行统计学分析。
结果:563例患者中包括Ⅰ型503例(89.3%)和Ⅱ型60例(10.7%)。Ⅰ型患者平均年龄55岁,Ⅱ型平均年龄63岁。Ⅰ型患者中早期(Ⅰ-Ⅱ期)占81.1%,晚期(Ⅲ-Ⅳ期)仅占18.9%;而Ⅱ型患者中早期占55%,晚期患者占45%。Ⅰ型患者术后病理G1-2者占82.5%,而Ⅱ型患者中G3占65%。78.3%的Ⅰ型患者浸润≤1/2肌层,而Ⅱ型患者中43.3%浸润＞1/2肌层。平均随访时间33个月,随访期间48例患者死亡。Ⅰ、Ⅱ型患者的3年总生存率(Overall Survival,OS)分别为92.1%和56.5%,5年OS分别为91%和46.8%,差异有显著性(P＜0.01)。Ⅰ、Ⅱ型患者的3年无病生存期(DFS,Disease Free Survival)分别为91.6%和62.5%,5年DFS分别为89.5%和56.5%,差异有显著性(P＜0.01)。单因素分析发现,Ⅰ型患者中手术病理分期、肌层浸润深度、细胞分化、BMI(体重指数)、绝经、LVSI有统计学意义,与预后相关(P＜0.05);而Ⅱ型中仅手术病理分期、肌层浸润深度和淋巴结受累与预后相关(P＜0.05)。多因素分析显示,Ⅰ型患者中手术病理分期、细胞分化和肌层浸润深度的P值＜0.05,Ⅱ型患者中手术病理分期P值＜0.05,为独立的预后因素。
结论:Ⅱ型患者与Ⅰ型患者相比,发病年龄大,诊断时多为晚期,肿瘤细胞分化差,多伴有脉管癌栓和深肌层浸润,部分侵及浆膜层,故较易发生复发和转移,3年和5年总生存率和无病生存率均较Ⅰ型患者低,是预后不良的重要因素之一。对这部分患者术后应加强辅助治疗,以改善患者的预后。
第二部分Ⅰ、Ⅱ型子宫内膜癌中Wnt通路相关基因的启动子甲基化研究
目的:分析WIF-1、E-cadherin和PTEN基因在子宫内膜癌中的启动子甲基化情况,检测E-cadherin、PTEN和β-catenin的蛋白表达情况,探讨Ⅰ、Ⅱ型子宫内膜癌不同的分子特征。
方法:采用甲基化特异性PCR方法检测105例子宫内膜癌组织和46例配对的癌旁子宫内膜组织中WIF-1、E-cadherin和PTEN基因启动子区的异常甲基化,免疫组化方法检测E-cadherin、PTEN和β-catenin的蛋白表达情况。
结果:105例患者包括8l例Ⅰ型子宫内膜癌和24例Ⅱ型子宫内膜癌,中位年龄57岁。子宫内膜癌组织中WIF-1、E-cadherin和PTEN基因启动子甲基化率分别为26.7%(28/105)、27.6%(29/105)和18.1%(19/105),在癌组织中的甲基化率均高于癌旁组织(P＜0.05)。E-cadhefin基因启动子甲基化多见于预后差的Ⅱ型患者,两型之间有显著性差异(P＜0.05);WIF-1基因甲基化多见于FIGO分期晚的患者(P＜0.05)。子宫内膜癌组织中E-cadherin蛋白表达缺失率为60.0%(63/105),PTEN蛋白表达缺失率为24.8%(26/105),β-catenin蛋白表达异常者占29.5%(31/105)。E-cadherin蛋白表达缺失与患者的病理分型(Ⅰ型和Ⅱ型)、FIGO分期和肌层浸润深度显著相关(P＜0.05),β-catenin蛋白表达异常多见于Ⅰ型患者(P＜0.05)。单因素分析发现,WIF-1基因启动子甲基化、E-cadherin基因启动子甲基化、PTEN蛋白表达缺失与Ⅰ型患者预后差显著相关(P＜0.05);E-cadhcdn蛋白表达缺失与Ⅱ型患者预后显著差相关(P＜0.05)。
结论:I、Ⅱ型子宫内膜癌有不同的分子特征,E-cadhcdn基因启动子甲基化和蛋白表达缺失多见于预后差的Ⅱ型患者,而β-catenin表达异常多见于Ⅰ型患者。基因启动子甲基化是引起相应的蛋白表达缺失的重要机制。WIF-1基因启动子甲基化、E-cadherin基因启动子甲基化、PTEN蛋白表达缺失和E-cadherin蛋白表达缺失分别是Ⅰ、Ⅱ型子宫内膜癌预后不良的重要指标。
第三部分Ⅱ型子宫内膜癌UPSC中Her-2/neu基因扩增及临床意义研究
目的:检测Her-2/neu基因在子宫浆液性乳头状癌(Uterine Papillary SerousCarcinoma,UPSC)中的扩增和蛋白表达情况,并分析与临床病理及预后的关系。
方法:回顾性分析1996年1月-2006年1月在我院手术治疗的36例子宫内膜浆液性乳头状癌患者的临床病理资料,分别用色素原位杂交(chromogenic insitu hybridization,CISH)和免疫组化方法(immunohistochemistry,IHC)检测Her-2/neu基因在UPSC中的扩增和蛋白表达情况。
结果:IHC检测发现,36例患者中,36.1%(13/36)患者存在Her-2/neu基因蛋白高表达(2+-3+),其中27.8%(10/36)Her-2/neu蛋白染色2+,8.3%(3/36)染色3+。CISH检测发现11.1%(4/36)患者存在Her-2/neu基因扩增。Her-2/neu基因蛋白过表达与手术分期晚(P=0.015)和预后差显著相关(P=0.0093)。
结论:UPSC中存在Her-2/neu蛋白的高表达,并且与手术分期晚和预后差显著相关。CISH是检测Her-2/neu基因扩增情况的一种方便的方法。针对Her-2/neu基因的靶向治疗可能是对化疗耐药、复发或转移UPSC的一种新的治疗方法。
Endometrial cancer(EC)is one of the most common gynecological malignancies. Two different clinicopathologic subtypes are recognized:the estrogen-related(typeⅠ, endometrioid) and the non-estrogen-related types(typeⅡ,nonendometrioid such as papillary serous and clear cell).Although recent studies have revealed several molecular differences in these two types of endometrial cancer,there are still many mechanisms remained unclear.Therefore,further research was needed to divide new molecular subtypes and find the mechanisms of the aggressive typeⅡendometrial cancer,more molecular biomarkers are urged needed.The current research project is comprised of the following three parts.
PartⅠ.Clinicopathological Characteristics of TypeⅠand TypeⅡEndometrial Cancer
Objectives:To study the different clinicopathological characteristics and prognostic factors of typeⅠand typeⅡendometrial cancer.
Methods:Five hundreds and sixty-three patients with endometrial cancer were treated in our hospital between January,1996 and December,2006.The clinico-pathologic characteristics,treatment and prognosis were retrospectively analyzed.
Results:563 patients included 503(89.3%) typeⅠcases and 60(10.7%) typeⅡcases.Mean age of typeⅠand typeⅡpatients was 55 and 63,respectively.In typeⅠpatients,the early stage(stageⅠ～Ⅱ) accounted for 81.1%,while late stage(stageⅢ～Ⅳ) only accounted for 18.9%.In typeⅡcases,the early stage and late stage accounted for 55%and 45%,respectively.For typeⅠpatients,82.5%tumors were G1～2 differentiation and 78.3%invaded less than half myometrium,while for typeⅡcases,65%were G3 and 43.3%invaded more than half myometrium.Mean follow-up duration was 33 months.During follow-up,48 cases died.The 3-year overall survival (OS) for typeⅠand typeⅡpatients was 92.1%and 56.5%,and the 5-year OS was 91%and 46.8%,respectively(P＜0.01).The 3-year disease free survival(DFS) for typeⅠand typeⅡpatients was 91.6%and 62.5%,and the 5-year OS was 89.5%and 56.5%,respectively(P＜0.01).In univariate analysis,FIGO stages,myometrial invasion,tumor cell differentiation,Body-mass Index,menopause,lymph-vascular space invasion were significant for typeⅠpatients(P＜0.05),with only FIGO stages, myometrial invasion and lymph node metastasis significant for typeⅡpatients (P＜0.05).In multivariate analysis,FIGO stages,myometrial invasion and tumor cell differentiation were found to be associated with poor prognoses for typeⅠand FIGO stages for typeⅡpatients,and considered as independent prognostic factors for them, respectively(P＜0.05).
Conclusion:Patients with typeⅡendometrial cancer,compared with typeⅠcases, were much older,with more advanced stage,poorer differentiation,more LVSI and deeper myometrial invasion.Therefore,the rate of recurrence and metastases were higher for typeⅡpatients than typeⅠ.Since typeⅡendometrial cancer was very aggressive and had a rather poor prognosis,more attention and postoperative treatment should be given to improve their prognoses。
PartⅡ.DNA Hypermethylation of Wnt pathway-related genes in TypeⅠand TypeⅡEndometrial Cancer
Objectives:To investigate promoter methylation status of WIF-1,E-cadherin and PTEN genes and protein expression of E-cadherin,PTEN andβ-cateninin in endometrial cancer,and to discuss the different molecular characters of typeⅠand typeⅡendometrial cancer.
Medthods:Methylation-specific PCR(MSP) was performed to detect the promoter methylation status of WIF-1,E-cadherin and PTEN genes in 105 endometrial cancer and 46 paired normal endometrium,with immunohistochemistry (IHC) to detect protein expression of E-cadherin,PTEN andβ-cateninin genes.
Results:105 patients included 81 typeⅠand 24 typeⅡcases,with median age of 57.The frequency of promoter methylation of WIF-1,E-cadherin and PTEN genes was 26.7%(28/105),27.6%(29/105)and 18.1%(19/105),respectively.The methylation frequency of endometrial tissues was higher than that of corresponding normal tissues(P＜0.05).E-cadherin promoter hypermethylation was associated with pathological subtypes(typeⅠand typeⅡEC),WIF-1 promoter methylation was correlated with FIGO stage,and PTEN promoter methylation was correlated with p53 expression(P＜0.05).Reduced E-cadherin expression was observed in 60.0% (63/105) of the cases,being more frequent in typeⅡcases,more advanced stage and carcinomas of deep myometrial invasion(P＜0.05).Abnormalβ-catenin expression was observed in 29.5%(31/105) of the cases,being more frequent in typeⅠEC(P＜0.05).In univariate analysis,patients with WIF-1 promoter methylation, E-cadherin promoter hypermethylation,and reduced PTEN expression were associated with worse prognoses in typeⅠpatients and reduced E-cadherin expression associated with worse prognoses in typeⅡpatients(P＜0.05).
Conclusions:There were different molecular charcaters between typeⅠand typeⅡEC,including more E-cadherin promoter hypermethylation and reduced E-cadherin expression in typeⅡand more abnormalβ-catenin expression in typeⅠ.Promoter hypermethylation was one of the important mechanisms of gene silence.WIF-1 promoter methylation,E-cadherin promoter hypermethylation,reduced PTEN expression and reduced E-cadherin expression were associated with worse prognoses for patients with typeⅠand typeⅡEC,respectively.
PartⅢ,Clinical Significance of Her-2/neu Status in Patients with Uterine Papillary Serous Carcinoma
Objectives:Uterine papillary serous carcinoma(UPSC) is a highly aggressive subtype of endometrial cancer.It is characterized by early metastasis,resistance to therapy,and a high mortality rate.The purpose of this study was to evaluate gene amplification by chromogenic in situ hybridization(CISH) and the protein expression of Her-2/neu gene in Asian patients with UPSC and to determine its prognostic value.
Methods:Thirty-six patients with confirmed pathologic diagnosis of UPSC in Cancer Hospital of Fudan University from 1/1/1996 to 1/1/2006 were analysed retrospectively.Chromogenic in situ hybridization(CISH) was performed to assess Her-2/neu gene amplification,and protein expression was evaluated by immunohistochemistry(IHC).
Results:In 36 cases with UPSC,13 patients(36.1%) showed moderate staining (2+) to strong staining(3+) for Her-2/neu protein,with 10 patients 2+ and 3 patients 3+.Amplification of the Her-2/neu gene by CISH was observed in 4 of the 36(11.1%) cases.Her-2/neu protein overexpression was significantly associated with advanced surgical stage and worse overall survival(P=0.015 and P=0.0093,respectively).
Conclusion:Her-2/neu protein overexpression was significantly associated with advanced surgical stage UPSC and poor survival outcome.CISH analysis is a convenient method used for confirmation of gene amplification in UPSC.Herceptin might be considered as an attractive therapy in the clinical management of patients with chemotherapy-resistant,recurrent,or metastatic UPSC.
第一部分Ⅰ、Ⅱ型子宫内膜癌不同的临床病理特征分析
目的:分析比较Ⅰ、Ⅱ型子宫内膜癌不同的临床病理特征及预后因素。
方法:回顾性分析1996年1月至2006年12月11年间我院收治的563例子宫内膜癌,并进行统计学分析。
结果:563例患者中包括Ⅰ型503例(89.3%)和Ⅱ型60例(10.7%)。Ⅰ型患者平均年龄55岁,Ⅱ型平均年龄63岁。Ⅰ型患者中早期(Ⅰ-Ⅱ期)占81.1%,晚期(Ⅲ-Ⅳ期)仅占18.9%;而Ⅱ型患者中早期占55%,晚期患者占45%。Ⅰ型患者术后病理G1-2者占82.5%,而Ⅱ型患者中G3占65%。78.3%的Ⅰ型患者浸润≤1/2肌层,而Ⅱ型患者中43.3%浸润＞1/2肌层。平均随访时间33个月,随访期间48例患者死亡。Ⅰ、Ⅱ型患者的3年总生存率(Overall Survival,OS)分别为92.1%和56.5%,5年OS分别为91%和46.8%,差异有显著性(P＜0.01)。Ⅰ、Ⅱ型患者的3年无病生存期(DFS,Disease Free Survival)分别为91.6%和62.5%,5年DFS分别为89.5%和56.5%,差异有显著性(P＜0.01)。单因素分析发现,Ⅰ型患者中手术病理分期、肌层浸润深度、细胞分化、BMI(体重指数)、绝经、LVSI有统计学意义,与预后相关(P＜0.05);而Ⅱ型中仅手术病理分期、肌层浸润深度和淋巴结受累与预后相关(P＜0.05)。多因素分析显示,Ⅰ型患者中手术病理分期、细胞分化和肌层浸润深度的P值＜0.05,Ⅱ型患者中手术病理分期P值＜0.05,为独立的预后因素。
结论:Ⅱ型患者与Ⅰ型患者相比,发病年龄大,诊断时多为晚期,肿瘤细胞分化差,多伴有脉管癌栓和深肌层浸润,部分侵及浆膜层,故较易发生复发和转移,3年和5年总生存率和无病生存率均较Ⅰ型患者低,是预后不良的重要因素之一。对这部分患者术后应加强辅助治疗,以改善患者的预后。
第二部分Ⅰ、Ⅱ型子宫内膜癌中Wnt通路相关基因的启动子甲基化研究
目的:分析WIF-1、E-cadherin和PTEN基因在子宫内膜癌中的启动子甲基化情况,检测E-cadherin、PTEN和β-catenin的蛋白表达情况,探讨Ⅰ、Ⅱ型子宫内膜癌不同的分子特征。
方法:采用甲基化特异性PCR方法检测105例子宫内膜癌组织和46例配对的癌旁子宫内膜组织中WIF-1、E-cadherin和PTEN基因启动子区的异常甲基化,免疫组化方法检测E-cadherin、PTEN和β-catenin的蛋白表达情况。
结果:105例患者包括8l例Ⅰ型子宫内膜癌和24例Ⅱ型子宫内膜癌,中位年龄57岁。子宫内膜癌组织中WIF-1、E-cadherin和PTEN基因启动子甲基化率分别为26.7%(28/105)、27.6%(29/105)和18.1%(19/105),在癌组织中的甲基化率均高于癌旁组织(P＜0.05)。E-cadhefin基因启动子甲基化多见于预后差的Ⅱ型患者,两型之间有显著性差异(P＜0.05);WIF-1基因甲基化多见于FIGO分期晚的患者(P＜0.05)。子宫内膜癌组织中E-cadherin蛋白表达缺失率为60.0%(63/105),PTEN蛋白表达缺失率为24.8%(26/105),β-catenin蛋白表达异常者占29.5%(31/105)。E-cadherin蛋白表达缺失与患者的病理分型(Ⅰ型和Ⅱ型)、FIGO分期和肌层浸润深度显著相关(P＜0.05),β-catenin蛋白表达异常多见于Ⅰ型患者(P＜0.05)。单因素分析发现,WIF-1基因启动子甲基化、E-cadherin基因启动子甲基化、PTEN蛋白表达缺失与Ⅰ型患者预后差显著相关(P＜0.05);E-cadhcdn蛋白表达缺失与Ⅱ型患者预后显著差相关(P＜0.05)。
结论:I、Ⅱ型子宫内膜癌有不同的分子特征,E-cadhcdn基因启动子甲基化和蛋白表达缺失多见于预后差的Ⅱ型患者,而β-catenin表达异常多见于Ⅰ型患者。基因启动子甲基化是引起相应的蛋白表达缺失的重要机制。WIF-1基因启动子甲基化、E-cadherin基因启动子甲基化、PTEN蛋白表达缺失和E-cadherin蛋白表达缺失分别是Ⅰ、Ⅱ型子宫内膜癌预后不良的重要指标。
第三部分Ⅱ型子宫内膜癌UPSC中Her-2/neu基因扩增及临床意义研究
目的:检测Her-2/neu基因在子宫浆液性乳头状癌(Uterine Papillary SerousCarcinoma,UPSC)中的扩增和蛋白表达情况,并分析与临床病理及预后的关系。
方法:回顾性分析1996年1月-2006年1月在我院手术治疗的36例子宫内膜浆液性乳头状癌患者的临床病理资料,分别用色素原位杂交(chromogenic insitu hybridization,CISH)和免疫组化方法(immunohistochemistry,IHC)检测Her-2/neu基因在UPSC中的扩增和蛋白表达情况。
结果:IHC检测发现,36例患者中,36.1%(13/36)患者存在Her-2/neu基因蛋白高表达(2+-3+),其中27.8%(10/36)Her-2/neu蛋白染色2+,8.3%(3/36)染色3+。CISH检测发现11.1%(4/36)患者存在Her-2/neu基因扩增。Her-2/neu基因蛋白过表达与手术分期晚(P=0.015)和预后差显著相关(P=0.0093)。
结论:UPSC中存在Her-2/neu蛋白的高表达,并且与手术分期晚和预后差显著相关。CISH是检测Her-2/neu基因扩增情况的一种方便的方法。针对Her-2/neu基因的靶向治疗可能是对化疗耐药、复发或转移UPSC的一种新的治疗方法。
Endometrial cancer(EC)is one of the most common gynecological malignancies. Two different clinicopathologic subtypes are recognized:the estrogen-related(typeⅠ, endometrioid) and the non-estrogen-related types(typeⅡ,nonendometrioid such as papillary serous and clear cell).Although recent studies have revealed several molecular differences in these two types of endometrial cancer,there are still many mechanisms remained unclear.Therefore,further research was needed to divide new molecular subtypes and find the mechanisms of the aggressive typeⅡendometrial cancer,more molecular biomarkers are urged needed.The current research project is comprised of the following three parts.
PartⅠ.Clinicopathological Characteristics of TypeⅠand TypeⅡEndometrial Cancer
Objectives:To study the different clinicopathological characteristics and prognostic factors of typeⅠand typeⅡendometrial cancer.
Methods:Five hundreds and sixty-three patients with endometrial cancer were treated in our hospital between January,1996 and December,2006.The clinico-pathologic characteristics,treatment and prognosis were retrospectively analyzed.
Results:563 patients included 503(89.3%) typeⅠcases and 60(10.7%) typeⅡcases.Mean age of typeⅠand typeⅡpatients was 55 and 63,respectively.In typeⅠpatients,the early stage(stageⅠ～Ⅱ) accounted for 81.1%,while late stage(stageⅢ～Ⅳ) only accounted for 18.9%.In typeⅡcases,the early stage and late stage accounted for 55%and 45%,respectively.For typeⅠpatients,82.5%tumors were G1～2 differentiation and 78.3%invaded less than half myometrium,while for typeⅡcases,65%were G3 and 43.3%invaded more than half myometrium.Mean follow-up duration was 33 months.During follow-up,48 cases died.The 3-year overall survival (OS) for typeⅠand typeⅡpatients was 92.1%and 56.5%,and the 5-year OS was 91%and 46.8%,respectively(P＜0.01).The 3-year disease free survival(DFS) for typeⅠand typeⅡpatients was 91.6%and 62.5%,and the 5-year OS was 89.5%and 56.5%,respectively(P＜0.01).In univariate analysis,FIGO stages,myometrial invasion,tumor cell differentiation,Body-mass Index,menopause,lymph-vascular space invasion were significant for typeⅠpatients(P＜0.05),with only FIGO stages, myometrial invasion and lymph node metastasis significant for typeⅡpatients (P＜0.05).In multivariate analysis,FIGO stages,myometrial invasion and tumor cell differentiation were found to be associated with poor prognoses for typeⅠand FIGO stages for typeⅡpatients,and considered as independent prognostic factors for them, respectively(P＜0.05).
Conclusion:Patients with typeⅡendometrial cancer,compared with typeⅠcases, were much older,with more advanced stage,poorer differentiation,more LVSI and deeper myometrial invasion.Therefore,the rate of recurrence and metastases were higher for typeⅡpatients than typeⅠ.Since typeⅡendometrial cancer was very aggressive and had a rather poor prognosis,more attention and postoperative treatment should be given to improve their prognoses。
PartⅡ.DNA Hypermethylation of Wnt pathway-related genes in TypeⅠand TypeⅡEndometrial Cancer
Objectives:To investigate promoter methylation status of WIF-1,E-cadherin and PTEN genes and protein expression of E-cadherin,PTEN andβ-cateninin in endometrial cancer,and to discuss the different molecular characters of typeⅠand typeⅡendometrial cancer.
Medthods:Methylation-specific PCR(MSP) was performed to detect the promoter methylation status of WIF-1,E-cadherin and PTEN genes in 105 endometrial cancer and 46 paired normal endometrium,with immunohistochemistry (IHC) to detect protein expression of E-cadherin,PTEN andβ-cateninin genes.
Results:105 patients included 81 typeⅠand 24 typeⅡcases,with median age of 57.The frequency of promoter methylation of WIF-1,E-cadherin and PTEN genes was 26.7%(28/105),27.6%(29/105)and 18.1%(19/105),respectively.The methylation frequency of endometrial tissues was higher than that of corresponding normal tissues(P＜0.05).E-cadherin promoter hypermethylation was associated with pathological subtypes(typeⅠand typeⅡEC),WIF-1 promoter methylation was correlated with FIGO stage,and PTEN promoter methylation was correlated with p53 expression(P＜0.05).Reduced E-cadherin expression was observed in 60.0% (63/105) of the cases,being more frequent in typeⅡcases,more advanced stage and carcinomas of deep myometrial invasion(P＜0.05).Abnormalβ-catenin expression was observed in 29.5%(31/105) of the cases,being more frequent in typeⅠEC(P＜0.05).In univariate analysis,patients with WIF-1 promoter methylation, E-cadherin promoter hypermethylation,and reduced PTEN expression were associated with worse prognoses in typeⅠpatients and reduced E-cadherin expression associated with worse prognoses in typeⅡpatients(P＜0.05).
Conclusions:There were different molecular charcaters between typeⅠand typeⅡEC,including more E-cadherin promoter hypermethylation and reduced E-cadherin expression in typeⅡand more abnormalβ-catenin expression in typeⅠ.Promoter hypermethylation was one of the important mechanisms of gene silence.WIF-1 promoter methylation,E-cadherin promoter hypermethylation,reduced PTEN expression and reduced E-cadherin expression were associated with worse prognoses for patients with typeⅠand typeⅡEC,respectively.
PartⅢ,Clinical Significance of Her-2/neu Status in Patients with Uterine Papillary Serous Carcinoma
Objectives:Uterine papillary serous carcinoma(UPSC) is a highly aggressive subtype of endometrial cancer.It is characterized by early metastasis,resistance to therapy,and a high mortality rate.The purpose of this study was to evaluate gene amplification by chromogenic in situ hybridization(CISH) and the protein expression of Her-2/neu gene in Asian patients with UPSC and to determine its prognostic value.
Methods:Thirty-six patients with confirmed pathologic diagnosis of UPSC in Cancer Hospital of Fudan University from 1/1/1996 to 1/1/2006 were analysed retrospectively.Chromogenic in situ hybridization(CISH) was performed to assess Her-2/neu gene amplification,and protein expression was evaluated by immunohistochemistry(IHC).
Results:In 36 cases with UPSC,13 patients(36.1%) showed moderate staining (2+) to strong staining(3+) for Her-2/neu protein,with 10 patients 2+ and 3 patients 3+.Amplification of the Her-2/neu gene by CISH was observed in 4 of the 36(11.1%) cases.Her-2/neu protein overexpression was significantly associated with advanced surgical stage and worse overall survival(P=0.015 and P=0.0093,respectively).
Conclusion:Her-2/neu protein overexpression was significantly associated with advanced surgical stage UPSC and poor survival outcome.CISH analysis is a convenient method used for confirmation of gene amplification in UPSC.Herceptin might be considered as an attractive therapy in the clinical management of patients with chemotherapy-resistant,recurrent,or metastatic UPSC.
引文
1.Cancer statistics 2007.http://www.cancer.org.
2.Jemal A,Siegel R,Ward E,et al.Cancer Statistics[J].CA Cancer J Clin,2007;57:43-66.
3.Bockman JV.Two pathogenetic types of endometrial carcinoma[J].Gynecol Oncol,1983,15:10-7.
4.Liu FS.Molecular carcinogenesis of endometrial cancer[J].Taiwan J Obstet Gynecol,2007,46:26-32.
5.Amant F,Moerman P,Neven P,et al.Endometrial cancer[J].Lancet,2005;366:491-505.
6.Berchuck A,Boyd J.Molecular basis of endometrial cancer[J].Cancer,1995,76:2034-40.
7.Niederacher D,An HX,Cho YJ,et al.Mutations and amplification of oncogenes in endometrial cancer[J].Ontology,1999,56:59-65.
8.Risinger JI,Hayes AK,Berchuck A,et al.PTEN/MMAC1 mutations in endometrial cancers[J].Cancer Res,1997,57:4736-8.
9.Salvesen HB,MacDonald N,Ryan A,Jacobs IJ,Lynch ED,Akslen LA,Das S.PTEN methylation is associated with advanced stage and microsatellite instability in endometrial cancer[J].Int J Cancer 2001;91:22-26.
10.MacDonald ND,Salvesen HB,Ryan A,et al.Frequency and prognostic impact of microsatellite instability in a large population-based study of endometdal carcinomas[J].Cancer Res,2000,60:1750-2.
11.Busmanis I,Ho TH,Tan SB,et al.p53 and bcl-2 expression in invasive and pre-invasive uterine papillary serous carcinoma and atrophic endometrium[J].Ann Acad Med Singapore,2005,34:421-5.
12.King SA,Adas AA,Livolsi VA,et al.Expression and mutation of the p53 gene in uterine papillary serous carcinoma[J].Cancer,1995,75(11):2700-2705.
13.Kovalev S,Marchenko ND,Gugliotta BG,et al.Loss of p53 funtion in uterine papillary serous carcinoma[J].Human Pathol,1998,29(6):613-619.
14.Sherman ME,Bur ME,Kurman RJ.P53 in endometrial cancer and its putative precursors-evidence for diverse pathways of tumorigenesis[J].Hum Pathol,1995,26(11):1268-1274.
15.Lengauer C,Kinzler KW,Vogelstein B.Genetic instability in colorectal cancers[J].Nature,1997;386:623-627.
16. Staebler A, Lax SF, Ellenson LH. Altered expression of hMLH1 and hMSH2 protein in endometrial carcinomas with MSI [J]. Hum Pathol 2000;31:354-358.
17. Esteller M, Levine R, Baylin SB, Ellenson LH, Herman JG MLH1 promoter hypermethylation is associated with the microsatellite instability phenotype in sporadic endometrial carcinomas [J]. Oncogene 1998;17:2413-2417.
18. Salvesen HB, MacDonald N, Ryan A, Jacobs IJ, Akslen LA, et al. Methylation of hMLHl in a population-based series of endometrial carcinomas[J]. Clin Cancer Res 2000;6:3607-3613.
19. Sasaki M, Dharia A, Oh BR, Tanaka Y, Fujimoto S, Dahiya R. Progesterone receptor B gene inactivation and CpG hypermethylation in human uterine endometrial cancer[J]. Cancer Res 2001;61:97-102.
20. Salvesen HB, Das S,Akslen LA. Loss of nuclear pl6 protein expression is not associated with μpromoter methylation but defines a subgroup of aggressive endometrial carcinomas with poor prognosis [J]. Clin Cancer Res 2000;6:153-159.
21. Hsieh JC, Kodjabachian L, Rebbert ML, et al. A new secreted protein that binds to Wnt proteins and inhibits their activities [J]. Nature, 1999, 398: 431-436.
22. He BA, Reguart N, You L, et al. Blockade of Wnt-1 signaling induces apoptosis in human colorectal cancer cells containing downstream mutations [J]. Oncogene, 2005, 24 ( 18 ) : 3054-3058.
23. Wissmann C, Wild PJ, Kaiser S, et al. WIF1, a component of the Wnt pathway, is down-regulated in prostate, breast, lung, and bladder cancer [J]. J Pathol, 2003, 201 (2) : 204-212.
24. Mazieres J, He B, You L, et al. Wnt inhibitory factor-1 is silenced by promoter hypermethylation in human lung cancer [J]. Cancer Res, 2004, 64 (14): 4717-4720.
25. Taniguchi H, Yamamoto H, Hirata T, et al. Epigenetic inactivation of Wnt inhibitory factor-1 in human gastrointestinal cancers[J]. Oncogene, 2005, 24 (53) : 7946-7952.
26. Urakami S, Shiina H, Enokida H, et al. Epigenetic inactivation of Wnt inhibitory factor-1 plays an important role in bladder cancer through aberrant canonical Wnt /beta-catenin signaling pathway [J]. Clin Cancer Res, 2006, 12 (2): 383-391.
27. Price FV, Chambers SK, Carcangiu ML, et al. Intravenous cisplatin, doxorubicin, and cyclophosphamide in the treatment of uterine papillary serous carcinoma (UPSC) [J]. Gynecol Oncol, 1993,51:383-389.
1.Bokhman JV.Two pathogenetic types of endometrial carcinoma[J].Gynecol Oncol,1983,15:10-17.
2.ShermanME,BurMa,Kurman RJ.p53 in endometrial cancer and its putative precursors:evidence for diverse pathways of tumorigenesis[J].Hum Pathol,1995,26:1268-1274.
3.Liu FS.Molecular carcinogenesis of endometrial cancer[J].Taiwan J Obstet Gynecol,2007,46:26-32.
4.Mikuta JJ.International Federation of Gynecology and Obstetrics staging of endometrial cancer 1988[J].Cancer,1993,71:1460-1463.
5.Silverberg SG,Kurman RJ,Nogales F,et al.Tumors of the uterine corpus[M]//Tavassoli FA,Devilee P,editors.Pathology and genetics of tumours of the breast and female genital organs.World Health Organization classification of tumours,Lyon,France:IARC Press,2003:217-232.
6.Cancer statistics 2007.http://www.cancer.org.
7.Jemal A,Siegel R,Ward E,et al.Cancer Statistics,2007[J].CA Cancer J Clin,2007;57:43-66.
8.张薇、项永兵等.1973-1999年上海市区老年人恶性肿瘤发病趋势分析[J].中华老年医学杂志,2005,24(9):701-704.
9.杨丹,韩立敏.1969-2003年子宫内膜癌发病率及发病因素分析[J].Fudan Univ J Med Sci,2005,32(4):479-480.
10.Liu FS.Molecular carcinogenesis of endometrial cancer[J].Taiwan J Obstet Gynecol,2007,46:26-32.
11.Amant F,Moerman P,Neven P,et al.Endometrial cancer[J].Lancet,2005;366:491-505.
12.任玉兰,王华英,沈磊,等.子宫内膜浆液性乳头状癌33例临床分析[J].中华妇产科杂志,2006,41(12):817-821.
13.李斌,吴令英,李淑敏,等.子宫内膜癌的预后影响因素分析[J].癌症,2004,23:1085-1088.
14.Calle EE,Rodriguez C,Walker-Thurmond K,Thun MJ.Overweight,obesity,and mortality from cancer in a prospectively studied cohort of U.S.adults[J].N Engl J Med,2003;348:1625-38.
15.张志毅,章文华,主编.现代妇科肿瘤外科学.第1版[M].北京:科学出版社, 2003:136-137.
16.Yasunaga M,Yamasaki F,Tokunaga O,et al.Endometrial carcinomas with lymph node involvement:novel histopathologic factors for predicting prognosis[J].Int J Gynecol Pathol,2003,22(4):341-346.
17.Chan JK,Cheung MK,Huh WK,et al.Therapeutic Role of Lymph Node Resection in Endometrioid Corpus Cancer:A Study of 12,333 Patients [J].Cancer,2006,107(8):1823-1830.
18.Bristow RE,Zahurak ML,Alexander CJ,et al.FIGO stage Ⅲc endometrial carcinoma:resection of macroscopic nodal disease and other determinants of survival[J].Int J Gynecol Cancer,2003,13:664-672.
19.Elliott P,Green D,Coates A,et al.The efficacy of postoperative vaginal irradiation in preventing vaginal recurrence in endometrial cancer[J].International Journal of Gynecological Cancer,1994,4(2):84-93.
20.Creasman WT,Odicino F,Maisonneuve P,et al.Carcinoma of the corpus uteri.FIGO 6th Annual Report on the Results of Treatment in Gynecological Cancer[J].Int J Gynaecol Obstet,2006,95(Suppl 1):S105-143.
21.吴鸣,沈铿,郎景和,等.子宫内膜癌206例临床分析[J].中华妇产科杂志,2002,37:620-621.
22.Steiner E,Eicher O,Sagemuller J,et al.Multivariate independent prognostic factors in endometrial carcinoma:A clinicpathologic study in 181 patients:10 years experience at the Department of Obstetrics and Gynecology of the Mainz University[J].Int J Cancer,2003,13:197-203.
23.Mariani A,Webb MJ,Keeney GL,et al.Surgical stage I endometrial cancer:Predictors of distant failure and death[J].Gynecol Oncol,2002,87:274-280.
24.任玉兰,王华英.绝经与子宫内膜癌预后的关系[J].实用癌症杂志,2006,1:59-62.
25.Nakanishi T,Ishikawa H,Suzuki Y,et al.Association between menopausal state and prognosis of endomet rial cancer[J].Int J Gynecol Cancer,2001,11:483.
1. Hsieh JC, Kodjabachian L, Rebbert ML, et al. A new secreted protein that binds to Wnt proteins and inhibits their activities [J]. Nature, 1999, 398: 431-436.
2. He BA, Reguart N, You L, et al. Blockade of Wnt-1 signaling induces apoptosis in human colorectal cancer cells containing downstream mutations [J]. Oncogene, 2005, 24 (18): 3054-3058.
3. Wissmann C, Wild PJ, Kaiser S, et al. WIF1, a component of the Wnt pathway, is down-regulated in prostate, breast, lung, and bladder cancer [J]. J Pathol, 2003, 201 (2) : 204-212.
4. Mazieres J, He B, You L, et al. Wnt inhibitory factor-1 is silenced by promoter hypermethylation in human lung cancer [J]. Cancer Res, 2004, 64 (14) : 4717-4720.
5. Taniguchi H, Yamamoto H, Hirata T, et al. Epigenetic inactivation of Wnt inhibitory factor-1 in human gastrointestinal cancers [J]. Oncogene, 2005, 24 (53) : 7946-7952.
6. Urakami S, Shiina H, Enokida H, et al. Epigenetic inactivation of Wnt inhibitory factor-1 plays an important role in bladder cancer through aberrant canonical Wnt /beta-catenin signaling pathway [J]. Clin Cancer Res, 2006, 12 (2): 383-391.
7. Lin YC, You L, Xu ZD, et al. Wnt signaling activation and WEF-1 silencing in nasopharyngeal cancer cell lines [J]. Biochem Biophys Res Commun, 2006, 341 (2) : 635-640.
8. Li J, Yen C, Liaw D, et al. PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer [J]. Science, 1997;275:1943-1947.
9. Steck PA, Pershouse MA, Jasser SA, et al. Identification of a candidate tumour suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers [J]. Nat Genet. 1997;15:356-362.
10. Tashiro H, Blazes MS, Wu R, et al. Mutations in PTEN are frequent in endometrial carcinoma but rare in other common gynecological malignancies [J]. Cancer Res, 1997, 57: 3935-3940.
11. Sharma M, Chuang WW, Sun Z. Phosphatidylinositol 3-Kinase/Akt Stimulates Androgen Pathway through GSK3_ Inhibition and Nuclear _-Catenin Accumulation[J]. J Biol Chem, 2002, 277(34): 30935-30941.
12. Ohigashi T., Mizuno R., Nakashima J., et al. Inhibition of Wnt Signaling Downregulates Akt Activity and Induces Chemosensitivity in PTEN-Mutated Prostate Cancer Cells [J]. Prostate,2005, 62: 61- 68.
13. Wu R, Hendrix-Lucas N, Kuick R, et al. Mouse Model of Human Ovarian Endometrioid Adenocarcinoma Based on Somatic Defects in the Wnt/b-Catenin and PI3K/Pten Signaling Pathways [J]. Cancer Cell, 2007,11: 321-333.
14. Tian Q, He XC, Hood L, Li LH, et al. Bridging the BMP and Wnt pathways by PI3 kinase/Akt and 14-3-3 zeta [J]. Cell Cycle, 2005,4 (2): 215-216.
15. Herman JG, Graff JR, Myohanen S, et al. Methylation-specific PCR: a novel PCR assay for methylation status of CpG islands [J]. Proc Natl Acad Sci U S A, 1996, 93: 9821-9826.
16. Moreno-Bueno G, Hardisson D, Sarrio D, et al.Abnormalities of E- and P-cadherin and catenin expression in endometrial cancer and endometrial atypical hyperplasia [J]. JPathol 2003; 199: 471-478.
17. Salvesen H B, MacDonald N, Ryan A, et al. Methylation of hMLH1 in a Population-based Series of Endometrial Carcinomas [J]. Clin Cancer Res,2000, 6: 3607-3613.
18. Yuan J R, Fu S B, Fu H, et al. Significance of Methylation and Abnormal Expression of p16 Gene in Endometrial Carcinoma [J]. Acta Genetica Sinica, 2004,31 (5): 454—459.
19. Saito T, Nishimura M, Yamasaki H, et al. Hypermethylation in promoter region of E-cadherin gene is associated with tumor dedifferention and myometrial invasion in endometrial carcinoma [J]. Cancer, 2003,97, 1002-1009.
20. Salvesen H.B.,MacDonald N,Ryan A, et al. PTEN methylation is associated with advanced stage and microsatellite instability in endometrial carcinoma [J]. Int. J. Cancer,2001: 91, 22-26.
21. Salvesen H.B., Stefansson I, Kretzschmar E.I.,et al. Significance of PTEN alterations in endometrial carcinoma: A population-based study of mutations, promoter methylation and PTEN protein expression [J]. Int J Oncol,2004,25: 1615-1623.
22. Nan X, Ng HH, Johnson CA, et al. Transcriptional repression by the methyl-CpG-binding protein MeCP2 involves a hi stone deacetylase complex [J]. Nature, 1998, 393: 386-389.
23. Kawano Y, Kypta R. Secreted antagonist s of the Wnt signalling pathway [J] . J Cell Sci ,2003,116 (13) :2627.
24.Chima C.S.,Funga T.K.,Wong K.F.,et al.Infrequent Wnt inhibitory factor-1(Wif-1) methylation in chronic lymphocytic leukemia[J].Leukemia Research,2006,30:1135-1139.
25.Preferential methylation of Wnt inhibitory factor-1 in acute promyelocytic leukemia:an independent poor prognostic factor[J].Leukemia,2006,20:907-909.
26.Lingbao Ai,Qian Tao1,Sheng Zhong,Inactivation of Wnt inhibitory factor-1(WIF1) expression by epigenetic silencing is a common event in breast cancer[J].Carcinogenesis,2006,27(7):1341-1348.
27.Lin,YC;You,L;Xu,ZD,et al.Wnt inhibitory factor-1 gene transfer inhibits melanoma cell growth[J].Human gene therapy.2007,18(4):379-386.
28.Mell LK,Meyer JJ,Tretiakova M,et al.Prognostic Significance of E-cadherin Protein Expression in Pathological Stage Ⅰ-Ⅲ Endometrial Cancer[J].Clin Cancer Res.2004,10,5546-5553.
29.Salvesen H.B.,Stefansson I,Kretzschmar E.I.,et al.Loss of PTEN expression is associated with metastatic disease in patients with endometrial carcinoma[J].Cancer,2002,94:2185-2191.
30.高庆蕾,李静,邢辉,等.PTEN基因在子宫内膜癌中的表达及其临床意义[J].中华医学杂志2003,83(2):142-143.
31.Athanassiadou P,Athanassiades P,Grapsa D,et al.The prognostic value of PTEN,p53,and beta-catenin in endometrial carcinoma:a prospective immunocytochemical study[J].Int J Gynecol Cancer.2007,17(3):697-704.
32.Moreno-Bueno G,Hardisson D,Sanchez C,et al.Abnormalities of APC/β-catenin pathway in endometrial cancer[J].Oncogene,2002,21:7981-7990.
1 Slomovitz BM,Burke TW,Eifel PJ,et al.Uterine papillary serous carcinoma (UPSC):a single institution review of 129 cases[J].Gynecol Oncol,2003,91:463-469.
2 Hendrickson M,Ross J,Eifel PJ,et al.Adenocarcinoma of the endometrium:analysis of 256 cases with carcinoma limited to the uterine corpus[J].Pathology review and analysis of prognostic variables.Gynecol Oncol,1982,13:373-392.
3 Chan JK,Loizzi V,Youssef M,et al.Significance of comprehensive surgical staging in noninvasive papillary serous carcinoma of the endometrium[J].Gynecol Oncol 2003;90:181-185.
4 Casalini P,Iorio MV,Galmozzi E,Menard S.Role of HER receptors family in development and differentiation[J].J Cell Physiol 2004;200:343-50.
5 Slamon DJ,Godolphin W,Jones LA,et al.Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer[J].Science,1989;244:707-12.
6 Slamon DJ,Clark GM,Wong SG,et al.Human breast cancer:correlation of relapse and survival with amplification of Her-2/neu oncogene[J].Science 1987;235:177-82.
7 Santin AD,Bellone S,Gokden M,et al.Overexpression of HER-2/neu in uterine serous papillary cancer[J].Clin Cancer Res 2002;8:1271- 9.
8 Santin AD.,Bellone S,Stedum S V,et al.Determination of HER2/neu status in uterine serous papillary carcinoma:Comparative analysis of immunohistochemistry and fluorescence in situ hybridization[J].Gynecol Oncol 2005;98:24-30
9 Slomovitz BM,Broaddus RR,Burke TW,Sneige N,Soliman PT,Wu W,et al.Her-2/neu overexpression and amplification in uterine papillary serous carcinoma[J].J Clin Oncol 2004;22:3126- 32.
10 Diaz-Montes T.P.,Ji H,Sehdev AE.S.et al.Clinical significance of Her-2/neu overexpression in uterine serous carcinoma[J].Gynecol Oncol 2006;100:139-44.
11 Mikuta JJ.International Federation of Gynecology and Obstetrics staging of endometrial cancer 1988[J].Cancer,1993,71:1460-1463.
12 李斌,吴令英,李淑敏,等.子宫内膜癌的预后影响因素分析[J].癌症,2004,23:1085-1088.
13 任玉兰,王华英,沈磊,等.子宫内膜浆液性乳头状癌33例临床分析[J].中 华妇产科杂志,2006,12:817-821.
14 吴鸣,郎景和,郭丽娜.子宫内膜癌的特殊类型——子宫乳头状浆液性癌[J].中华妇产科杂志,1996:3-7.
15 Chan JK,Loizzi V,Youssef M,et al.Significance of comprehensive surgical staging in noninvasive papillary serous carcinoma of the endometrium[J].Gynecol Oncol,2003,90:181-185.
16 Gehrig PA,Groben PA,Fowler WC Jr,et al.Noninvasive papillary serous carcinoma of the endometrium[J].Obstet Gynecol,2001,97:153-157.
17 Price FV,Chambers SK,Carcangiu ML,et al.Intravenous cisplatin,doxorubicin,and cyclophosphamide in the treatment of uterine papillary serous carcinoma (UPSC)[J].Gynecol Oncol,1993,51:383-389.
18 Zanotti KM,Belinson JL,Kennedy AW,et al.The use of paclitaxel and platinum-based chemotherapy in uterine papillary serous carcinoma[J].Gynel Oncol,1999,74(2):272-277.
19 Martin JD,Gilks B,Lim P.Papillary serous carcinoma:a less radio-sensitive subtype of endometfial cancer[J].Gynecol Oncol,2005,98:299-303.
20 Santin AD,Siegel ER,Cane' S,Bellone S,Palmieri M,Thomas M,et al.Racial differences in overexpression of epidermal growth factor type Ⅱ receptor (HER2/neu):a major prognostic indicator in uterine serous papillary cancer[J].Am J Obstet Gynecol 2005;192:813-8.
21 Hanna WM;Kwok K.Chromogenic in-situ hybridization:a viable alternative to fluorescence in-situ hybridization in the HER2 testing algorithm[J].Modern Pathology 2006;19:481-487.
22 Di Palma S,Collins N,Faulkes C,et al.Chromogenic in-situ hybridisation(CISH)should be an accepted method in the routine diagnostic evaluation of HER2 status in breast cancer[J].J Clin Pathol.2007;9:1067-8.
23 Saez A,Andreu FJ,Segui MA,et al.HER-2 gene amplification by chromogenic in situ hybridisation(CISH) compared with fluorescence in situ hybridisation (FISH) in breast cancer-A study of two hundred cases[J].Breast.2006;15:519-27.
24 Li-Ning-T E,Ronchetti R,Tortes-Cabala C,et al.Role of chromogenic in situ hybridization(CISH) in the evaluation of HER2 status in breast carcinoma:comparison with immunohistochemistry and FISH[J].Int J Surg Pathol.2005;13:343-51.
25 Todorovic-Rakovic N,Jovanovic D,Neskovic-Konstantinovic Z,et al. Comparison between immunohistochemistry and chromogenic in situ hybridization in assessing HER-2 status in breast cancer[J]. Pathol Int. 2005;55:318-23.
26 Madrid MA, Lo RW. Chromogenic in situ hybridization (CISH): a novel alternative in screening archival breast cancer tissue samples for HER-2/neu status[J]. Breast Cancer Res. 2004;6:R593-600.
27 Park DI, Yun JW, Park JH, et al. HER-2/neu amplification is an independent prognostic factor in gastric cancer[J]. Dig Dis Sci. 2006;51:1371-9.
28 Tanner M, Hollmen M, Junttila TT, et al. Amplification of HER-2 in gastric carcinoma: association with Topoisomerase Ilalpha gene amplification, intestinal type, poor prognosis and sensitivity to trastuzumab[J]. Ann Oncol. 2005;16:273-8.
29 Shia J, Klimstra D S, Li A R, et al. Epidermal growth factor receptor expression and gene amplification in colorectal carcinoma: an immunohistochemical and chromogenic in situ hybridization study[J]. Modern Pathology 2005; 18: 1350-1356.
1.Wu Ct,Morris JR.Genes,genetics,and epigenetics:a correspondence[J].Science,2001,293:1103-1105.
2.Esteller M.DNAmethylation and cancer therapy:newdevelopments and expectations[J].Curr Oncol,2005,17(1):55-60.
3.Dahl C,Guldberg P.DNA methylation analysis techniques[J].Biogerontology,2003,4:233-250.
4.Das PM,Singal R.DNA methylation and cancer[J].J Clin Oncol,2004,22:4632-4642.
5.Hsieh JC,Kodjabachian L,Rebbert ML,et al.A new secreted protein that binds to Wnt proteins and inhibits their activities[J].Nature,1999,398:431-436.
6.He BA,Reguart N,You L,et al.Blockade of Wnt-1 signaling induces apoptosis in human colorectal cancer cells containing downstream mutations[J].Oncogene,2005,24(18):3054-3058.
7.Wissmann C,Wild PJ,Kaiser S,et al.W IF1,a component of the Wnt pathway,is down-regulated in prostate,breast,lung,and bladder cancer[J].J Pathol,2003,201(2):204-212.
8.Mazieres J,He B,You L,et al.Wnt inhibitory factor-1 is silenced by promoter hypermethylation in human lung cancer[J].Cancer Res,2004,64(14):4717-4720.
9.Taniguchi H,Yamamoto H,Hirata T,et al.Epigenetic inactivation of Wnt inhibitory factor-1 in human gastrointestinal cancers[J].Oncogene,2005,24(53):7946-7952.
10.Urakami S,Shiina H,Enokida H,et al.Epigenetic inactivation of Wnt inhibitory factor-1 plays an important role in bladder cancer through aberrant canonical Wnt /beta-catenin signaling pathway[J].Clin Cancer Res,2006,12(2):383-391.
11.Lin YC,You L,Xu ZD,et al.Wnt signaling activation and WIF-1 silencing in nasopharyngeal cancer cell lines[J].Biochem Biophys Res Commun,2006,341(2):635-640.
12.Moreno-Bueno G,Hardisson D,Sanchez C,et al.Abnormalities of APC/β-catenin pathway in endometrial cancer.Oncogene,2002,21:7981-7990.
13.Moreno-Bueno G;Hardisson D,Sarrio D,et al.Abnormalities of E- and P-cadherin and catenin expression in endometrial cancer and endometrial atypical hyperplasia.J Pathol 2003;199:471-478.
14.Mell LK,Meyer JJ,Tretiakova M,et al.Prognostic Significance of E-cadherin Protein Expression in Pathological Stage Ⅰ-Ⅲ Endometrial Cancer.Clin Cancer Res.2004,10,5546-5553.
15.Saito T,Nishimura M,Yamasaki H,et al.Hypermethylation in promoter region of E-cadherin gene is associated with tumor dedifferention and myometrial invasion in endometrial carcinoma.Cancer,2003,97,1002-1009.
16.Salvesen H.B.,Stefansson I,Kretzschmar E.I.,et al.Significance of PTEN alterations in endometrial carcinoma:A population-based study of mutations,promoter methylation and PTEN protein expression[J].Int J Oncol,2004,25:1615-1623.
17.Kovalenko TF,Vaniusheva OV,Shilov IA,et al.Promoters of genes MTHFR from patients with hyperhomocysteinemia and PTEN from patients with malignant and benign endometrial and ovarian tumors[J].Bioorg Khim,2006,32(4):414-423.
18.Semczuk A,Boltze C,Marzec B,et al.p16INK4A alterations are accompanied by aberrant protein immunostaining in endometrial carcinomas[J].J Cancer Res Clin Oncol,2003,129(10):589-596.
19.Pijnenborg J,Dam-de Veen G,Kisters N,et al.RASSF1Amethylation and K-ras and B-raf mutations and recurrent endometrial cancer[J].Ann Oncol,2007,18(3):491-497.
20.Abal M,Planaguma J,Gil-Moreno A,et al.Molecular pathology of endometrial carcinoma:transcriptional signature in endometrioid tumors[J].Histol Histopathol,2006,21(2):197-204.
21.MacDonald ND,Salvesen HB,Ryan A,et al.Frequency and prognostic impact of microsatellite instability in a large population-based study of endometrial carcinomas[J].Cancer Res,2000,60:1750-2.
22.Helmle KE,OttoCJ,Constantinescu G;et al.Variable MLH1 promoter methylation patterns in endometrial carcinomas of endometrioid subtype lacking DNA mismatch repair[J].Gynecol Cancer,2005,15(6):1089- 1096.
23.Xiong Y,Dowdy SC,Eberhardt NL,et al.hMLH1 promoter methylation and silencing in primary endometrial cancers are associated with specific alterations in MBDs occupancy and histone modifications[J].Gynecol Oncol,2006,103(1):321-328.
24.Brueckner B,Lyko F.DNA methyltransferase inhibitors:old and new drugs for an epigenetic cancer therapy[J].Trends Pharmacol Sci,2004,25(11):551-554.
25.Issa JP,Garcia-Manero G,Giles FJ.Phase I study of low-dose prolonged exposure schedules of the hypomethylating agent 5-aza-2'-deoxycytidine (decitabine) in hematopoietic malignancies[J].Blood,2004,103(5):1635-1640.
26.Yanokura M,Banno K,Kawaguchi M,et al.Relationship of aberrant DNA hypermethylation of CHFR with sensitivity to taxanes in endometrial cancer[J].Oncol Rep,2007,17(1):41-48.
27.Campan M,Weisenberger DJ,Laird PW,et al.DNA methylation profiles of female steroid hormone-driven human malignancies[J].Curr Top Microbiol Immunol,2006,310:141-178.
1.Hendrickson M,Ross J,Eifel P,et al.Uterinepapillary serous carcinoma:a highly malignant form of endometrialadenocarcinoma[J].Am J Surg Pathol,1982,6(2):93-108.
2.Zehavi S,Schneider D,Bukovsky I,et al.Pathological findings in early-stage endometrial cancer[J].Eur J Gyneacol Oncol,2003,24(1):18-20.
3.Slomovitz BM,Burke TW,Eifel PJ,et al.A single institution review of 129cases[J].Gynecol Oncol,2003,91(3):463-9.
4.Memarzadeh S,Holschneider CH,Bristow RE,et al.FIGO stage Ⅲ and Ⅳuterine papillary serous carcinoma:Impact of residual disease on survival[J].Int J Gynecol Cancer,2002,12(5):454-458.
5.Geisler JP,Sorosky JI,Duong HL,et al.Papillary serous carcinoma of the uterus:Increased risk of subsequent or concurrent development of breast carcinoma[J].Gynecol Oncol,2001,83(3):501-503.
6.Goshen R,Chu W,Elit L,et al.Is uterine papillary serous adenocarcinoma a manifestation of the hereditary breast-ovarian cancer syndrome?[J]Gynecol Oncol,2000,79(3):477-481.
7.Behtash N,Tehranian A,Ardalan FA,et al.Uterine papillary serous carcinoma after pelvic radiation therapy for cancer of the cervix[J].J Obstet Gynaecol,2002,22(1):96-7.
8.Abramovich D,Markman M,Kennedy A,et al.Serum CA-125 as a marker of disease activity in uterine papillary serous carcinoma[J].J Cancer Res Clin Oncol,1999,125(12):697-698.
9.King SA,Adas AA,Livolsi VA,et al.Expression and mutation of the p53 gene in uterine papillary serous carcinoma[J].Cancer,1995,75(11):2700-2705.
10.Kovalev S,Marchenko ND,Gugliotta BG,et al.Loss of p53 funtion in uterine papillary serous carcinoma[J].Human Pathol,1998,29(6):613-619.
11.Sherman ME,Bur ME,Kurman RJ.P53 in endometrial cancer and its putative precursors-evidence for diverse pathways of tumorigenesis[J].Hum Pathol,1995,26(11):1268-1274.
12.Hornreich G,Beller U,Lavie O,et al.Is uterine serous papillary carcinoma a BRCA1-related disease? Case report and review of the literature[J].Gynecol Oncol,1999,75(2):300-304.
13.Lavie O,Hornreich G,Arie AB,et al.BRCA1 germline mutations in women with uterine serous papillary carcinoma[J].Obstet Gynecol,2000,96(1):28-32.
14.Lavie O,Hornreich G,Arie AB,et al.BRCA germline mutations in Jewish women with uterine serous papillary carcinoma[J].Gynecol Oncol,2004,92(13):521-524.
15.葛霞,谢群,姚敏.子宫乳头状浆液性癌组织中雌激素受体和CerB2的表达及意义[J].中华妇产科杂志,1999,34(3):186.
16.Sood BM,Jones J,Gupta S,et al.Patterns of failure after multidality treatment of uterine papillary serous carcinoma[J].Int J Radiat Oncol Biol Phys,2003,57(1):208-216.
17.Ambros RA,Sherman ME,Zahn CM,et al.Endometrial intraepithelial carcinoma:a distinctive lesion specifically associated with tumor displaying serous differentiation[J].Hum Pahthol,1995,26(11):1260-1267.
18.Bristow RE,Asrari F,Trimble EL,et al.Extended surgical staging for uterine papillary serous carcinoma:Survival outcome of locoregional(Stage Ⅰ-Ⅲ)disease[J].Gynecol Oncol,2001,81(2):279-286.
19.Bristow RE,Duska LR,Montz FJ,et al.The role of cytoreductive surgery in the management of Stage Ⅳ uterine papillary serous carcinoma[J].Gynecol Oncol,2001,81(1):92-99.
20.Gehrig PA,Groben PA,Fowler WC,et al.Noninvasive papillary serous carcinoma of the endometrium[J].Obstet Gynecol,2001,97(1):153-157.
21.Chan JK,Loizzi V,Youssef M,et al.Significance of comprehensive surgical staging in noninvasive papillary serous carcinoma of the endometrium[J].Gynecol Oncol,2003,90(1):181-185.
22.Grice J,Merit EK,Greer B,et al.Uterine papillary serous carcinoma:evaluation of long-term survival in surgically-staged patients[J].Gynecol Oncol,1998,69(1):69-73.
23.Turner BC,Knisely JPS,Kacinski BM,et al.Effective treatment of Stage Ⅰ uterine papillary serous carcinoma with high dose-rate vaginal apex radiation (~(192) Ir) and chemotherapy[J].Int J Radiat Oncol Biol Phys,1998,40(1):77-84.
24.Mehta N,Yamada SD,Rotmensch J,et al.Outcome and pattern of failure in pathologic Stage Ⅰ-Ⅱ papillary serous carcinoma of the endometrium:Implications for adjuvant radiation therapy[J].Int J Radiat Oncol Biol Phys,2003,57(4):1004-1009.
25.Price FV,Chambers SK,Carcangiu ML,et al.Intravenous cisplatin,doxornbinsin,and cyclophosphamide in the treatment of uterine papillary serous papillary (UPSC)[J].Gynecol Oncol,1993,51(3):383-389
26.Zanotti KM,Belinson JL,Kennedy AW,et al.The use of paclitaxel and platinum-based chemotherapy in uterine papillary serous carcinoma[J].Gynel Oncol,1999,74(2):272-277.
27.Ramondetta L,Burke TW,Levenback CH,et al.Treatment of uterine papillary serous carcinoma with paclitaxel.[J].Gynecol Oncol,2001,82(1):156-161.
28.Chambers JT,Rutherford TJ,Schwartz PE,et al.A pilot study of topotecan in the treatment of serous carcinoma of the uterus[J],Int J Gynel Cancer,2003,13(2):216-222.
29.Goff BA,Kato D,Schmidt RA,et al.Uterine papillary serous carcinoma:patterns of metastatic spread[J].Gynecol Oncol,1994,54(3):264-268.
2.Jemal A,Siegel R,Ward E,et al.Cancer Statistics[J].CA Cancer J Clin,2007;57:43-66.
3.Bockman JV.Two pathogenetic types of endometrial carcinoma[J].Gynecol Oncol,1983,15:10-7.
4.Liu FS.Molecular carcinogenesis of endometrial cancer[J].Taiwan J Obstet Gynecol,2007,46:26-32.
5.Amant F,Moerman P,Neven P,et al.Endometrial cancer[J].Lancet,2005;366:491-505.
6.Berchuck A,Boyd J.Molecular basis of endometrial cancer[J].Cancer,1995,76:2034-40.
7.Niederacher D,An HX,Cho YJ,et al.Mutations and amplification of oncogenes in endometrial cancer[J].Ontology,1999,56:59-65.
8.Risinger JI,Hayes AK,Berchuck A,et al.PTEN/MMAC1 mutations in endometrial cancers[J].Cancer Res,1997,57:4736-8.
9.Salvesen HB,MacDonald N,Ryan A,Jacobs IJ,Lynch ED,Akslen LA,Das S.PTEN methylation is associated with advanced stage and microsatellite instability in endometrial cancer[J].Int J Cancer 2001;91:22-26.
10.MacDonald ND,Salvesen HB,Ryan A,et al.Frequency and prognostic impact of microsatellite instability in a large population-based study of endometdal carcinomas[J].Cancer Res,2000,60:1750-2.
11.Busmanis I,Ho TH,Tan SB,et al.p53 and bcl-2 expression in invasive and pre-invasive uterine papillary serous carcinoma and atrophic endometrium[J].Ann Acad Med Singapore,2005,34:421-5.
12.King SA,Adas AA,Livolsi VA,et al.Expression and mutation of the p53 gene in uterine papillary serous carcinoma[J].Cancer,1995,75(11):2700-2705.
13.Kovalev S,Marchenko ND,Gugliotta BG,et al.Loss of p53 funtion in uterine papillary serous carcinoma[J].Human Pathol,1998,29(6):613-619.
14.Sherman ME,Bur ME,Kurman RJ.P53 in endometrial cancer and its putative precursors-evidence for diverse pathways of tumorigenesis[J].Hum Pathol,1995,26(11):1268-1274.
15.Lengauer C,Kinzler KW,Vogelstein B.Genetic instability in colorectal cancers[J].Nature,1997;386:623-627.
16. Staebler A, Lax SF, Ellenson LH. Altered expression of hMLH1 and hMSH2 protein in endometrial carcinomas with MSI [J]. Hum Pathol 2000;31:354-358.
17. Esteller M, Levine R, Baylin SB, Ellenson LH, Herman JG MLH1 promoter hypermethylation is associated with the microsatellite instability phenotype in sporadic endometrial carcinomas [J]. Oncogene 1998;17:2413-2417.
18. Salvesen HB, MacDonald N, Ryan A, Jacobs IJ, Akslen LA, et al. Methylation of hMLHl in a population-based series of endometrial carcinomas[J]. Clin Cancer Res 2000;6:3607-3613.
19. Sasaki M, Dharia A, Oh BR, Tanaka Y, Fujimoto S, Dahiya R. Progesterone receptor B gene inactivation and CpG hypermethylation in human uterine endometrial cancer[J]. Cancer Res 2001;61:97-102.
20. Salvesen HB, Das S,Akslen LA. Loss of nuclear pl6 protein expression is not associated with μpromoter methylation but defines a subgroup of aggressive endometrial carcinomas with poor prognosis [J]. Clin Cancer Res 2000;6:153-159.
21. Hsieh JC, Kodjabachian L, Rebbert ML, et al. A new secreted protein that binds to Wnt proteins and inhibits their activities [J]. Nature, 1999, 398: 431-436.
22. He BA, Reguart N, You L, et al. Blockade of Wnt-1 signaling induces apoptosis in human colorectal cancer cells containing downstream mutations [J]. Oncogene, 2005, 24 ( 18 ) : 3054-3058.
23. Wissmann C, Wild PJ, Kaiser S, et al. WIF1, a component of the Wnt pathway, is down-regulated in prostate, breast, lung, and bladder cancer [J]. J Pathol, 2003, 201 (2) : 204-212.
24. Mazieres J, He B, You L, et al. Wnt inhibitory factor-1 is silenced by promoter hypermethylation in human lung cancer [J]. Cancer Res, 2004, 64 (14): 4717-4720.
25. Taniguchi H, Yamamoto H, Hirata T, et al. Epigenetic inactivation of Wnt inhibitory factor-1 in human gastrointestinal cancers[J]. Oncogene, 2005, 24 (53) : 7946-7952.
26. Urakami S, Shiina H, Enokida H, et al. Epigenetic inactivation of Wnt inhibitory factor-1 plays an important role in bladder cancer through aberrant canonical Wnt /beta-catenin signaling pathway [J]. Clin Cancer Res, 2006, 12 (2): 383-391.
27. Price FV, Chambers SK, Carcangiu ML, et al. Intravenous cisplatin, doxorubicin, and cyclophosphamide in the treatment of uterine papillary serous carcinoma (UPSC) [J]. Gynecol Oncol, 1993,51:383-389.
1.Bokhman JV.Two pathogenetic types of endometrial carcinoma[J].Gynecol Oncol,1983,15:10-17.
2.ShermanME,BurMa,Kurman RJ.p53 in endometrial cancer and its putative precursors:evidence for diverse pathways of tumorigenesis[J].Hum Pathol,1995,26:1268-1274.
3.Liu FS.Molecular carcinogenesis of endometrial cancer[J].Taiwan J Obstet Gynecol,2007,46:26-32.
4.Mikuta JJ.International Federation of Gynecology and Obstetrics staging of endometrial cancer 1988[J].Cancer,1993,71:1460-1463.
5.Silverberg SG,Kurman RJ,Nogales F,et al.Tumors of the uterine corpus[M]//Tavassoli FA,Devilee P,editors.Pathology and genetics of tumours of the breast and female genital organs.World Health Organization classification of tumours,Lyon,France:IARC Press,2003:217-232.
6.Cancer statistics 2007.http://www.cancer.org.
7.Jemal A,Siegel R,Ward E,et al.Cancer Statistics,2007[J].CA Cancer J Clin,2007;57:43-66.
8.张薇、项永兵等.1973-1999年上海市区老年人恶性肿瘤发病趋势分析[J].中华老年医学杂志,2005,24(9):701-704.
9.杨丹,韩立敏.1969-2003年子宫内膜癌发病率及发病因素分析[J].Fudan Univ J Med Sci,2005,32(4):479-480.
10.Liu FS.Molecular carcinogenesis of endometrial cancer[J].Taiwan J Obstet Gynecol,2007,46:26-32.
11.Amant F,Moerman P,Neven P,et al.Endometrial cancer[J].Lancet,2005;366:491-505.
12.任玉兰,王华英,沈磊,等.子宫内膜浆液性乳头状癌33例临床分析[J].中华妇产科杂志,2006,41(12):817-821.
13.李斌,吴令英,李淑敏,等.子宫内膜癌的预后影响因素分析[J].癌症,2004,23:1085-1088.
14.Calle EE,Rodriguez C,Walker-Thurmond K,Thun MJ.Overweight,obesity,and mortality from cancer in a prospectively studied cohort of U.S.adults[J].N Engl J Med,2003;348:1625-38.
15.张志毅,章文华,主编.现代妇科肿瘤外科学.第1版[M].北京:科学出版社, 2003:136-137.
16.Yasunaga M,Yamasaki F,Tokunaga O,et al.Endometrial carcinomas with lymph node involvement:novel histopathologic factors for predicting prognosis[J].Int J Gynecol Pathol,2003,22(4):341-346.
17.Chan JK,Cheung MK,Huh WK,et al.Therapeutic Role of Lymph Node Resection in Endometrioid Corpus Cancer:A Study of 12,333 Patients [J].Cancer,2006,107(8):1823-1830.
18.Bristow RE,Zahurak ML,Alexander CJ,et al.FIGO stage Ⅲc endometrial carcinoma:resection of macroscopic nodal disease and other determinants of survival[J].Int J Gynecol Cancer,2003,13:664-672.
19.Elliott P,Green D,Coates A,et al.The efficacy of postoperative vaginal irradiation in preventing vaginal recurrence in endometrial cancer[J].International Journal of Gynecological Cancer,1994,4(2):84-93.
20.Creasman WT,Odicino F,Maisonneuve P,et al.Carcinoma of the corpus uteri.FIGO 6th Annual Report on the Results of Treatment in Gynecological Cancer[J].Int J Gynaecol Obstet,2006,95(Suppl 1):S105-143.
21.吴鸣,沈铿,郎景和,等.子宫内膜癌206例临床分析[J].中华妇产科杂志,2002,37:620-621.
22.Steiner E,Eicher O,Sagemuller J,et al.Multivariate independent prognostic factors in endometrial carcinoma:A clinicpathologic study in 181 patients:10 years experience at the Department of Obstetrics and Gynecology of the Mainz University[J].Int J Cancer,2003,13:197-203.
23.Mariani A,Webb MJ,Keeney GL,et al.Surgical stage I endometrial cancer:Predictors of distant failure and death[J].Gynecol Oncol,2002,87:274-280.
24.任玉兰,王华英.绝经与子宫内膜癌预后的关系[J].实用癌症杂志,2006,1:59-62.
25.Nakanishi T,Ishikawa H,Suzuki Y,et al.Association between menopausal state and prognosis of endomet rial cancer[J].Int J Gynecol Cancer,2001,11:483.
1. Hsieh JC, Kodjabachian L, Rebbert ML, et al. A new secreted protein that binds to Wnt proteins and inhibits their activities [J]. Nature, 1999, 398: 431-436.
2. He BA, Reguart N, You L, et al. Blockade of Wnt-1 signaling induces apoptosis in human colorectal cancer cells containing downstream mutations [J]. Oncogene, 2005, 24 (18): 3054-3058.
3. Wissmann C, Wild PJ, Kaiser S, et al. WIF1, a component of the Wnt pathway, is down-regulated in prostate, breast, lung, and bladder cancer [J]. J Pathol, 2003, 201 (2) : 204-212.
4. Mazieres J, He B, You L, et al. Wnt inhibitory factor-1 is silenced by promoter hypermethylation in human lung cancer [J]. Cancer Res, 2004, 64 (14) : 4717-4720.
5. Taniguchi H, Yamamoto H, Hirata T, et al. Epigenetic inactivation of Wnt inhibitory factor-1 in human gastrointestinal cancers [J]. Oncogene, 2005, 24 (53) : 7946-7952.
6. Urakami S, Shiina H, Enokida H, et al. Epigenetic inactivation of Wnt inhibitory factor-1 plays an important role in bladder cancer through aberrant canonical Wnt /beta-catenin signaling pathway [J]. Clin Cancer Res, 2006, 12 (2): 383-391.
7. Lin YC, You L, Xu ZD, et al. Wnt signaling activation and WEF-1 silencing in nasopharyngeal cancer cell lines [J]. Biochem Biophys Res Commun, 2006, 341 (2) : 635-640.
8. Li J, Yen C, Liaw D, et al. PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer [J]. Science, 1997;275:1943-1947.
9. Steck PA, Pershouse MA, Jasser SA, et al. Identification of a candidate tumour suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers [J]. Nat Genet. 1997;15:356-362.
10. Tashiro H, Blazes MS, Wu R, et al. Mutations in PTEN are frequent in endometrial carcinoma but rare in other common gynecological malignancies [J]. Cancer Res, 1997, 57: 3935-3940.
11. Sharma M, Chuang WW, Sun Z. Phosphatidylinositol 3-Kinase/Akt Stimulates Androgen Pathway through GSK3_ Inhibition and Nuclear _-Catenin Accumulation[J]. J Biol Chem, 2002, 277(34): 30935-30941.
12. Ohigashi T., Mizuno R., Nakashima J., et al. Inhibition of Wnt Signaling Downregulates Akt Activity and Induces Chemosensitivity in PTEN-Mutated Prostate Cancer Cells [J]. Prostate,2005, 62: 61- 68.
13. Wu R, Hendrix-Lucas N, Kuick R, et al. Mouse Model of Human Ovarian Endometrioid Adenocarcinoma Based on Somatic Defects in the Wnt/b-Catenin and PI3K/Pten Signaling Pathways [J]. Cancer Cell, 2007,11: 321-333.
14. Tian Q, He XC, Hood L, Li LH, et al. Bridging the BMP and Wnt pathways by PI3 kinase/Akt and 14-3-3 zeta [J]. Cell Cycle, 2005,4 (2): 215-216.
15. Herman JG, Graff JR, Myohanen S, et al. Methylation-specific PCR: a novel PCR assay for methylation status of CpG islands [J]. Proc Natl Acad Sci U S A, 1996, 93: 9821-9826.
16. Moreno-Bueno G, Hardisson D, Sarrio D, et al.Abnormalities of E- and P-cadherin and catenin expression in endometrial cancer and endometrial atypical hyperplasia [J]. JPathol 2003; 199: 471-478.
17. Salvesen H B, MacDonald N, Ryan A, et al. Methylation of hMLH1 in a Population-based Series of Endometrial Carcinomas [J]. Clin Cancer Res,2000, 6: 3607-3613.
18. Yuan J R, Fu S B, Fu H, et al. Significance of Methylation and Abnormal Expression of p16 Gene in Endometrial Carcinoma [J]. Acta Genetica Sinica, 2004,31 (5): 454—459.
19. Saito T, Nishimura M, Yamasaki H, et al. Hypermethylation in promoter region of E-cadherin gene is associated with tumor dedifferention and myometrial invasion in endometrial carcinoma [J]. Cancer, 2003,97, 1002-1009.
20. Salvesen H.B.,MacDonald N,Ryan A, et al. PTEN methylation is associated with advanced stage and microsatellite instability in endometrial carcinoma [J]. Int. J. Cancer,2001: 91, 22-26.
21. Salvesen H.B., Stefansson I, Kretzschmar E.I.,et al. Significance of PTEN alterations in endometrial carcinoma: A population-based study of mutations, promoter methylation and PTEN protein expression [J]. Int J Oncol,2004,25: 1615-1623.
22. Nan X, Ng HH, Johnson CA, et al. Transcriptional repression by the methyl-CpG-binding protein MeCP2 involves a hi stone deacetylase complex [J]. Nature, 1998, 393: 386-389.
23. Kawano Y, Kypta R. Secreted antagonist s of the Wnt signalling pathway [J] . J Cell Sci ,2003,116 (13) :2627.
24.Chima C.S.,Funga T.K.,Wong K.F.,et al.Infrequent Wnt inhibitory factor-1(Wif-1) methylation in chronic lymphocytic leukemia[J].Leukemia Research,2006,30:1135-1139.
25.Preferential methylation of Wnt inhibitory factor-1 in acute promyelocytic leukemia:an independent poor prognostic factor[J].Leukemia,2006,20:907-909.
26.Lingbao Ai,Qian Tao1,Sheng Zhong,Inactivation of Wnt inhibitory factor-1(WIF1) expression by epigenetic silencing is a common event in breast cancer[J].Carcinogenesis,2006,27(7):1341-1348.
27.Lin,YC;You,L;Xu,ZD,et al.Wnt inhibitory factor-1 gene transfer inhibits melanoma cell growth[J].Human gene therapy.2007,18(4):379-386.
28.Mell LK,Meyer JJ,Tretiakova M,et al.Prognostic Significance of E-cadherin Protein Expression in Pathological Stage Ⅰ-Ⅲ Endometrial Cancer[J].Clin Cancer Res.2004,10,5546-5553.
29.Salvesen H.B.,Stefansson I,Kretzschmar E.I.,et al.Loss of PTEN expression is associated with metastatic disease in patients with endometrial carcinoma[J].Cancer,2002,94:2185-2191.
30.高庆蕾,李静,邢辉,等.PTEN基因在子宫内膜癌中的表达及其临床意义[J].中华医学杂志2003,83(2):142-143.
31.Athanassiadou P,Athanassiades P,Grapsa D,et al.The prognostic value of PTEN,p53,and beta-catenin in endometrial carcinoma:a prospective immunocytochemical study[J].Int J Gynecol Cancer.2007,17(3):697-704.
32.Moreno-Bueno G,Hardisson D,Sanchez C,et al.Abnormalities of APC/β-catenin pathway in endometrial cancer[J].Oncogene,2002,21:7981-7990.
1 Slomovitz BM,Burke TW,Eifel PJ,et al.Uterine papillary serous carcinoma (UPSC):a single institution review of 129 cases[J].Gynecol Oncol,2003,91:463-469.
2 Hendrickson M,Ross J,Eifel PJ,et al.Adenocarcinoma of the endometrium:analysis of 256 cases with carcinoma limited to the uterine corpus[J].Pathology review and analysis of prognostic variables.Gynecol Oncol,1982,13:373-392.
3 Chan JK,Loizzi V,Youssef M,et al.Significance of comprehensive surgical staging in noninvasive papillary serous carcinoma of the endometrium[J].Gynecol Oncol 2003;90:181-185.
4 Casalini P,Iorio MV,Galmozzi E,Menard S.Role of HER receptors family in development and differentiation[J].J Cell Physiol 2004;200:343-50.
5 Slamon DJ,Godolphin W,Jones LA,et al.Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer[J].Science,1989;244:707-12.
6 Slamon DJ,Clark GM,Wong SG,et al.Human breast cancer:correlation of relapse and survival with amplification of Her-2/neu oncogene[J].Science 1987;235:177-82.
7 Santin AD,Bellone S,Gokden M,et al.Overexpression of HER-2/neu in uterine serous papillary cancer[J].Clin Cancer Res 2002;8:1271- 9.
8 Santin AD.,Bellone S,Stedum S V,et al.Determination of HER2/neu status in uterine serous papillary carcinoma:Comparative analysis of immunohistochemistry and fluorescence in situ hybridization[J].Gynecol Oncol 2005;98:24-30
9 Slomovitz BM,Broaddus RR,Burke TW,Sneige N,Soliman PT,Wu W,et al.Her-2/neu overexpression and amplification in uterine papillary serous carcinoma[J].J Clin Oncol 2004;22:3126- 32.
10 Diaz-Montes T.P.,Ji H,Sehdev AE.S.et al.Clinical significance of Her-2/neu overexpression in uterine serous carcinoma[J].Gynecol Oncol 2006;100:139-44.
11 Mikuta JJ.International Federation of Gynecology and Obstetrics staging of endometrial cancer 1988[J].Cancer,1993,71:1460-1463.
12 李斌,吴令英,李淑敏,等.子宫内膜癌的预后影响因素分析[J].癌症,2004,23:1085-1088.
13 任玉兰,王华英,沈磊,等.子宫内膜浆液性乳头状癌33例临床分析[J].中 华妇产科杂志,2006,12:817-821.
14 吴鸣,郎景和,郭丽娜.子宫内膜癌的特殊类型——子宫乳头状浆液性癌[J].中华妇产科杂志,1996:3-7.
15 Chan JK,Loizzi V,Youssef M,et al.Significance of comprehensive surgical staging in noninvasive papillary serous carcinoma of the endometrium[J].Gynecol Oncol,2003,90:181-185.
16 Gehrig PA,Groben PA,Fowler WC Jr,et al.Noninvasive papillary serous carcinoma of the endometrium[J].Obstet Gynecol,2001,97:153-157.
17 Price FV,Chambers SK,Carcangiu ML,et al.Intravenous cisplatin,doxorubicin,and cyclophosphamide in the treatment of uterine papillary serous carcinoma (UPSC)[J].Gynecol Oncol,1993,51:383-389.
18 Zanotti KM,Belinson JL,Kennedy AW,et al.The use of paclitaxel and platinum-based chemotherapy in uterine papillary serous carcinoma[J].Gynel Oncol,1999,74(2):272-277.
19 Martin JD,Gilks B,Lim P.Papillary serous carcinoma:a less radio-sensitive subtype of endometfial cancer[J].Gynecol Oncol,2005,98:299-303.
20 Santin AD,Siegel ER,Cane' S,Bellone S,Palmieri M,Thomas M,et al.Racial differences in overexpression of epidermal growth factor type Ⅱ receptor (HER2/neu):a major prognostic indicator in uterine serous papillary cancer[J].Am J Obstet Gynecol 2005;192:813-8.
21 Hanna WM;Kwok K.Chromogenic in-situ hybridization:a viable alternative to fluorescence in-situ hybridization in the HER2 testing algorithm[J].Modern Pathology 2006;19:481-487.
22 Di Palma S,Collins N,Faulkes C,et al.Chromogenic in-situ hybridisation(CISH)should be an accepted method in the routine diagnostic evaluation of HER2 status in breast cancer[J].J Clin Pathol.2007;9:1067-8.
23 Saez A,Andreu FJ,Segui MA,et al.HER-2 gene amplification by chromogenic in situ hybridisation(CISH) compared with fluorescence in situ hybridisation (FISH) in breast cancer-A study of two hundred cases[J].Breast.2006;15:519-27.
24 Li-Ning-T E,Ronchetti R,Tortes-Cabala C,et al.Role of chromogenic in situ hybridization(CISH) in the evaluation of HER2 status in breast carcinoma:comparison with immunohistochemistry and FISH[J].Int J Surg Pathol.2005;13:343-51.
25 Todorovic-Rakovic N,Jovanovic D,Neskovic-Konstantinovic Z,et al. Comparison between immunohistochemistry and chromogenic in situ hybridization in assessing HER-2 status in breast cancer[J]. Pathol Int. 2005;55:318-23.
26 Madrid MA, Lo RW. Chromogenic in situ hybridization (CISH): a novel alternative in screening archival breast cancer tissue samples for HER-2/neu status[J]. Breast Cancer Res. 2004;6:R593-600.
27 Park DI, Yun JW, Park JH, et al. HER-2/neu amplification is an independent prognostic factor in gastric cancer[J]. Dig Dis Sci. 2006;51:1371-9.
28 Tanner M, Hollmen M, Junttila TT, et al. Amplification of HER-2 in gastric carcinoma: association with Topoisomerase Ilalpha gene amplification, intestinal type, poor prognosis and sensitivity to trastuzumab[J]. Ann Oncol. 2005;16:273-8.
29 Shia J, Klimstra D S, Li A R, et al. Epidermal growth factor receptor expression and gene amplification in colorectal carcinoma: an immunohistochemical and chromogenic in situ hybridization study[J]. Modern Pathology 2005; 18: 1350-1356.
1.Wu Ct,Morris JR.Genes,genetics,and epigenetics:a correspondence[J].Science,2001,293:1103-1105.
2.Esteller M.DNAmethylation and cancer therapy:newdevelopments and expectations[J].Curr Oncol,2005,17(1):55-60.
3.Dahl C,Guldberg P.DNA methylation analysis techniques[J].Biogerontology,2003,4:233-250.
4.Das PM,Singal R.DNA methylation and cancer[J].J Clin Oncol,2004,22:4632-4642.
5.Hsieh JC,Kodjabachian L,Rebbert ML,et al.A new secreted protein that binds to Wnt proteins and inhibits their activities[J].Nature,1999,398:431-436.
6.He BA,Reguart N,You L,et al.Blockade of Wnt-1 signaling induces apoptosis in human colorectal cancer cells containing downstream mutations[J].Oncogene,2005,24(18):3054-3058.
7.Wissmann C,Wild PJ,Kaiser S,et al.W IF1,a component of the Wnt pathway,is down-regulated in prostate,breast,lung,and bladder cancer[J].J Pathol,2003,201(2):204-212.
8.Mazieres J,He B,You L,et al.Wnt inhibitory factor-1 is silenced by promoter hypermethylation in human lung cancer[J].Cancer Res,2004,64(14):4717-4720.
9.Taniguchi H,Yamamoto H,Hirata T,et al.Epigenetic inactivation of Wnt inhibitory factor-1 in human gastrointestinal cancers[J].Oncogene,2005,24(53):7946-7952.
10.Urakami S,Shiina H,Enokida H,et al.Epigenetic inactivation of Wnt inhibitory factor-1 plays an important role in bladder cancer through aberrant canonical Wnt /beta-catenin signaling pathway[J].Clin Cancer Res,2006,12(2):383-391.
11.Lin YC,You L,Xu ZD,et al.Wnt signaling activation and WIF-1 silencing in nasopharyngeal cancer cell lines[J].Biochem Biophys Res Commun,2006,341(2):635-640.
12.Moreno-Bueno G,Hardisson D,Sanchez C,et al.Abnormalities of APC/β-catenin pathway in endometrial cancer.Oncogene,2002,21:7981-7990.
13.Moreno-Bueno G;Hardisson D,Sarrio D,et al.Abnormalities of E- and P-cadherin and catenin expression in endometrial cancer and endometrial atypical hyperplasia.J Pathol 2003;199:471-478.
14.Mell LK,Meyer JJ,Tretiakova M,et al.Prognostic Significance of E-cadherin Protein Expression in Pathological Stage Ⅰ-Ⅲ Endometrial Cancer.Clin Cancer Res.2004,10,5546-5553.
15.Saito T,Nishimura M,Yamasaki H,et al.Hypermethylation in promoter region of E-cadherin gene is associated with tumor dedifferention and myometrial invasion in endometrial carcinoma.Cancer,2003,97,1002-1009.
16.Salvesen H.B.,Stefansson I,Kretzschmar E.I.,et al.Significance of PTEN alterations in endometrial carcinoma:A population-based study of mutations,promoter methylation and PTEN protein expression[J].Int J Oncol,2004,25:1615-1623.
17.Kovalenko TF,Vaniusheva OV,Shilov IA,et al.Promoters of genes MTHFR from patients with hyperhomocysteinemia and PTEN from patients with malignant and benign endometrial and ovarian tumors[J].Bioorg Khim,2006,32(4):414-423.
18.Semczuk A,Boltze C,Marzec B,et al.p16INK4A alterations are accompanied by aberrant protein immunostaining in endometrial carcinomas[J].J Cancer Res Clin Oncol,2003,129(10):589-596.
19.Pijnenborg J,Dam-de Veen G,Kisters N,et al.RASSF1Amethylation and K-ras and B-raf mutations and recurrent endometrial cancer[J].Ann Oncol,2007,18(3):491-497.
20.Abal M,Planaguma J,Gil-Moreno A,et al.Molecular pathology of endometrial carcinoma:transcriptional signature in endometrioid tumors[J].Histol Histopathol,2006,21(2):197-204.
21.MacDonald ND,Salvesen HB,Ryan A,et al.Frequency and prognostic impact of microsatellite instability in a large population-based study of endometrial carcinomas[J].Cancer Res,2000,60:1750-2.
22.Helmle KE,OttoCJ,Constantinescu G;et al.Variable MLH1 promoter methylation patterns in endometrial carcinomas of endometrioid subtype lacking DNA mismatch repair[J].Gynecol Cancer,2005,15(6):1089- 1096.
23.Xiong Y,Dowdy SC,Eberhardt NL,et al.hMLH1 promoter methylation and silencing in primary endometrial cancers are associated with specific alterations in MBDs occupancy and histone modifications[J].Gynecol Oncol,2006,103(1):321-328.
24.Brueckner B,Lyko F.DNA methyltransferase inhibitors:old and new drugs for an epigenetic cancer therapy[J].Trends Pharmacol Sci,2004,25(11):551-554.
25.Issa JP,Garcia-Manero G,Giles FJ.Phase I study of low-dose prolonged exposure schedules of the hypomethylating agent 5-aza-2'-deoxycytidine (decitabine) in hematopoietic malignancies[J].Blood,2004,103(5):1635-1640.
26.Yanokura M,Banno K,Kawaguchi M,et al.Relationship of aberrant DNA hypermethylation of CHFR with sensitivity to taxanes in endometrial cancer[J].Oncol Rep,2007,17(1):41-48.
27.Campan M,Weisenberger DJ,Laird PW,et al.DNA methylation profiles of female steroid hormone-driven human malignancies[J].Curr Top Microbiol Immunol,2006,310:141-178.
1.Hendrickson M,Ross J,Eifel P,et al.Uterinepapillary serous carcinoma:a highly malignant form of endometrialadenocarcinoma[J].Am J Surg Pathol,1982,6(2):93-108.
2.Zehavi S,Schneider D,Bukovsky I,et al.Pathological findings in early-stage endometrial cancer[J].Eur J Gyneacol Oncol,2003,24(1):18-20.
3.Slomovitz BM,Burke TW,Eifel PJ,et al.A single institution review of 129cases[J].Gynecol Oncol,2003,91(3):463-9.
4.Memarzadeh S,Holschneider CH,Bristow RE,et al.FIGO stage Ⅲ and Ⅳuterine papillary serous carcinoma:Impact of residual disease on survival[J].Int J Gynecol Cancer,2002,12(5):454-458.
5.Geisler JP,Sorosky JI,Duong HL,et al.Papillary serous carcinoma of the uterus:Increased risk of subsequent or concurrent development of breast carcinoma[J].Gynecol Oncol,2001,83(3):501-503.
6.Goshen R,Chu W,Elit L,et al.Is uterine papillary serous adenocarcinoma a manifestation of the hereditary breast-ovarian cancer syndrome?[J]Gynecol Oncol,2000,79(3):477-481.
7.Behtash N,Tehranian A,Ardalan FA,et al.Uterine papillary serous carcinoma after pelvic radiation therapy for cancer of the cervix[J].J Obstet Gynaecol,2002,22(1):96-7.
8.Abramovich D,Markman M,Kennedy A,et al.Serum CA-125 as a marker of disease activity in uterine papillary serous carcinoma[J].J Cancer Res Clin Oncol,1999,125(12):697-698.
9.King SA,Adas AA,Livolsi VA,et al.Expression and mutation of the p53 gene in uterine papillary serous carcinoma[J].Cancer,1995,75(11):2700-2705.
10.Kovalev S,Marchenko ND,Gugliotta BG,et al.Loss of p53 funtion in uterine papillary serous carcinoma[J].Human Pathol,1998,29(6):613-619.
11.Sherman ME,Bur ME,Kurman RJ.P53 in endometrial cancer and its putative precursors-evidence for diverse pathways of tumorigenesis[J].Hum Pathol,1995,26(11):1268-1274.
12.Hornreich G,Beller U,Lavie O,et al.Is uterine serous papillary carcinoma a BRCA1-related disease? Case report and review of the literature[J].Gynecol Oncol,1999,75(2):300-304.
13.Lavie O,Hornreich G,Arie AB,et al.BRCA1 germline mutations in women with uterine serous papillary carcinoma[J].Obstet Gynecol,2000,96(1):28-32.
14.Lavie O,Hornreich G,Arie AB,et al.BRCA germline mutations in Jewish women with uterine serous papillary carcinoma[J].Gynecol Oncol,2004,92(13):521-524.
15.葛霞,谢群,姚敏.子宫乳头状浆液性癌组织中雌激素受体和CerB2的表达及意义[J].中华妇产科杂志,1999,34(3):186.
16.Sood BM,Jones J,Gupta S,et al.Patterns of failure after multidality treatment of uterine papillary serous carcinoma[J].Int J Radiat Oncol Biol Phys,2003,57(1):208-216.
17.Ambros RA,Sherman ME,Zahn CM,et al.Endometrial intraepithelial carcinoma:a distinctive lesion specifically associated with tumor displaying serous differentiation[J].Hum Pahthol,1995,26(11):1260-1267.
18.Bristow RE,Asrari F,Trimble EL,et al.Extended surgical staging for uterine papillary serous carcinoma:Survival outcome of locoregional(Stage Ⅰ-Ⅲ)disease[J].Gynecol Oncol,2001,81(2):279-286.
19.Bristow RE,Duska LR,Montz FJ,et al.The role of cytoreductive surgery in the management of Stage Ⅳ uterine papillary serous carcinoma[J].Gynecol Oncol,2001,81(1):92-99.
20.Gehrig PA,Groben PA,Fowler WC,et al.Noninvasive papillary serous carcinoma of the endometrium[J].Obstet Gynecol,2001,97(1):153-157.
21.Chan JK,Loizzi V,Youssef M,et al.Significance of comprehensive surgical staging in noninvasive papillary serous carcinoma of the endometrium[J].Gynecol Oncol,2003,90(1):181-185.
22.Grice J,Merit EK,Greer B,et al.Uterine papillary serous carcinoma:evaluation of long-term survival in surgically-staged patients[J].Gynecol Oncol,1998,69(1):69-73.
23.Turner BC,Knisely JPS,Kacinski BM,et al.Effective treatment of Stage Ⅰ uterine papillary serous carcinoma with high dose-rate vaginal apex radiation (~(192) Ir) and chemotherapy[J].Int J Radiat Oncol Biol Phys,1998,40(1):77-84.
24.Mehta N,Yamada SD,Rotmensch J,et al.Outcome and pattern of failure in pathologic Stage Ⅰ-Ⅱ papillary serous carcinoma of the endometrium:Implications for adjuvant radiation therapy[J].Int J Radiat Oncol Biol Phys,2003,57(4):1004-1009.
25.Price FV,Chambers SK,Carcangiu ML,et al.Intravenous cisplatin,doxornbinsin,and cyclophosphamide in the treatment of uterine papillary serous papillary (UPSC)[J].Gynecol Oncol,1993,51(3):383-389
26.Zanotti KM,Belinson JL,Kennedy AW,et al.The use of paclitaxel and platinum-based chemotherapy in uterine papillary serous carcinoma[J].Gynel Oncol,1999,74(2):272-277.
27.Ramondetta L,Burke TW,Levenback CH,et al.Treatment of uterine papillary serous carcinoma with paclitaxel.[J].Gynecol Oncol,2001,82(1):156-161.
28.Chambers JT,Rutherford TJ,Schwartz PE,et al.A pilot study of topotecan in the treatment of serous carcinoma of the uterus[J],Int J Gynel Cancer,2003,13(2):216-222.
29.Goff BA,Kato D,Schmidt RA,et al.Uterine papillary serous carcinoma:patterns of metastatic spread[J].Gynecol Oncol,1994,54(3):264-268.