王铭洋;范文生;叶明侠;杨雯;王楠;李明霞;孟元光;

• 1:中国人民解放军总医院第一医学中心
• 2:南开大学医学院

摘要(Abstract)：

子宫内膜癌(EC)是女性生殖系统常见的恶性肿瘤,在全球范围内其发病率逐年升高。多数EC患者经手术治疗后预后较好,但对于晚期或复发、转移性EC来说,传统的治疗手段效果有限,患者预后较差。1983年Bokhman根据流行病学、内分泌及预后特点将EC分为I型(雌激素依赖型)和II型(非雌激素依赖型),然而在临床应用中该分型手段具有一定局限性。随着分子生物学及基因测序技术的发展,EC的研究深入分子水平。2013年美国TCGA第一次归纳提出EC的4种分子分型,由于其费用高昂、技术复杂,临床不易获得。2015年Talhouk等提出简易替代分型并在后续的研究中将其命名为ProMisE分子风险分型,包括:POLE突变型、MSI高突变型、p53野生型、p53突变型。EC分子分型的研究具有重要的临床指导意义。本文就EC传统分型到分子分型的转变做一回顾,并对分子分型与临床相关的研究做一总结与分析。EC分子分型的不断完善有助于实现临床诊疗中的精准化、规范化、个体化,在精准医学背景下有重要价值。

关键词(KeyWords)： 子宫内膜癌;分子分型;精准医学

Abstract:

Keywords:

基金项目(Foundation): 多孔腹腔镜手术机器人系统设计与产品研发(No:2017YFC0110405)

作者(Authors): 王铭洋;范文生;叶明侠;杨雯;王楠;李明霞;孟元光;

DOI: 10.13283/j.cnki.xdfckjz.2021.04.033

参考文献(References)：

• [1] Timmerman S,Van Rompuy AS,Van Gorp T,et al.Analysis of 108 patients with endometrial carcinoma using the PROMISE classification and additional genetic analyses for MMR-D[J].Gynecol Oncol,2020,157(1):245-251
• [2] Jiang X,Tang H,Chen T.Epidemiology of gynecologic cancers in China[J].J Gynecol Oncol,2018,29(1):e7
• [3] Bokhman JV.Two pathogenetic types of endometrial carcinoma[J].Gynecol Oncol,1983,15(1):10-17
• [4] Wilczynski M,Danielska J,Wilczynski J.An update of the classical Bokhman's dualistic model of endometrial cancer[J].Prz Menopauzalny,2016,15(2):63-68
• [5] Zhang K,Li H,Yan Y,et al.Identification of key genes and pathways between type I and type II endometrial cancer using bioinformatics analysis[J].Oncol Lett,2019,18(3):2464-2476
• [6] Schultheis AM,Martelotto LG,De Filippo MR,et al.TP53 mutational spectrum in endometrioid and serous endometrial cancers[J].Int J Gynecol Pathol,2016,35(4):289-300
• [7] Lu Z,Chen J.Introduction of WHO classification of tumours of female reproductive organs,fourth edition[J].Zhonghua Bing Li Xue Za Zhi,2014,43(10):649-650
• [8] Soslow RA,Tornos C,Park KJ,et al.,Endometrial Carcinoma Diagnosis[J].Int J Gynecol Pathol,2019,38:S64-S74
• [9] Gilks CB,Oliva E,Soslow RA.Poor interobserver reproducibility in the diagnosis of high-grade endometrial carcinoma[J].Am J Surg Pathol,2013,37(6):874-881
• [10] Hamilton CA,Cheung MK,Osann K,et al.Uterine papillary serous and clear cell carcinomas predict for poorer survival compared to grade 3 endometrioid corpus cancers[J].Br J Cancer,2006,94(5):642-646
• [11] Hayes MP,Wang H,Espinal-Witter R,et al.PIK3CA and PTEN mutations in uterine endometrioid carcinoma and complex atypical hyperplasia[J].Clin Cancer Res,2006,12(20 Pt 1):5932-5935
• [12] Cancer Genome Atlas Research Network,Kandoth C,Schultz N,et al.Integrated genomic characterization of endometrial carcinoma[J].Nature,2013,497(7447):67-73
• [13] Church DN,Briggs SE,Palles C,et al.DNA polymerase epsilon and delta exonuclease domain mutations in endometrial cancer[J].Hum Mol Genet,2013,22(14):2820-2828
• [14] Van Gool IC,Ubachs JEH,Stelloo E,et al.Blinded histopathological characterisation of POLE exonuclease domain-mutant endometrial cancers:sheep in wolf's clothing[J].Histopathol,2018,72(2):248-258
• [15] Markowska A,Pawalowska M,Lubin J,et al.Signalling pathways in endometrial cancer[J].Contemp Oncol (Pozn),2014,18(3):143-148
• [16] Liang Y,Lin B,Ye Z,et al.Triple-high expression of phosphatase and tensin homolog (PTEN),estrogen receptor (ER) and progesterone receptor (PR) may predict favorable prognosis for patients with Type I endometrial carcinoma[J].J Cancer,2020,11(6):1436-1445
• [17] Kunitomi H,Banno K,Yanokura M,et al.New use of microsatellite instability analysis in endometrial cancer[J].Oncol Lett,2017,14(3):3297-3301
• [18] Ozdemir TR,Alan M,Sanci M,et al.Targeted next-generation sequencing of MLH1,MSH2,and MSH6 genes in patients with endometrial carcinoma under 50 years of age[J].Balkan Med J,2019,36(1):37-42
• [19] Vermij L,Smit V,Nout R,et al.Incorporation of molecular characteristics into endometrial cancer management[J].Histopathol,2020,76(1):52-63
• [20] Dedes KJ,Wetterskog D,Ashworth A,et al.Emerging therapeutic targets in endometrial cancer[J].Nat Rev Clin Oncol,2011,8(5):261-271
• [21] Kurnit KC,Kim GN,Fellman BM,et al.CTNNB1 (beta-catenin) mutation identifies low grade,early stage endometrial cancer patients at increased risk of recurrence[J].Mod Pathol,2017,30(7):1032-1041
• [22] Winterhoff B,Thomaier L,Mullany S,et al.Molecular characterization of endometrial cancer and therapeutic implications[J].Curr Opin Obstet Gynecol,2020,32(1):76-83
• [23] Kobel M,Ronnett BM,Singh N,et al.Interpretation of P53 immunohistochemistry in endometrial carcinomas:toward increased reproducibility[J].Int J Gynecol Pathol,2019,38(Suppl 1):S123-S131
• [24] Talhouk A,McConechy MK,Leung S,et al.A clinically applicable molecular-based classification for endometrial cancers[J].Br J Cancer,2015,113(2):299-310
• [25] McConechy MK,Talhouk A,Li-Chang HH,et al.Detection of DNA mismatch repair (MMR) deficiencies by immunohistochemistry can effectively diagnose the microsatellite instability (MSI) phenotype in endometrial carcinomas[J].Gynecol Oncol,2015,137(2):306-310
• [26] Talhouk A,Hoang LN,McConechy MK,et al.Molecular classification of endometrial carcinoma on diagnostic specimens is highly concordant with final hysterectomy:Earlier prognostic information to guide treatment[J].Gynecol Oncol,2016,143(1):46-53
• [27] McConechy MK,Talhouk A,Leung S,et al.Confirmation of ProMisE:A simple,genomics-based clinical classifier for endometrial cancer[J].Cancer,2017,123(5):802-813
• [28] McConechy MK,Talhouk A,Leung S,et al.Endometrial carcinomas with POLE exonuclease domain mutations have a favorable prognosis[J].Clin Cancer Res,2016,22(12):2865-2873
• [29] Stelloo E,Bosse T,Nout RA,et al.Refining prognosis and identifying targetable pathways for high-risk endometrial cancer;a TransPORTEC initiative[J].Mod Pathol,2015,28(6):836-844
• [30] McMeekin DS,Tritchler DL,Cohn DE,et al.Clinicopathologic significance of mismatch repair defects in endometrial cancer:an NRG oncology/gynecologic oncology group study[J].J Clin Oncol,2016,34(25):3062-3068
• [31] Charo LM,Plaxe SC.Recent advances in endometrial cancer:a review of key clinical trials from 2015 to 2019[J].F1000Res,2019,8:F1000 Faculty Rev-849
• [32] Santin AD,Bellone S,Buza N,et al.Regression of chemotherapy-resistant polymerase ε (pole) ultra-mutated and msh6 hyper-mutated endometrial tumors with nivolumab[J].Clin Cancer Res,2016,22(23):5682-5687
• [33] Mehnert JM,Panda A,Zhong H,et al.Immune activation and response to pembrolizumab in POLE-mutant endometrial cancer[J].J Clin Invest.2016;126(6):2334-2340
• [34] Chapel DB,Yamada SD,Cowan M,et al.Immunohistochemistry for mismatch repair protein deficiency in endometrioid endometrial carcinoma yields equivalent results when performed on endometrial biopsy/curettage or hysterectomy specimens[J].Gynecol Oncol,2018,149(3):570-574
• [35] Wortman BG,Creutzberg CL,Putter H,et al.Ten-year results of the PORTEC-2 trial for high-intermediate risk endometrial carcinoma:improving patient selection for adjuvant therapy[J].Br J Cancer,2018,119(9):1067-1074
• [36] Bosse T,Nout RA,McAlpine JN,et al.Molecular classification of grade 3 endometrioid endometrial cancers identifies distinct prognostic subgroups[J].Am J Surg Pathol,2018,42(5):561-568
• [37] Makker V,Green AK,Wenham RM,et al.New therapies for advanced,recurrent,and metastatic endometrial cancers[J].Gynecol Oncol Res Pract,2017,4:19
• [38] Le DT,Durham JN,Smith KN,et al.Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade[J].Science,2017,357(6349):409-413
• [39] Ott PA,Bang YJ,Berton-Rigaud D,et al.Safety and antitumor activity of pembrolizumab in advanced programmed death ligand 1-positive endometrial cancer:results from the KEYNOTE-028 Study[J].J Clin Oncol,2017,35(22):2535-2541
• [40] Prendergast EN,Holman LL,Liu AY,et al.Comprehensive genomic profiling of recurrent endometrial cancer:Implications for selection of systemic therapy[J].Gynecol Oncol,2019,154(3):461-466