子宫内膜癌的分子机制及分子分型研究进展

doi:10.12280/gjfckx.20210256

摘要/Abstract

摘要：

子宫内膜癌近年发病呈上升趋势且发病年龄不断年轻化,晚期子宫内膜癌治疗效果不理想。传统的分类方法在患者的诊疗中存在严重的不足,不能为患者精准治疗提供足够的依据。随着分子生物学的快速发展,越来越多的研究发现子宫内膜癌发病的多组学研究和信号通路关联,临床上迫切需要将其纳入患者的常规诊疗中。传统分型根据有无雌激素刺激将子宫内膜癌分成Ⅰ、Ⅱ两型,Ⅰ型子宫内膜癌的诊断和预后与人第10号染色体缺失的磷酸酶及张力蛋白同源的基因（PTEN）、磷脂酰肌醇3激酶基因（PI3KCA）、磷酸肌醇3激酶调节亚单位1（PI3KR1）、AT丰富结合域1A（ARID1A）、Kristen鼠肉瘤病毒原癌基因同源体（KRAS）、POLE、CTNNB1、TP53突变,DNA错配修复（MMR）蛋白缺失,雌激素受体（ER）、孕激素受体（PR）表达情况有关。Ⅱ型子宫内膜癌的预后与人表皮生长因子受体2（HER2）过表达、TP53突变、ARID1A突变有关。磷脂酰肌醇3激酶/蛋白激酶B（PI3K/Akt）、P53、丝裂原活化蛋白激酶（MAPK）和Wnt/β-连环蛋白信号通路与子宫内膜癌的发病密切相关。TCGA分型的替代分子分型ProMisE和Parra-Herran分子分型目前被临床用以评估子宫内膜癌的预后与治疗方案,但该分型与预后仍存在部分不匹配的病例,需要对该分型进行进一步细化研究。

关键词: 子宫内膜肿瘤, 分子生物学, 信号传导, 基因, 突变

Abstract:

The incidence of endometrial carcinoma has been on the rise in recent years and the age of onset is getting younger. The treatment effect of advanced endometrial cancer is not ideal. The traditional classification method has serious deficiencies in the diagnosis and treatment of patients, and cannot provide sufficient basis for accurate treatment of patients. With the rapid development of molecular biology, more and more multi-omics studies and signal pathway associations in the onset of endometrial cancer have been discovered, and there is an urgent clinical need to include it in the routine diagnosis and treatment of patients. This article summarizes the latest progress in molecular biology and signaling pathways of type I and type II endometrial carcinoma. The diagnosis and prognosis of type I endometrial carcinoma are related to PTEN, PI3KCA, PI3KR1, ARID1A, KRAS, POLE, CTNNB1, TP53 mutation, MMR deletion, ER and PR expression are related. The prognosis of type II endometrial cancer is related to HER2 overexpression, TP53 mutation, and ARID1A mutation. PI3K/Akt, P53, MAPK and Wnt/β-catenin signaling pathways are closely related to the pathogenesis of endometrial carcinoma. ProMisE and Parra-Herran molecular classification, an alternative to TCGA classification, are currently used clinically to assess the prognosis and treatment options of endometrial carcinoma, but there are still some cases that do not match the prognosis, further refinement of the typing is needed.

Key words: Endometrial neoplasms, Molecular biology, Signal transduction, Genes, Mutation

杨琳, 蔡雨晗, 李华. 子宫内膜癌的分子机制及分子分型研究进展[J]. 国际妇产科学杂志, 2022, 49(1): 10-14.

YANG Lin, CAI Yu-han, LI Hua. Research Progress on Molecular Mechanism and Molecular Typing of Endometrial Carcinoma[J]. Journal of International Obstetrics and Gynecology, 2022, 49(1): 10-14.

参考文献 35

[1]	Chen W, Zheng R, Baade PD, et al. Cancer statistics in China, 2015[J]. CA Cancer J Clin, 2016, 66(2):115-132. doi: 10.3322/caac.21338. doi: 10.3322/caac.21338
[2]	Lu KH, Broaddus RR. Endometrial Cancer[J]. N Engl J Med, 2020, 383(21):2053-2064. doi: 10.1056/NEJMra1514010. doi: 10.1056/NEJMra1514010
[3]	曹楚楚, 黄炉仁, 傅芬. PI3K/Akt/mTOR信号通路及其相关基因突变与子宫内膜癌靶向性药物治疗的研究进展[J]. 基础医学与临床, 2017, 37(1):118-122. doi: 10.3969/j.issn.1001-6325.2017.01.043. doi: 10.3969/j.issn.1001-6325.2017.01.043
[4]	Castellucci E, He T, Goldstein DY, et al. DNA Polymerase ε Deficiency Leading to an Ultramutator Phenotype: A Novel Clinically Relevant Entity[J]. Oncologist, 2017, 22(5):497-502. doi: 10.1634/theoncologist.2017-0034. doi: 10.1634/theoncologist.2017-0034 pmid: 28465371
[5]	Monsur M, Yamaguchi M, Tashiro H, et al. Endometrial cancer with a POLE mutation progresses frequently through the type I pathway despite its high-grade endometrioid morphology: a cohort study at a single institution in Japan[J]. Med Mol Morphol, 2021, 54:133-145. doi: 10.1007/s00795-020-00273-3. doi: 10.1007/s00795-020-00273-3
[6]	戴一博, 王婧元, 赵路阳, 等. 子宫内膜癌DNA错配修复基因异常的相关研究进展[J]. 中华妇产科杂志, 2019, 54(12):869-872. doi: 10.3760/cma.j.issn.0529?567x.2019.12.013. doi: 10.3760/cma.j.issn.0529?567x.2019.12.013
[7]	Vietri MT, D′Elia G, Caliendo G, et al. Prevalence of mutations in BRCA and MMR genes in patients affected with hereditary endometrial cancer[J]. Med Oncol, 2021, 38(2):13. doi: 10.1007/s12032-021-01454-5. doi: 10.1007/s12032-021-01454-5
[8]	Kim SR, Tone A, Kim RH, et al. Understanding the clinical implication of mismatch repair deficiency in endometrioid endometrial cancer through a prospective study[J]. Gynecol Oncol, 2021, 161(1):221-227. doi: 10.1016/j.ygyno.2021.01.002. doi: 10.1016/j.ygyno.2021.01.002
[9]	Hu H, Chen Z, Ji L, et al. ARID1A-dependent permissive chromatin accessibility licenses estrogen-receptor signaling to regulate circadian rhythms genes in endometrial cancer[J]. Cancer Lett, 2020, 492:162-173. doi: 10.1016/j.canlet.2020.08.034. doi: 10.1016/j.canlet.2020.08.034
[10]	Kir G, Olgun ZC, Gunel H, et al. KRAS-mutated Uterine Endometrioid Carcinoma With Extensive Surface Changes Resulting in Striking Morphologic Mimicry of an Ovarian Serous Borderline Tumor[J]. Int J Gynecol Pathol, 2020, 39(6):573-577. doi: 10.1097/PGP.0000000000000652. doi: 10.1097/PGP.0000000000000652
[11]	Imboden S, Tapia C, Scheiwiller N, et al. Early-stage endometrial cancer, CTNNB1 mutations, and the relation between lymphovascular space invasion and recurrence[J]. Acta Obstet Gynecol Scand, 2020, 99(2):196-203. doi: 10.1111/aogs.13740. doi: 10.1111/aogs.13740
[12]	Russo M, Broach J, Sheldon K, et al. Clonal evolution in paired endometrial intraepithelial neoplasia/atypical hyperplasia and endometrioid adenocarcinoma[J]. Hum Pathol, 2017, 67:69-77. doi: 10.1016/j.humpath.2017.07.003. doi: 10.1016/j.humpath.2017.07.003
[13]	Twomey JD, Brahme NN, Zhang B. Drug-biomarker co-development in oncology-20 years and counting[J]. Drug Resist Updat, 2017, 30:48-62. doi: 10.1016/j.drup.2017.02.002. doi: 10.1016/j.drup.2017.02.002
[14]	Buza N. HER2 Testing and Reporting in Endometrial Serous Carcinoma: Practical Recommendations for HER2 Immunohistochemistry and Fluorescent In Situ Hybridization: Proceedings of the ISGyP Companion Society Session at the 2020 USCAP Annual Meeting[J]. Int J Gynecol Pathol, 2021, 40(1):17-23. doi: 10.1097/PGP.0000000000000711. doi: 10.1097/PGP.0000000000000711
[15]	Fader AN, Roque DM, Siegel E, et al. Randomized Phase II Trial of Carboplatin-Paclitaxel Versus Carboplatin-Paclitaxel-Trastuzumab in Uterine Serous Carcinomas That Overexpress Human Epidermal Growth Factor Receptor 2/neu[J]. J Clin Oncol, 2018, 36(20):2044-2051. doi: 10.1200/JCO.2017.76.5966. doi: 10.1200/JCO.2017.76.5966
[16]	Fader AN, Roque DM, Siegel E, et al. Randomized Phase II Trial of Carboplatin-Paclitaxel Compared with Carboplatin-Paclitaxel-Trastuzumab in Advanced (Stage III-IV) or Recurrent Uterine Serous Carcinomas that Overexpress Her2/Neu (NCT01367002): Updated Overall Survival Analysis[J]. Clin Cancer Res, 2020, 26(15):3928-3935. doi: 10.1158/1078-0432.CCR-20-0953. doi: 10.1158/1078-0432.CCR-20-0953
[17]	Chang YH, Ding DC. A clear cancer cell line (150057) derived from human endometrial carcinoma harbors two novel mutations[J]. BMC Cancer, 2020, 20(1):1058. doi: 10.1186/s12885-020-07567-w. doi: 10.1186/s12885-020-07567-w
[18]	Zhang X, Kan H, Liu Y, et al. Plumbagin induces Ishikawa cell cycle arrest, autophagy, and apoptosis via the PI3K/Akt signaling pathway in endometrial cancer[J]. Food Chem Toxicol, 2021, 148:111957. doi: 10.1016/j.fct.2020.111957. doi: 10.1016/j.fct.2020.111957
[19]	Liu Z, Hong Z, Ma H, et al. Key factors mediated by PI3K signaling pathway and related genes in endometrial carcinoma[J]. J Bioenerg Biomembr, 2020, 52(6):465-473. doi: 10.1007/s10863-020-09854-4. doi: 10.1007/s10863-020-09854-4
[20]	Costa BP, Nassr MT, Diz FM, et al. Methoxyeugenol regulates the p53/p21 pathway and suppresses human endometrial cancer cell proliferation[J]. J Ethnopharmacol, 2021, 267:113645. doi: 10.1016/j.jep.2020.113645. doi: 10.1016/j.jep.2020.113645
[21]	Liu Q, Chen CY, Chen GL. High APOBEC1 Complementation Factor Expression Positively Modulates the Proliferation, Invasion, and Migration of Endometrial Cancer Cells Through Regulating P53/P21 Signaling Pathway[J]. Cancer Biother Radiopharm, 2020 Aug 18. doi: 10.1089/cbr.2020.3957. doi: 10.1089/cbr.2020.3957
[22]	Zhang XJ, Qi GT, Zhang XM, et al. lncRNA RHPN1-AS1 promotes the progression of endometrial cancer through the activation of ERK/MAPK pathway[J]. J Obstet Gynaecol Res, 2021, 47(2):533-543. doi: 10.1111/jog.14548. doi: 10.1111/jog.14548
[23]	鲍伟, 蔡斌, 杨懿霞, 等. 子宫内膜癌中ERK1/2信号转导通路与雌、孕激素受体的相关性[J]. 上海交通大学学报(医学版), 2009, 29(1):5-8. doi: CNKI:SUN:SHEY.0.2009-01-003. doi: CNKI:SUN:SHEY.0.2009-01-003
[24]	Zhang F, Ni ZJ, Ye L, et al. Asparanin A inhibits cell migration and invasion in human endometrial cancer via Ras/ERK/MAPK pathway[J]. Food Chem Toxicol, 2021, 150:112036. doi: 10.1016/j.fct.2021.112036. doi: 10.1016/j.fct.2021.112036 pmid: 33561516
[25]	Park SA, Kim LK, Kim YT, et al. Long non-coding RNA steroid receptor activator promotes the progression of endometrial cancer via Wnt/β-catenin signaling pathway[J]. Int J Biol Sci, 2020, 16(1):99-115. doi: 10.7150/ijbs.35643. doi: 10.7150/ijbs.35643
[26]	Kandoth C, Schultz N, Cherniack AD, et al. Integrated genomic characterization of endometrial carcinoma[J]. Nature, 2013, 497(7447):67-73. doi: 10.1038/nature12113. doi: 10.1038/nature12113
[27]	Stelloo E, Nout RA, Osse EM, et al. Improved Risk Assessment by Integrating Molecular and Clinicopathological Factors in Early-stage Endometrial Cancer-Combined Analysis of the PORTEC Cohorts[J]. Clin Cancer Res, 2016, 22(16):4215-4224. doi: 10.1158/1078-0432.CCR-15-2878. doi: 10.1158/1078-0432.CCR-15-2878 pmid: 27006490
[28]	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. doi: 10.1097/PAS.0000000000001020. doi: 10.1097/PAS.0000000000001020
[29]	Stelloo E, Nout RA, Osse EM, et al. Improved Risk Assessment by Integrating Molecular and Clinicopathological Factors in Early-stage Endometrial Cancer-Combined Analysis of the PORTEC Cohorts[J]. Clin Cancer Res, 2016, 22(16):4215-4224. doi: 10.1158/1078-0432.CCR-15-2878. doi: 10.1158/1078-0432.CCR-15-2878 pmid: 27006490
[30]	Travaglino A, Raffone A, Saccone G, et al. Immunophenotype of Atypical Polypoid Adenomyoma of the Uterus: Diagnostic Value and Insight on Pathogenesis[J]. Appl Immunohistochem Mol Morphol, 2020, 28(8):646-653. doi: 10.1097/PAI.0000000000000780. doi: 10.1097/PAI.0000000000000780
[31]	Wortman BG, Bosse T, Nout RA, et al. Molecular-integrated risk profile to determine adjuvant radiotherapy in endometrial cancer: Evaluation of the pilot phase of the PORTEC-4a trial[J]. Gynecol Oncol, 2018, 151(1):69-75. doi: 10.1016/j.ygyno.2018.07.020. doi: S0090-8258(18)31084-9 pmid: 30078506
[32]	Travaglino A, Raffone A, Mollo A, et al. TCGA molecular subgroups and FIGO grade in endometrial endometrioid carcinoma[J]. Arch Gynecol Obstet, 2020, 301(5):1117-1125. doi: 10.1007/s00404-020-05531-4. doi: 10.1007/s00404-020-05531-4 pmid: 32253551
[33]	Parra-Herran C, Lerner-Ellis J, Xu B, et al. Molecular-based classification algorithm for endometrial carcinoma categorizes ovarian endometrioid carcinoma into prognostically significant groups[J]. Mod Pathol, 2017, 30(12):1748-1759. doi: 10.1038/modpathol.2017.81. doi: 10.1038/modpathol.2017.81
[34]	Talhouk A, McConechy MK, Leung S, et al. Confirmation of ProMisE: A simple, genomics-based clinical classifier for endometrial cancer[J]. Cancer, 2017, 123(5):802-813. doi: 10.1002/cncr.30496. doi: 10.1002/cncr.30496 pmid: 28061006
[35]	杜宁宁, 刘岩, 任彩霞, 等. 癌症基因组图谱子宫内膜癌分子分型在子宫内膜样癌中的临床应用探索[J]. 中华病理学杂志, 2019, 48(8):596-603. doi: 10.3760/cma.j.issn.0529?5807.2019.08.003. doi: 10.3760/cma.j.issn.0529?5807.2019.08.003