携带CTNNB1突变的早期子宫内膜样癌一例及文献复习

doi:10.12280/gjfckx.20220640

摘要/Abstract

摘要：

近年子宫内膜癌发病率呈上升趋势，且趋于年轻化。大部分的子宫内膜癌是低级别、早期子宫内膜样癌，预后良好。然而，部分低级别、早期子宫内膜样癌患者易复发且预后较差，早期识别这些高危患者有助于确定哪些患者需要额外的辅助治疗和更密切的随访。近年来CTNNB1突变被认为是此类患者潜在的复发风险因素，具有独立的预后价值，但到目前为止对于低级别、早期且伴有CTNNB1突变的子宫内膜样癌患者是否需要辅助治疗尚无明确的指南。结合收治的1例ⅠA期、低级别、伴有CTNNB1基因突变的子宫内膜样癌患者诊治情况，对该基因突变加以探讨，以期提高对具有此类突变患者的预后及后续治疗的进一步认识。

关键词: 子宫内膜肿瘤, CTNNB1基因, 突变, 基因检测, 治疗, 预后

Abstract:

The incidence of endometrial carcinoma has been increasing in recent years, and the age of onset is tends to younger. Most endometrial carcinomas are low-grade, early-stage endometrioid carcinomas (EECs) with a good prognosis. However, some patients with low-grade, early-stage EECs are prone to recurrence and have a poor prognosis. Early identification of these high-risk patients with EECs can help determine which patients need additional adjuvant therapy and closer follow-up. In recent years, CTNNB1 mutation has been considered as a potential risk factor for recurrence, which has independent prognostic value. But so far, there are no clear guidelines on whether adjuvant therapy is needed for low-grade and early-stage EECs patients with CTNNB1 mutation. Combined with a patient with an ⅠA stage, low-grade patient with CTNNB1 gene mutation in our hospital, this gene mutation is mainly discussed in order to improve clinicians′ further understanding of the prognosis and follow-up treatment of patients with such mutation.

Key words: Endometrial neoplasms, CTNNB1 gene, Mutation, Genetic testing, Therapy, Prognosis

杨鸣, 陈明珠, 田书屹, 刘小艳, 张立会. 携带CTNNB1突变的早期子宫内膜样癌一例及文献复习[J]. 国际妇产科学杂志, 2023, 50(3): 318-321.

YANG Ming, CHEN Ming-zhu, TIAN Shu-yi, LIU Xiao-yan, ZHANG Li-hui. Early Endometrioid Carcinoma with CTNNB1 Mutation: A Case Report and Literature Review[J]. Journal of International Obstetrics and Gynecology, 2023, 50(3): 318-321.

图/表 1

参考文献 25

[1]	Costigan DC, Dong F, Nucci MR, et al. Clinicopathologic and Immunohistochemical Correlates of CTNNB1 Mutated Endometrial Endometrioid Carcinoma[J]. Int J Gynecol Pathol, 2020, 39(2):119-127. doi: 10.1097/PGP.0000000000000583. doi: 10.1097/PGP.0000000000000583
[2]	Cancer Genome Atlas Research Network, Kandoth C, Schultz N, et al. Integrated genomic characterization of endometrial carcinoma[J]. Nature, 2013, 497(7447):67-73. doi: 10.1038/nature12113. doi: 10.1038/nature12113
[3]	Liu Y, Patel L, Mills GB, et al. Clinical significance of CTNNB1 mutation and Wnt pathway activation in endometrioid endometrial carcinoma[J]. J Natl Cancer Inst, 2014, 106(9):dju245. doi: 10.1093/jnci/dju245. doi: 10.1093/jnci/dju245
[4]	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
[5]	Liu Y, Broaddus RR, Zhang W. Identifying aggressive forms of endometrioid-type endometrial cancer: new insights into molecular subtyping[J]. Expert Rev Anticancer Ther, 2015, 15(1):1-3. doi: 10.1586/14737140.2015.992420. doi: 10.1586/14737140.2015.992420
[6]	中国抗癌协会妇科肿瘤专业委员会. 子宫内膜癌诊断与治疗指南(2021年版)[J]. 中国癌症杂志, 2021, 31(6):501-512. doi: 10.19401/j.cnki.1007-3639.2021.06.08. doi: 10.19401/j.cnki.1007-3639.2021.06.08
[7]	何翊姣, 王益勤, 戴一博, 等. 子宫内膜非典型增生及早期子宫内膜癌初次保留生育功能治疗的临床疗效[J]. 中华肿瘤杂志, 2022, 44(3):291-296. doi: 10.3760/cma.j.cn112152-20201014-00897. doi: 10.3760/cma.j.cn112152-20201014-00897
[8]	何翊姣, 王益勤, 周蓉, 等. 早期子宫内膜癌保留生育功能治疗中特殊问题处理的研究进展[J]. 中华妇产科杂志, 2021, 56(2):153-156. doi: 10.3760/cma.j.cn112141-20200512-00402. doi: 10.3760/cma.j.cn112141-20200512-00402
[9]	Guillon S, Popescu N, Phelippeau J, et al. A systematic review and meta-analysis of prognostic factors for remission in fertility-sparing management of endometrial atypical hyperplasia and adenocarcinoma[J]. Int J Gynaecol Obstet, 2019, 146(3):277-288. doi: 10.1002/ijgo.12882. doi: 10.1002/ijgo.12882 pmid: 31197826
[10]	McMellen A, Woodruff ER, Corr BR, et al. Wnt Signaling in Gynecologic Malignancies[J]. Int J Mol Sci, 2020, 21(12):4272. doi: 10.3390/ijms21124272. doi: 10.3390/ijms21124272
[11]	Ledinek Ž, Sobočan M, Knez J. The Role of CTNNB1 in Endometrial Cancer[J]. Dis Markers, 2022, 2022:1442441. doi: 10.1155/2022/1442441. doi: 10.1155/2022/1442441
[12]	Wang Y, van der Zee M, Fodde R, et al. Wnt/Β-catenin and sex hormone signaling in endometrial homeostasis and cancer[J]. Oncotarget, 2010, 1(7):674-684. doi: 10.18632/oncotarget.101007. doi: 10.18632/oncotarget.101007 pmid: 21317462
[13]	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. doi: 10.1038/modpathol.2017.15. doi: 10.1038/modpathol.2017.15
[14]	Ruz-Caracuel I, López-Janeiro Á, Heredia-Soto V, et al. Clinicopathological features and prognostic significance of CTNNB1 mutation in low-grade, early-stage endometrial endometrioid carcinoma[J]. Virchows Arch, 2021, 479(6):1167-1176. doi: 10.1007/s00428-021-03176-5. doi: 10.1007/s00428-021-03176-5
[15]	van der Zee M, Jia Y, Wang Y, et al. Alterations in Wnt-β-catenin and Pten signalling play distinct roles in endometrial cancer initiation and progression[J]. J Pathol, 2013, 230(1):48-58. doi: 10.1002/path.4160. doi: 10.1002/path.4160
[16]	Jeong JW, Lee HS, Franco HL, et al. beta-catenin mediates glandular formation and dysregulation of beta-catenin induces hyperplasia formation in the murine uterus[J]. Oncogene, 2009, 28(1):31-40. doi: 10.1038/onc.2008.363. doi: 10.1038/onc.2008.363 pmid: 18806829
[17]	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
[18]	Kurnit KC, Fellman BM, Mills GB, et al. Adjuvant treatment in early-stage endometrial cancer: context-dependent impact of somatic CTNNB1 mutation on recurrence-free survival[J]. Int J Gynecol Cancer, 2022, 32(7):869-874. doi: 10.1136/ijgc-2021-003340. doi: 10.1136/ijgc-2021-003340
[19]	Deshmukh V, O′Green AL, Bossard C, et al. Modulation of the Wnt pathway through inhibition of CLK2 and DYRK1A by lorecivivint as a novel, potentially disease-modifying approach for knee osteoarthritis treatment[J]. Osteoarthritis Cartilage, 2019, 27(9):1347-1360. doi: 10.1016/j.joca.2019.05.006. doi: 10.1016/j.joca.2019.05.006
[20]	Deshmukh V, Hu H, Barroga C, et al. A small-molecule inhibitor of the Wnt pathway (SM04690) as a potential disease modifying agent for the treatment of osteoarthritis of the knee[J]. Osteoarthritis Cartilage, 2018, 26(1):18-27. doi: 10.1016/j.joca.2017.08.015. doi: 10.1016/j.joca.2017.08.015
[21]	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
[22]	Zaman G, de Roos J, Libouban M, et al. TTK Inhibitors as a Targeted Therapy for CTNNB1(β-catenin) Mutant Cancers[J]. Mol Cancer Ther, 2017, 16(11):2609-2617. doi: 10.1158/1535-7163.MCT-17-0342. doi: 10.1158/1535-7163.MCT-17-0342
[23]	秘嘉庆, 秦倩, 马惠涵, 等. TTK在肿瘤中的研究进展[J]. 实用肿瘤学杂志, 2021, 35(2):188-192. doi: 10.11904/j.issn.1002-3070.2021.02.017. doi: 10.11904/j.issn.1002-3070.2021.02.017
[24]	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. doi: 10.12280/gjfckx.20210256. doi: 10.12280/gjfckx.20210256
[25]	Kim G, Kurnit KC, Djordjevic B, et al. Nuclear β-catenin localization and mutation of the CTNNB1 gene: a context-dependent association[J]. Mod Pathol, 2018, 31(10):1553-1559. doi: 10.1038/s41379-018-0080-0. doi: 10.1038/s41379-018-0080-0

基因变异	染色体位置	突变丰度/ 拷贝数	变异分级	蛋白质功能影响	功能预测		数据库编号（COSMIC）
基因变异	染色体位置	突变丰度/ 拷贝数	变异分级	蛋白质功能影响	SIFT	Polyphen2	数据库编号（COSMIC）
CTNNB1 NM_001904.3 exon3 p.G34E c.101G>A	chr3:41266104	31.66%	Ⅱ类	预测功能获得（PMID:18519687）	D	D	COSV62688267； OCCURENCE=130
PIK3CA NM_006218.3 exon10 p.E545K c.1633G>A	chr3:178936091	30.57%	Ⅱ类	功能获得（PMID:29533785,26627007）	D	D	COSV55873239；OCCURENCE=2798

基因变异	染色体位置	突变丰度/ 拷贝数	变异分级	蛋白质功能影响	功能预测		数据库编号（COSMIC）
基因变异	染色体位置	突变丰度/ 拷贝数	变异分级	蛋白质功能影响	SIFT	Polyphen2	数据库编号（COSMIC）
CTNNB1 NM_001904.3 exon3 p.G34E c.101G>A	chr3:41266104	31.66%	Ⅱ类	预测功能获得（PMID:18519687）	D	D	COSV62688267； OCCURENCE=130
PIK3CA NM_006218.3 exon10 p.E545K c.1633G>A	chr3:178936091	30.57%	Ⅱ类	功能获得（PMID:29533785,26627007）	D	D	COSV55873239；OCCURENCE=2798