基于基因组学图谱构建的子宫平滑肌肉瘤前沿进展

doi:10.12280/gjfckx.20240791

摘要/Abstract

摘要：

子宫平滑肌肉瘤（uterine leiomyosarcoma，uLMS）是最常见的子宫肉瘤之一，具有染色体不稳定、侵袭性强和预后差等特征，其诊断主要基于组织病理学，其他辅助检验检查技术缺乏特异性。近年随着高通量测序技术的成熟，基因组学在uLMS的发病机制研究中发展迅猛，发现了多个基因上调、基因下调、基因突变、基因融合等特异性基因分子的改变。综述基因组学在uLMS基因标志物方面的研究进展，并根据肿瘤的生物学行为对众多基因分子的改变进行分类，以构建多角度、多方面的uLMS异质性基因图谱，为uLMS分子水平的精准诊断及早期诊疗提供依据及方向。

关键词: 子宫肿瘤, 平滑肌肉瘤, 高通量核苷酸序列分析, 基因组学, 肿瘤生物学行为

Abstract:

Uterine leiomyosarcoma (uLMS) is one of the most common uterine sarcomas with features such as chromosome instability, strong invasiveness and poor prognosis. The diagnosis of uLMS is mainly based on histopathology, with a lack of specificity in other auxiliary examination techniques. In recent years，with the maturation of high-throughput sequencing technology, genomics has witnessed rapid development in the research on the pathogenesis of uLMS, uncovering multiple gene-specific molecular alterations such as gene upregulation, downregulation, mutations, and gene fusions. This review will systematically introduce the latest progress of uLMS in genomics research. The goal is to construct a multi-angle and multi-faceted heterogenetic map of uLMS, and provide basis and direction for the accurate and early diagnosis of uLMS at the molecular level as well.

Key words: Uterine neoplasms, Leiomyosarcoma, High-throughput nucleotide sequencing, Genomics, Tumor biological behavior

陈星羽, 韦雅婧, 梁炎春. 基于基因组学图谱构建的子宫平滑肌肉瘤前沿进展[J]. 国际妇产科学杂志, 2024, 51(6): 641-647.

CHEN Xing-yu, WEI Ya-jing, LIANG Yan-chun. Advances in Uterine Leiomyosarcoma：Mapping Based on Genomics[J]. Journal of International Obstetrics and Gynecology, 2024, 51(6): 641-647.

图/表 5

参考文献 55

[1]	Abeler VM, Royne O, Thoresen S, et al. Uterine sarcomas in Norway. A histopathological and prognostic survey of a total population from 1970 to 2000 including 419 patients[J]. Histopathology, 2009, 54(3):355-364. doi:10.1111/j.1365-2559.2009.03231.x. pmid: 19236512
[2]	Cree IA, White VA, Indave BI, et al. Revising the WHO classification:female genital tract tumours[J]. Histopathology, 2020, 76(1):151-156. doi:10.1111/his.13977. pmid: 31846528
[3]	Sherman RM, Salzberg SL. Pan-genomics in the human genome era[J]. Nat Rev Genet, 2020, 21(4):243-254. doi:10.1038/s41576-020-0210-7. pmid: 32034321
[4]	Haffner MC, Zwart W, Roudier MP, et al. Genomic and phenotypic heterogeneity in prostate cancer[J]. Nat Rev Urol, 2021, 18(2):79-92. doi:10.1038/s41585-020-00400-w. pmid: 33328650
[5]	Höhn AK, Brambs CE, Hiller GGR, et al. 2020 WHO Classification of Female Genital Tumors[J]. Geburtshilfe Frauenheilkd, 2021, 81(10):1145-1153. doi:10.1055/a-1545-4279.
[6]	Mbatani N, Olawaiye AB, Prat J. Uterine sarcomas[J]. Int J Gynaecol Obstet, 2018, 143(Suppl 2):51-58. doi:10.1002/ijgo.12613.
[7]	Dall GV, Hamilton A, Ratnayake G, et al. Interrogating the Genomic Landscape of Uterine Leiomyosarcoma:A Potential for Patient Benefit[J]. Cancers(Basel), 2022, 14(6):1561. doi:10.3390/cancers14061561.
[8]	Momeni-Boroujeni A, Yousefi E, Balakrishnan R, et al. Molecular-Based Immunohistochemical Algorithm for Uterine Leiomyosarcoma Diagnosis[J]. Mod Pathol, 2023, 36(4):100084. doi:10.1016/j.modpat.2022.100084.
[9]	中国抗癌协会妇科肿瘤专业委员会. 子宫肉瘤诊断与治疗指南(2021年版)[J]. 中国癌症杂志, 2021, 31(6):513-519. doi:10.19401/j.cnki.1007-3639.2021.06.09.
[10]	Gao T, Finkelman BS, Ban Y, et al. Integrated histologic and molecular analysis of uterine leiomyosarcoma and 2 benign variants with nuclear atypia[J]. Cancer Sci, 2021, 112(5):2046-2059. doi:10.1111/cas.14775.
[11]	Makinen N, Aavikko M, Heikkinen T, et al. Exome Sequencing of Uterine Leiomyosarcomas Identifies Frequent Mutations in TP53,ATRX,and MED12[J]. PLoS Genet, 2016, 12(2):e1005850. doi:10.1371/journal.pgen.1005850.
[12]	Cuppens T, Moisse M, Depreeuw J, et al. Integrated genome analysis of uterine leiomyosarcoma to identify novel driver genes and targetable pathways[J]. Int J Cancer, 2018, 142(6):1230-1243. doi:10.1002/ijc.31129. pmid: 29063609
[13]	Hensley ML, Chavan SS, Solit DB, et al. Genomic Landscape of Uterine Sarcomas Defined Through Prospective Clinical Sequencing[J]. Clin Cancer Res, 2020, 26(14):3881-3888. doi:10.1158/1078-0432.CCR-19-3959. pmid: 32299819
[14]	Yarchoan M, Hopkins A, Jaffee EM. Tumor Mutational Burden and Response Rate to PD-1 Inhibition[J]. N Engl J Med, 2017, 377(25):2500-2501. doi:10.1056/NEJMc1713444.
[15]	Malumbres M, Barbacid M. Cell cycle,CDKs and cancer:a changing paradigm[J]. Nat Rev Cancer, 2009, 9(3):153-166. doi:10.1038/nrc2602. pmid: 19238148
[16]	Williams EA, Sharaf R, Decker B, et al. CDKN2C-Null Leiomyosarcoma:A Novel,Genomically Distinct Class of TP53/RB1-Wild-Type Tumor With Frequent CIC Genomic Alterations and 1p/19q-Codeletion[J]. JCO Precis Oncol, 2020, 4:PO.20.00040. doi:10.1200/PO.20.00040.
[17]	Gao X, Leone GW, Wang H. Cyclin D-CDK4/6 functions in cancer[J]. Adv Cancer Res, 2020, 148:147-169. doi:10.1016/bs.acr.2020.02.002. pmid: 32723562
[18]	Zang Y, Gu L, Zhang Y, et al. Identification of key genes and pathways in uterine leiomyosarcoma through bioinformatics analysis[J]. Oncol Lett, 2018, 15(6):9361-9368. doi:10.3892/ol.2018.8503. pmid: 29844831
[19]	Seligson ND, Kautto EA, Passen EN, et al. BRCA1/2 Functional Loss Defines a Targetable Subset in Leiomyosarcoma[J]. Oncologist, 2019, 24(7):973-979. doi:10.1634/theoncologist.2018-0448. pmid: 30541756
[20]	Xie C, Luo J, He Y, et al. BRCA2 gene mutation in cancer[J]. Medicine(Baltimore), 2022, 101(45):e31705. doi:10.1097/MD.0000000000031705.
[21]	Ke Y, You L, Xu Y, et al. DPP6 and MFAP5 are associated with immune infiltration as diagnostic biomarkers in distinguishing uterine leiomyosarcoma from leiomyoma[J]. Front Oncol, 2022, 12:1084192. doi:10.3389/fonc.2022.1084192.
[22]	Uhlen M, Fagerberg L, Hallstrom BM, et al. Proteomics. Tissue-based map of the human proteome[J]. Science, 2015, 347(6220):1260419. doi:10.1126/science.1260419.
[23]	Croce S, Ducoulombier A, Ribeiro A, et al. Genome profiling is an efficient tool to avoid the STUMP classification of uterine smooth muscle lesions:a comprehensive array-genomic hybridization analysis of 77 tumors[J]. Mod Pathol, 2018, 31(5):816-828. doi:10.1038/modpathol.2017.185.
[24]	Keck JM, Summers MK, Tedesco D, et al. Cyclin E overexpression impairs progression through mitosis by inhibiting APC(Cdh1)[J]. J Cell Biol, 2007, 178(3):371-385. doi:10.1083/jcb.200703202. pmid: 17664332
[25]	Pilotte L, Larrieu P, Stroobant V, et al. Reversal of tumoral immune resistance by inhibition of tryptophan 2,3-dioxygenase[J]. Proc Natl Acad Sci U S A, 2012, 109(7):2497-2502. doi:10.1073/pnas.1113873109.
[26]	Chen L, Li J, Wu X, et al. Identification of Somatic Genetic Alterations Using Whole-Exome Sequencing of Uterine Leiomyosarcoma Tumors[J]. Front Oncol, 2021, 11:687899. doi:10.3389/fonc.2021.687899.
[27]	Kodama M, Shimura H, Tien JC, et al. Sleeping Beauty Transposon Mutagenesis Identifies Genes Driving the Initiation and Metastasis of Uterine Leiomyosarcoma[J]. Cancer Res, 2021, 81(21):5413-5424. doi:10.1158/0008-5472.CAN-21-0356. pmid: 34475109
[28]	Wang Y, Ma C, Yang X, et al. ZNF217:An Oncogenic Transcription Factor and Potential Therapeutic Target for Multiple Human Cancers[J]. Cancer Manag Res, 2024, 16:49-62. doi:10.2147/CMAR.S431135.
[29]	Choong LY, Lim SK, Chen Y, et al. Elevated NRD1 metalloprotease expression plays a role in breast cancer growth and proliferation[J]. Genes Chromosomes Cancer, 2011, 50(10):837-847. doi:10.1002/gcc.20905.
[30]	Su PH, Huang RL, Lai HC, et al. NKX6-1 mediates cancer stem-like properties and regulates sonic hedgehog signaling in leiomyosarcoma[J]. J Biomed Sci, 2021, 28(1):32. doi:10.1186/s12929-021-00726-6.
[31]	Mas A, Alonso R, Garrido-Gomez T, et al. The differential diagnoses of uterine leiomyomas and leiomyosarcomas using DNA and RNA sequencing[J]. Am J Obstet Gynecol, 2019, 221(4):320.e321-e323. doi:10.1016/j.ajog.2019.05.018.
[32]	Stangis MM, Colah AN, McLean DT, et al. Potential roles of FGF5 as a candidate therapeutic target in prostate cancer[J]. Am J Clin Exp Urol, 2023, 11(6):452-466. pmid: 38148937
[33]	Searcy MB, Larsen RK 4th, Stevens BT, et al. PAX3-FOXO1 dictates myogenic reprogramming and rhabdomyosarcoma identity in endothelial progenitors[J]. Nat Commun, 2023, 14(1):7291. doi:10.1038/s41467-023-43044-1. pmid: 37968277
[34]	Zhang S, Wang J, Liu Q, et al. PAX3-FOXO1 coordinates enhancer architecture,eRNA transcription,and RNA polymerase pause release at select gene targets[J]. Mol Cell, 2022, 82(23):4428-4442.e7. doi:10.1016/j.molcel.2022.10.025. pmid: 36395771
[35]	Cope BM, Traweek RS, Lazcano R, et al. Targeting the Molecular and Immunologic Features of Leiomyosarcoma[J]. Cancers(Basel), 2023, 15(7):2099. doi:10.3390/cancers15072099.
[36]	Travaglino A, Raffone A, Raimondo D, et al. Diagnostic and prognostic value of Bcl-2 in uterine leiomyosarcoma[J]. Arch Gynecol Obstet, 2023, 307(2):379-386. doi:10.1007/s00404-022-06531-2.
[37]	Hanahan D, Weinberg RA. The hallmarks of cancer[J]. Cell, 2000, 100(1):57-70. doi:10.1016/s0092-8674(00)81683-9. pmid: 10647931
[38]	Yoon JY, Marino-Enriquez A, Stickle N, et al. Myxoid smooth muscle neoplasia of the uterus:comprehensive analysis by next-generation sequencing and nucleic acid hybridization[J]. Mod Pathol, 2019, 32(11):1688-1697. doi:10.1038/s41379-019-0299-4.
[39]	Jiao Q, Bi L, Ren Y, et al. Advances in studies of tyrosine kinase inhibitors and their acquired resistance[J]. Mol Cancer, 2018, 17(1):36. doi:10.1186/s12943-018-0801-5. pmid: 29455664
[40]	Dermawan JK, Chiang S, Hensley ML, et al. High-Grade Sarcomas with Myogenic Differentiation Harboring Hotspot PDGFRB Mutations[J]. Mod Pathol, 2023, 36(5):100104. doi:10.1016/j.modpat.2023.100104.
[41]	Machado-Lopez A, Alonso R, Lago V, et al. Integrative Genomic and Transcriptomic Profiling Reveals a Differential Molecular Signature in Uterine Leiomyoma versus Leiomyosarcoma[J]. Int J Mol Sci, 2022, 23(4):2190. doi:10.3390/ijms23042190.
[42]	Ren B, Yang J, Wang C, et al. High-resolution Hi-C maps highlight multiscale 3D epigenome reprogramming during pancreatic cancer metastasis[J]. J Hematol Oncol, 2021, 14(1):120. doi:10.1186/s13045-021-01131-0.
[43]	Chiang S, Hensley ML, Vasudevaraja V, et al. 3D genomics identify alternate mechanisms of homologous recombination deficiency in uterine sarcoma[J]. J Clin Oncol, 2023, 41(16 suppl):e17624. doi:10.1200/JCO.2023.41.16_suppl.e17624.
[44]	Pavlova NN, Zhu J, Thompson CB. The hallmarks of cancer metabolism:Still emerging[J]. Cell Metab, 2022, 34(3):355-377. doi:10.1016/j.cmet.2022.01.007.
[45]	Regad T. Targeting RTK Signaling Pathways in Cancer[J]. Cancers(Basel), 2015, 7(3):1758-1784. doi:10.3390/cancers7030860.
[46]	Feng T, Zhao R, Zhang H, et al. Reciprocal negative feedback regulation of ATF6alpha and PTEN promotes prostate cancer progression[J]. Cell Mol Life Sci, 2023, 80(10):292. doi:10.1007/s00018-023-04940-3.
[47]	Weinberg RA. Coming full circle-from endless complexity to simplicity and back again[J]. Cell, 2014, 157(1):267-271. doi:10.1016/j.cell.2014.03.004. pmid: 24679541
[48]	Offin M, Chan JM, Tenet M, et al. Concurrent RB1 and TP53 Alterations Define a Subset of EGFR-Mutant Lung Cancers at risk for Histologic Transformation and Inferior Clinical Outcomes[J]. J Thorac Oncol, 2019, 14(10):1784-1793. doi:10.1016/j.jtho.2019.06.002.
[49]	Alvarez-Garcia V, Tawil Y, Wise HM, et al. Mechanisms of PTEN loss in cancer:It′s all about diversity[J]. Semin Cancer Biol, 2019, 59:66-79. doi:10.1016/j.semcancer.2019.02.001.
[50]	Roake CM, Artandi SE. Regulation of human telomerase in homeostasis and disease[J]. Nat Rev Mol Cell Biol, 2020, 21(7):384-397. doi:10.1038/s41580-020-0234-z.
[51]	Morad G, Helmink BA, Sharma P, et al. Hallmarks of response,resistance,and toxicity to immune checkpoint blockade[J]. Cell, 2021, 184(21):5309-5337. doi:10.1016/j.cell.2021.09.020.
[52]	Liu ZL, Chen HH, Zheng LL, et al. Angiogenic signaling pathways and anti-angiogenic therapy for cancer[J]. Signal Transduct Target Ther, 2023, 8(1):198. doi:10.1038/s41392-023-01460-1.
[53]	Apte RS, Chen DS, Ferrara N. VEGF in Signaling and Disease:Beyond Discovery and Development[J]. Cell, 2019, 176(6):1248-1264. doi:10.1016/j.cell.2019.01.021.
[54]	Giacomini A, Chiodelli P, Matarazzo S, et al. Blocking the FGF/FGFR system as a "two-compartment" antiangiogenic/antitumor approach in cancer therapy[J]. Pharmacol Res, 2016, 107:172-185. doi:10.1016/j.phrs.2016.03.024. pmid: 27013279
[55]	Suhail Y, Cain MP, Vanaja K, et al. Systems Biology of Cancer Metastasis[J]. Cell Syst, 2019, 9(2):109-127. doi:10.1016/j.cels.2019.07.003. pmid: 31465728

基因	相关通路效应	检测技术	参考文献
PTBP1、AGR2、 DUSP2、NR4A2、 MT1G、SIK1	抑制肿瘤细胞生长	WGS	[10]
PTEN	下调细胞增殖通路	WGS	[12]
TP53	抑制肿瘤细胞生长	WGS	[12]
RB1	抑制细胞周期进展	WGS	[12]
VIPR2	抑制肿瘤细胞生长	WGS	[12]
PDCD1	免疫逃逸	全外显子组测序	[13]
CDKN2C	调控细胞周期	杂交捕获测序	[16]
DPP6	未明确	GEO数据库	[21]
MFAP5	抑制肿瘤侵袭性	GEO数据库	[21]

基因	相关通路效应	检测技术	参考文献
PTBP1、AGR2、 DUSP2、NR4A2、 MT1G、SIK1	抑制肿瘤细胞生长	WGS	[10]
PTEN	下调细胞增殖通路	WGS	[12]
TP53	抑制肿瘤细胞生长	WGS	[12]
RB1	抑制细胞周期进展	WGS	[12]
VIPR2	抑制肿瘤细胞生长	WGS	[12]
PDCD1	免疫逃逸	全外显子组测序	[13]
CDKN2C	调控细胞周期	杂交捕获测序	[16]
DPP6	未明确	GEO数据库	[21]
MFAP5	抑制肿瘤侵袭性	GEO数据库	[21]

基因/染色体	相关通路效应	检测技术	参考文献
5p、17p	与肿瘤预后相关	比较基因组杂交分析	[23]
CCNE1	诱发染色体不稳定	WGS	[12]
TDO2	抑制抗肿瘤免疫反应	WGS	[12]
MAP2K4、RIT1	未知	外显子测序	[13]
SHARPIN	促进细胞增殖	外显子测序	[26]
ZNF217	促进细胞增殖与侵袭	GEPIA统计分析	[27]
NRDC	促进细胞迁移和黏附	GEPIA统计分析	[27]
NKX6-1	促进肿瘤细胞增殖	TCGA数据分析	[30]
FGF5	促进血管生成、侵袭转移	DNA和RNA测序	[31]
PAX3	影响细胞分化、增殖、转移	DNA和RNA测序	[31]

基因/染色体	相关通路效应	检测技术	参考文献
5p、17p	与肿瘤预后相关	比较基因组杂交分析	[23]
CCNE1	诱发染色体不稳定	WGS	[12]
TDO2	抑制抗肿瘤免疫反应	WGS	[12]
MAP2K4、RIT1	未知	外显子测序	[13]
SHARPIN	促进细胞增殖	外显子测序	[26]
ZNF217	促进细胞增殖与侵袭	GEPIA统计分析	[27]
NRDC	促进细胞迁移和黏附	GEPIA统计分析	[27]
NKX6-1	促进肿瘤细胞增殖	TCGA数据分析	[30]
FGF5	促进血管生成、侵袭转移	DNA和RNA测序	[31]
PAX3	影响细胞分化、增殖、转移	DNA和RNA测序	[31]

基因	基因突变后的效应	检测技术	参考文献
TP53、RB1	细胞增殖失控	WGS	[7]
ATRX	抑制端粒酶、促进细胞增殖	WGS	[35]
PTEN	促进细胞增殖	WGS	[8]
MED12	增强耐药性、侵袭性	WGS	[36]
BCL-2	增强耐药性，抵抗细胞凋亡	全外显子组测序	[37]
BRCA2	增加细胞发生DNA损伤	全外显子组测序	[38]
FRS3、SH2B3、SARM1、 BLK、FAM120A	酪氨酸激酶通路异常、细胞增殖异常	全外显子组测序	[38]
PDGFRB、CDKN2A/B、TERT	高度侵袭性、频繁的远处转移	全外显子组测序	[40]