子宫平滑肌肉瘤的分子遗传学特征与研究进展

doi:10.16288/j.yczz.24-132

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Hereditas(Beijing) ›› 2024, Vol. 46 ›› Issue (8): 603-626.doi: 10.16288/j.yczz.24-132

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Molecular genetics and research progress of uterine leiomyosarcoma

Chenying Wang¹^,²^,³(), Huiyin Xiao³^,⁴(), Zhipeng Zhu³, Suya Zheng¹^,², Liang Xu³^,⁵(), Ye Chen¹^,²^,⁵()

1. Department of Surgical Oncology, Children's Hospital Zhejiang University School of Medicine, Hangzhou 310052, China
2. Pediatric Cancer Research Center, National Clinical Research Center for Child Health, Hangzhou 310052, China
3. Institute of Biochemistry, College of Life Sciences, Zhejiang University, Hangzhou 310058, China
4. Chu Kochen Honors College, Zhejiang University, Hangzhou 310058, China
5. Cancer Center, Zhejiang University, Hangzhou 310058, China

Received:2024-05-08 Revised:2024-07-23 Online:2024-08-20 Published:2024-07-25
Contact: Liang Xu, Ye Chen E-mail:wangcary@zju.edu.cn;3210104172@zju.edu.cn;xuliang.phd@zju.edu.cn;chenyephd@zju.edu.cn
Supported by:
National Natural Science Foundation of China(32270746);National Natural Science Foundation of China(82203247);National Natural Science Foundation of China(82203415);Zhejiang Natural Science Foundation(LZ23C060002);Zhejiang Natural Science Foundation(LZ24H160004)

Abstract

Abstract:

Uterine leiomyosarcoma (uLMS) is a type of malignant soft-tissue tumor, which is developed from myometrium in the female reproductive system. This disease is difficult to be distinguished from benign uterine leiomyoma in the early stages, but it progresses aggressively and relentlessly. Hence, uLMS has a dismal prognosis and high rates of both misdiagnosis and missed diagnosis. Unfortunately, current studies of uLMS pathogenesis and disease biology are inadequate. uLMS disease models are also very limited, hindering the development of effective therapeutics. In this review, we focus on the pathological molecular biology of uLMS, and systematically review the molecular genetic features, epigenetic variants, experimental models, and clinical research progress of uLMS. We further discuss the development direction and potential needs of uLMS in the fields of tumor evolution, tumor microenvironment, and tumor therapy, with the aim of providing a better understanding of the pathobiological mechanism of uLMS and providing a reference for the development of potential diagnostic and therapeutic strategies.

Key words: uterine leiomyosarcoma, genetic dysregulation, molecular pathology, cancer therapy, disease models

Chenying Wang, Huiyin Xiao, Zhipeng Zhu, Suya Zheng, Liang Xu, Ye Chen. Molecular genetics and research progress of uterine leiomyosarcoma[J]. Hereditas(Beijing), 2024, 46(8): 603-626.

Figures/Tables 7

Table 1

Table 2

Table 3

Fig. 1

Table 4

Clinical trials of uLMS"

试验编号	入组范围	状态	测试药物	靶点	开始时间
NCT05649956	uLMS	招募中	来曲唑(letrozole)	芳香化酶	2024/3/1
NCT01637961	uLMS	已完成	Aurora A激酶抑制剂(alisertib)	Aurora A、Aurora B	2012/8/1
NCT02249702	uLMS	已完成	多西他赛(docetaxel)+吉西他滨多西他赛+曲贝替定	微管，DNA合成，DNA	2010/4/1
NCT05432791	含uLMS	招募中	奥拉帕利(olaparib)、帕唑帕尼(pazopanib)、替莫唑胺(temozolomide)、曲贝替定	PARP，酪氨酸激酶(VEGFR、PDGFRβ、FGFR1、c-KIT等)，DNA烷化剂，DNA	2023/3/30
NCT04727242	含uLMS	招募中	吉西他滨、达卡巴嗪	DNA合成，DNA烷化剂	2021/1/28
NCT03926936	含uLMS	招募中	氟维司群(fulvestrant)	雌激素受体	2019/3/13
NCT04200443	含uLMS	激活_未招募	卡博替尼(cabozantinib)、替莫唑胺	酪氨酸激酶(VEGFR2、MET等)，DNA烷化剂	2020/1/14
NCT02428192	含uLMS	激活_未招募	纳武利尤单抗(nivolumab)	PD-1	2015/4/22
NCT03880019	含uLMS	已完成	奥拉帕利、替莫唑胺	PARP，DNA烷化剂	2019/8/19
NCT03241745	含uLMS	已完成	纳武利尤单抗	PD-1	2017/8/3
NCT03509207	含uLMS	已完成	伏立诺他(vorinostat)	HDAC	2017/12/14
NCT01220609	含uLMS	已完成	伊沙匹隆(ixabepilone)	微管	2010/11/1
NCT02131480	含uLMS	已完成	阿霉素、曲贝替定	拓扑异构酶(topoisomerase I、Topoisomerase II)，DNA	2010/6/1
NCT02601209	含uLMS	终止	盐酸帕唑帕尼、沙帕色替(sapanisertib)	酪氨酸激酶(VEGFR、PDGFRβ、FGFR1、c-KIT等)，mTOR	2015/11/30
NCT01958580	含uLMS	终止	盐酸吉西他滨、多西他赛	DNA合成，微管	2013/9/17
NCT01533207	含uLMS	终止	多西他赛、盐酸阿霉素、非格司亭(filgrastim)、盐酸吉西他滨、培非格司亭(pegfilgrastim)	微管，拓扑异构酶(topoisomerase I、Topoisomerase II)，CSF3R，DNA合成	2012/6/4
NCT02997358	含uLMS	已完成	阿霉素、曲贝替定	拓扑异构酶(topoisomerase I、Topoisomerase II)，DNA	2017/1/18
NCT01442662	含uLMS	已完成	帕唑帕尼+吉西他滨	酪氨酸激酶(VEGFR1、PDGFRβ、FGFR1、c-KIT等)，DNA合成	2011/9/1
ChiCTR2300072293	含LMS	招募中	赛帕利单抗+安罗替尼(anlotinib)+艾日布林	PD-1，酪氨酸激酶(VEGFR、FGFR、PDGFR、c-KIT)，微管	2023/6/1
ChiCTR2100049157	含LMS	招募中	阿霉素+卡瑞利珠单抗	拓扑异构酶(topoisomerase I、topoisomerase II)，PD-1	2021/4/1
ChiCTR2100048014	含LMS	招募中	派安普利单抗+盐酸安罗替尼+表柔比星	PD-1，酪氨酸激酶(VEGFR、FGFR、PDGFR、c-KIT等)，拓扑异构酶(topoisomerase II)，DNA和RNA合成	2021/4/30
ChiCTR1900023065	含LMS	已完成	盐酸安罗替尼	酪氨酸激酶(VEGFR、FGFR、PDGFR、c-KIT等)	2019/3/1
ChiCTR2100052825	含LMS	伦理审批中	紫杉醇+卡瑞利珠单抗	微管，PD-1	2021/11/1

Table 4

Fig. 2

Table 5

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基因	MSK Leiomyosarcoma^[25] uLMS (n=255)	MSK Uterine Sarcoma/Mesenchymal^[26] uLMS (n=80)	TCGA Adult Soft Tissue Sarcomas^[24] uLMS (n=27)	GENIE Cohort v15.10^[27] uLMS (n=395)	Yale^[28] uLMS (n=55)
TP53	54.90%	46.30%	44.40%	52.90%	49.09%
ATRX	26.70%	30.00%	22.20%	28.10%	32.73%
TET3	NA	NA	3.70%	33.30%	3.64%
MED12	14.90%	12.50%	NA	14.00%	14.55%
RB1	10.60%	13.80%	3.70%	10.60%	7.27%
SYNE1	NA	NA	3.70%	16.70%	3.64%
TRRAP	NA	NA	3.70%	13.30%	5.45%
MYH11	NA	NA	3.70%	10.00%	1.82%
PTEN	4.70%	6.30%	NA	5.10%	7.27%
DOCK8	NA	NA	7.40%	9.40%	3.64%
LRP1B	NA	NA	3.70%	8.60%	3.64%
FAT1	3.50%	6.30%	NA	4.40%	1.82%
KMT2D	2.40%	1.30%	3.70%	4.60%	7.27%
SMARCAL1	NA	NA	3.70%	7.10%	1.82%
DAXX	5.10%	1.30%	NA	2.80%	5.45%
ATM	1.60%	2.50%	3.70%	4.60%	3.64%
KMT2A	3.10%	3.80%	3.70%	3.20%	1.82%
TERT	2.70%	1.30%	NA	3.90%	3.64%
TOPBP1	NA	NA	3.70%	5.70%	1.82%
BRINP3	NA	NA	7.40%	5.30%	1.82%

染色体区段	基因	MSK Leiomyosarcoma^[25]uLMS (n=255)	MSK Uterine Sarcoma/ Mesenchymal^[26] uLMS (n=80)	TCGA Adult Soft Tissue Sarcomas ^[24] uLMS (n=27)	GENIE Cohort v15.10 uLMS (n=395)
1q21.2	APH1A	NA	NA	7.40%	16.70%
1q21.2	MCL1	5.10%	2.50%	7.40%	3.40%
1q21.3	CKS1B	NA	NA	3.70%	16.70%
1q21.3	SETDB1	9.30%	NA	7.40%	6.50%
1q23.2	NCSTN	NA	NA	3.70%	16.70%
17p12	MAP2K4	7.80%	7.50%	7.40%	8.60%
17p12-p11.2	NCOR1	7.80%	6.30%	7.40%	7.50%
17p11.2	FLCN	8.20%	5.00%	11.10%	7.70%
17p11.2	GID4	NA	NA	7.40%	7.10%
2q13	RANBP2	20.00%	NA	3.70%	NA
1q32.1	BTG2	NA	NA	3.70%	12.50%
1q22	YY1AP1	NA	NA	3.70%	9.10%
1q22	RIT1	5.10%	2.50%	3.70%	3.60%
1q23.1	NTRK1	5.50%	3.80%	3.70%	4.00%
18q21.33	SERPINB3	5.30%	NA	NA	3.20%
18q21.33	SERPINB4	5.30%	NA	NA	3.20%
17p13.1	AURKB	3.90%	3.80%	NA	2.80%
17p13.1	ALOX12B	3.10%	3.80%	NA	2.80%
19p13.2	DNMT1	3.10%	1.30%	NA	3.20%
19p13.2	CARM1	3.20%	NA	NA	3.30%

染色体区段	基因	MSK Leiomyosarcoma^[25] uLMS (n=255)	MSK Uterine Sarcoma/Mesenchymal^[26] uLMS (n=80)	TCGA Adult Soft Tissue Sarcomas ^[24] uLMS (n=27)	GENIE Cohort v15.10^[27] uLMS (n=395)
13q14.2	RB1	40.80%	37.50%	18.50%	40.40%
13q14.2	CYSLTR2	30.70%	27.30%	14.80%	31.50%
17p13.1	TP53	19.20%	10.00%	3.70%	15.50%
10q23.31	PTEN	14.50%	12.50%	14.80%	13.10%
10q23.31	KLLN	NA	NA	7.40%	12.50%
2q37.3	PDCD1	10.60%	8.80%	7.40%	10.20%
9p21.3	CDKN2A	7.10%	8.80%	14.80%	8.20%
9p21.3	CDKN2B	6.70%	8.80%	14.80%	7.60%
9p21.3	MTAP	4.00%	NA	7.40%	6.30%
14q24.1	RAD51B	5.90%	3.80%	11.10%	5.40%
Xq21.1	ATRX	5.50%	6.30%	7.40%	4.30%
13q13.1	BRCA2	6.30%	5.00%	3.70%	3.60%
4q35.2	FAT1	4.70%	2.50%	NA	3.90%
Xp22.33和Yp11.2	CRLF2	3.50%	3.80%	NA	3.80%
6p25.3	IRF4	3.90%	1.30%	NA	3.90%
1p36.32	TNFRSF14	4.30%	3.80%	3.70%	2.70%
10q11.21	RET	3.50%	5.00%	NA	2.40%
9p21.2	TEK	2.10%	9.10%	NA	2.20%
1p32.3	CDKN2C	3.10%	NA	11.10%	2.50%
19q13.2	CIC	2.70%	1.30%	7.40%	2.40%

基因型	发病率	观察期	肿瘤类型	参考文献	首发年份
Lmp2^-/-	36%	12月	uLMS	[131]	2002
HS-cre1；β-actin^SVER/⁺	100%	3月	uLMS	[133]	2004
MMTV-CR1	20%	24月	uLMS	[134]	2007
Amhr2-Cre；Trp53^fl/fl	52%	13月	uLMS	[137]	2009
Amhr2-Cre；Trp53^fl/fl；Brca1^fl/fl	82%	13月	uLMS	[137]	2009
Amhr2-Cre；Pten^fl/fl；Kras^G12D/+；SB⁺	100%	3月	转移性uLMS	[138]	2021
Amhr2-Cre；Pten^fl/fl；Kras^G12V/+	90%	66周	UL、uLMS等	[139]	2020

Molecular genetics and research progress of uterine leiomyosarcoma

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