遗传 ›› 2024, Vol. 46 ›› Issue (8): 603-626.doi: 10.16288/j.yczz.24-132
王陈颖1,2,3(), 肖荟尹3,4(), 诸志鹏3, 郑素雅1,2, 徐良3,5(), 陈烨1,2,5()
收稿日期:
2024-05-08
修回日期:
2024-07-23
出版日期:
2024-08-20
发布日期:
2024-07-25
通讯作者:
徐良,博士,研究员,研究方向:肿瘤遗传学和表观遗传。E-mail: xuliang.phd@zju.edu.cn;作者简介:
王陈颖,硕士,研究助理,研究方向:肿瘤遗传学。E-mail: wangcary@zju.edu.cn;王陈颖和肖荟尹并列第一作者。
基金资助:
Chenying Wang1,2,3(), Huiyin Xiao3,4(), Zhipeng Zhu3, Suya Zheng1,2, Liang Xu3,5(), Ye Chen1,2,5()
Received:
2024-05-08
Revised:
2024-07-23
Published:
2024-08-20
Online:
2024-07-25
Supported by:
摘要:
子宫平滑肌肉瘤(uterine leiomyosarcoma,uLMS)是一种发生在女性生殖系统子宫肌层的恶性软组织肿瘤,漏诊误诊率高、侵袭性强、预后差。uLMS的发生机制尚未明确,疾病生物学研究相对滞后,实验模型和治疗手段也较为有限。本文重点关注了uLMS的病理分子生物学,系统梳理了uLMS的分子遗传学特征、表观遗传学变异、实验模型以及临床研究进展,同时还探讨了uLMS在肿瘤演进、肿瘤微环境、肿瘤治疗等生物学研究领域的发展方向和潜在需求,以期更好地理解uLMS的病理生物学机制并为开发潜在诊疗策略提供参考。
王陈颖, 肖荟尹, 诸志鹏, 郑素雅, 徐良, 陈烨. 子宫平滑肌肉瘤的分子遗传学特征与研究进展[J]. 遗传, 2024, 46(8): 603-626.
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.
表1
uLMS中发生高频突变的基因"
基因 | MSK Leiomyosarcoma[ uLMS (n=255) | MSK Uterine Sarcoma/Mesenchymal[ | TCGA Adult Soft Tissue Sarcomas[ uLMS (n=27) | GENIE Cohort v15.10[ uLMS (n=395) | Yale[ 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% |
表2
uLMS中发生高频拷贝数扩增的基因"
染色体区段 | 基因 | MSK Leiomyosarcoma[ uLMS (n=255) | MSK Uterine Sarcoma/ Mesenchymal[ uLMS (n=80) | TCGA Adult Soft Tissue Sarcomas [ 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% |
表3
uLMS中发生高频拷贝数缺失的基因"
染色体区段 | 基因 | MSK Leiomyosarcoma[ uLMS (n=255) | MSK Uterine Sarcoma/Mesenchymal[ | TCGA Adult Soft Tissue Sarcomas [ uLMS (n=27) | GENIE Cohort v15.10[ 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% |
表4
uLMS临床试验"
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 |
表5
uLMS相关的基因工程小鼠模型"
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 | [ | 2002 |
HS-cre1;β-actinSVER/+ | 100% | 3月 | uLMS | [ | 2004 |
MMTV-CR1 | 20% | 24月 | uLMS | [ | 2007 |
Amhr2-Cre;Trp53fl/fl | 52% | 13月 | uLMS | [ | 2009 |
Amhr2-Cre;Trp53fl/fl;Brca1fl/fl | 82% | uLMS | |||
Amhr2-Cre;Ptenfl/fl;KrasG12D/+;SB+ | 100% | 3月 | 转移性uLMS | [ | 2021 |
Amhr2-Cre;Ptenfl/fl;KrasG12V/+ | 90% | 66周 | UL、uLMS等 | [ | 2020 |
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