气候变化领域集成服务门户(CCPortal): Integrated mutational landscape analysis of uterine leiomyosarcomas

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DOI	10.1073/pnas.2025182118
	Integrated mutational landscape analysis of uterine leiomyosarcomas
	Choi J.; Manzano A.; Dong W.; Bellone S.; Bonazzoli E.; Zammataro L.; Yao X.; Deshpande A.; Zaidi S.; Guglielmi A.; Gnutti B.; Nagarkatti N.; Tymon-Rosario J.R.; Harold J.; Mauricio D.; Zeybek B.; Menderes G.; Altwerger G.; Jeong K.; Zhao S.; Buza N.; Hui P.; Ravaggi A.; Bignotti E.; Romani C.; Todeschini P.; Zanotti L.; Odicino F.; Pecorelli S.; Ardighieri L.; Bilguvar K.; Quick C.M.; Silasi D.-A.; Huang G.S.; Andikyan V.; Clark M.; Ratner E.; Azodi M.; Imielinski M.; Schwartz P.E.; Alexandrov L.B.; Lifton R.P.; Schlessinger J.; Santin A.D.
发表日期	2021
ISSN	00278424
卷号	118 期号:15
英文摘要	Uterine leiomyosarcomas (uLMS) are aggressive tumors arising from the smooth muscle layer of the uterus. We analyzed 83 uLMS sample genetics, including 56 from Yale and 27 from The Cancer Genome Atlas (TCGA). Among them, a total of 55 Yale samples including two patient-derived xenografts (PDXs) and 27 TCGA samples have whole-exome sequencing (WES) data; 10 Yale and 27 TCGA samples have RNA-sequencing (RNA-Seq) data; and 11 Yale and 10 TCGA samples have whole-genome sequencing (WGS) data. We found recurrent somatic mutations in TP53, MED12, and PTEN genes. Top somatic mutated genes included TP53, ATRX, PTEN, and MEN1 genes. Somatic copy number variation (CNV) analysis identified 8 copy-number gains, including 5p15.33 (TERT), 8q24.21 (C-MYC), and 17p11.2 (MYOCD, MAP2K4) amplifications and 29 copy-number losses. Fusions involving tumor suppressors or oncogenes were deetected, with most fusions disrupting RB1, TP53, and ATRX/DAXX, and one fusion (ACTG2-ALK) being potentially targetable. WGS results demonstrated that 76% (16 of 21) of the samples harbored chromoplexy and/or chromothripsis. Clinically actionable mutational signatures of homologous-recombination DNA-repair deficiency (HRD) and microsatellite instability (MSI) were identified in 25% (12 of 48) and 2% (1 of 48) of fresh frozen uLMS, respectively. Finally, we found olaparib (PARPi; P = 0.002), GS-626510 (C-MYC/BETi; P < 0.000001 and P = 0.0005), and copanlisib (PIK3CAi; P = 0.0001) monotherapy to significantly inhibit uLMS-PDXs harboring derangements in C-MYC and PTEN/PIK3CA/AKT genes (LEY11) and/ or HRD signatures (LEY16) compared to vehicle-treated mice. These findings define the genetic landscape of uLMS and suggest that a subset of uLMS may benefit from existing PARP-, PIK3CA-, and C-MYC/BET-targeted drugs. © 2021 National Academy of Sciences. All rights reserved.
英文关键词	Mutational landscape; Uterine leiomyosarcomas; Whole-exome sequencing; Whole-genome sequencing
语种	英语
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/179893
作者单位	Department of Biomedical Sciences, Korea University, College of Medicine, Seoul, 02841, South Korea; Department of Genetics, Yale University, School of Medicine, New Haven, CT 06510, United States; Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University, School of Medicine, New Haven, CT 06510, United States; Laboratory of Human Genetics and Genomics, Rockefeller University, New York, NY 10065, United States; Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, United States; New York Genome Center, New York, NY 10013, United States; Computational Biology and Medicine, Weill Cornell Medicine, New York, NY 10021, United States; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, United States; Department of Human Genetics, University of Chicago, Chicago, IL 60637, United States; Department of Pathology, Yale University, School of Medicine, New Haven, CT 06510, United States; Department of Obst...
推荐引用方式 GB/T 7714	Choi J.,Manzano A.,Dong W.,et al. Integrated mutational landscape analysis of uterine leiomyosarcomas[J],2021,118(15).
APA	Choi J..,Manzano A..,Dong W..,Bellone S..,Bonazzoli E..,...&Santin A.D..(2021).Integrated mutational landscape analysis of uterine leiomyosarcomas.Proceedings of the National Academy of Sciences of the United States of America,118(15).
MLA	Choi J.,et al."Integrated mutational landscape analysis of uterine leiomyosarcomas".Proceedings of the National Academy of Sciences of the United States of America 118.15(2021).