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Integrated mutational landscape analysis of uterine leiomyosarcomas [Genetics]
Proceedings of the National Academy of Sciences of the United States of America ( IF 9.412 ) Pub Date : 2021-04-13 , DOI: 10.1073/pnas.2025182118
Jungmin Choi, Aranzazu Manzano, Weilai Dong, Stefania Bellone, Elena Bonazzoli, Luca Zammataro, Xiaotong Yao, Aditya Deshpande, Samir Zaidi, Adele Guglielmi, Barbara Gnutti, Nupur Nagarkatti, Joan R. Tymon-Rosario, Justin Harold, Dennis Mauricio, Burak Zeybek, Gulden Menderes, Gary Altwerger, Kyungjo Jeong, Siming Zhao, Natalia Buza, Pei Hui, Antonella Ravaggi, Eliana Bignotti, Chiara Romani, Paola Todeschini, Laura Zanotti, Franco Odicino, Sergio Pecorelli, Laura Ardighieri, Kaya Bilguvar, Charles M. Quick, Dan-Arin Silasi, Gloria S. Huang, Vaagn Andikyan, Mitchell Clark, Elena Ratner, Masoud Azodi, Marcin Imielinski, Peter E. Schwartz, Ludmil B. Alexandrov, Richard P. Lifton, Joseph Schlessinger, Alessandro D. Santin

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.



中文翻译:

子宫平滑肌肉瘤的综合突变景观分析[遗传学]

子宫平滑肌肉瘤(uLMS)是由子宫平滑肌层引起的侵袭性肿瘤。我们分析了83个uLMS样本遗传学,包括来自耶鲁大学的56个和来自癌症基因组图谱(TCGA)的27个。其中,共有55个耶鲁样品,包括两个患者衍生的异种移植物(PDX)和27个TCGA样品,均具有全外显子测序(WES)数据。10个耶鲁大学和27个TCGA样本具有RNA测序(RNA-Seq)数据;11个耶鲁大学和10个TCGA样本具有全基因组测序(WGS)数据。我们发现TP53,MED12和PTEN基因中的复发性体细胞突变。顶级的体细胞突变基因包括TP53,ATRX,PTEN和MEN1基因。体细胞拷贝数变异(CNV)分析确定了8个拷贝数增益,包括5p15.33(TERT),8q24.21(C-MYC)和17p11.2(MYOCD,MAP2K4)扩增和29个拷贝数损失。检测到涉及肿瘤抑制因子或癌基因的融合蛋白,其中大多数融合蛋白会破坏RB1,TP53和ATRX / DAXX,而一种融合蛋白(ACTG2-ALK)可能是可靶向的。WGS结果表明,有76%(21个样本中的16个)样本具有染色体异常和/或染色质增生。分别在25%(48中的12)和2%(48中的1)的新鲜冷冻uLMS中鉴定出同源重组DNA修复缺陷(HRD)和微卫星不稳定性(MSI)的可临床操作的突变特征。最后,我们找到了olaparib(PARPi; 分别在25%(48中的12)和2%(48中的1)的新鲜冷冻uLMS中鉴定出同源重组DNA修复缺陷(HRD)和微卫星不稳定性(MSI)的可临床操作的突变特征。最后,我们找到了olaparib(PARPi; 分别在25%(48中的12)和2%(48中的1)的新鲜冷冻uLMS中鉴定出同源重组DNA修复缺陷(HRD)和微卫星不稳定性(MSI)的可临床操作的突变特征。最后,我们找到了olaparib(PARPi;P = 0.002),GS-626510(C-MYC / BETi; P <0.000001和P = 0.0005)和copanlisib(PIK3CAi; P = 0.0001)单一疗法可显着抑制uLMS-PDX在C-MYC和PTEN / PIK3CA中发生排列紊乱/ AKT基因(LEY11)和/或HRD签名(LEY16)与经媒介物处理的小鼠相比。这些发现定义了uLMS的遗传格局,并暗示uLMS的一个子集可能会受益于现有的针对PARP,PIK3CA和C-MYC / BET的药物。

更新日期:2021-04-06
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