Integrated mutational landscape analysis of uterine leiomyosarcomas

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 ZhaoNatalia 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

Research output: Contribution to journalArticlepeer-review

4 Citations (Scopus)

Abstract

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.

Original languageEnglish
Article numbere2025182118
JournalProceedings of the National Academy of Sciences of the United States of America
Volume118
Issue number15
DOIs
Publication statusPublished - 2021 Apr 13

Keywords

  • Mutational landscape
  • Uterine leiomyosarcomas
  • Whole-exome sequencing
  • Whole-genome sequencing

ASJC Scopus subject areas

  • General

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