Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 118, Issue 15, Pages -Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2025182118
Keywords
uterine leiomyosarcomas; whole-exome sequencing; mutational landscape; whole-genome sequencing
Categories
Funding
- Gilead Sciences Inc. (Foster City, CA)
- NIH [U01 CA176067-01A1]
- Deborah Bunn Alley Foundation
- Tina Brozman Foundation
- Discovery to Cure Foundation
- Guido Berlucchi Foundation
- NIH Research Grant from the National Cancer Institute [CA-16359]
- Stand Up To Cancer (SU2C) Convergence Grant 2.0
- Korea University Medical Center Grant
- Spanish Society of Medical Oncology
- American Heart Association [19PRE34380842]
Ask authors/readers for more resources
The study analyzed the genetics of uterine leiomyosarcomas and identified recurrent somatic mutations, copy number variations, and gene fusions. Some uLMS may benefit from existing PARP-, PIK3CA-, and C-MYC/BET-targeted drugs.
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 on-cogenes were deetected, with most fusions disrupting RB1, TP53, and ATRX/DAXX, and one fusion (ACTG2-ALK) being po-tentially targetable. WGS results demonstrated that 76% (16 of 21) of the samples harbored chromoplexy and/or chromothrip-sis. 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-62 6510 (C-MYC/BETi; P < 0.000001 and P = 0.0005), and copanlisib (PIK3CAi; P = 0.0001) monotherapy to significantly inhibit uLMS-PDXs harboring de-rangements 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 sug-gest that a subset of uLMS may benefit from existing PARP-, PIK3CA-, and C-MYC/BET-targeted drugs.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available