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Contributed by Joseph Schlessinger, February 16, 2021 (sent for review November 30, 2020; reviewed by Gottfried E. Konecny and John A. Martignetti)
Significance
Identification of novel, effective treatment modalities for patients with uterine leiomyosarcomas (uLMS) remains an unmet medical need. Using an integrated whole-genome, whole-exome, and RNA-Seq analysis, we identified recurrently mutated genes and deranged pathways, including the homologous-recombination repair (HRR) pathway deficiency (HRD), alternative lengthening of telomere (ALT), C-MYC/BET, and PI3K-AKT-mTOR pathways as potential targets. Using two fully sequenced patient-derived xenografts (PDXs) harboring deranged C-MYC/BET and PTEN/PIK3CA pathways and/or an HRD signature (i.e., LEY11 and LEY16), we found olaparib (PARPi), GS-626510 (BETi), and copanlisib (PIK3CAi) monotherapy to significantly inhibit in vivo uLMS PDXs growth. Our integrated genetic analysis, combined with in vivo preclinical validation experiments, suggests that a large subset of uLMS may potentially benefit from existing PARPi/BETi/PIK3CAi-targeted drugs.
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.
Footnotes
↵1J.C., A.M., and W.D. contributed equally to this work.
- ↵2To whom correspondence may be addressed. Email: Joseph.Schlessinger{at}Yale.edu.
Author contributions: R.P.L., J.S., and A.D.S. designed research; S.B., E. Bonazzoli, L. Zammataro, A.G., B.G., N.N., J.R.T.-R., J.H., D.M., B.Z., G.M., G.A., N.B., P.H., A.R., E. Bignotti, C.R., P.T., L. Zanotti, F.O., S.P., L.A., and V.A. performed research; K.B., C.M.Q., D.-A.S., G.S.H., E.R., M.A., M.I., P.E.S., and L.B.A. contributed new reagents/analytic tools; J.C., A.M., W.D., X.Y., A.D., S. Zaidi, K.J., S. Zhao, R.P.L., J.S., and A.D.S. analyzed data; and J.C., A.M., W.D., S. Zaidi, S. Zhao, M.C., J.S., and A.D.S. wrote the paper.
Reviewers: G.E.K., David Geffen School of Medicine at UCLA; and J.A.M., Mount Sinai School of Medicine.
The authors declare no competing interest.
This article contains supporting information online at https://www.pnas.org/lookup/suppl/doi:10.1073/pnas.2025182118/-/DCSupplemental.
Data Availability
All study data are included in the article and/or supporting information.
Published under the PNAS license.
References
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Integrated mutational landscape analysis of uterine leiomyosarcomas
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