Integrated mutational landscape analysis of uterine leiomyosarcomas

Jungmin Choi, Department of Biomedical Sciences, Korea University College of Medicine, 02841 Seoul, Korea.
Aranzazu Manzano, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06510.
Weilai Dong, Department of Genetics, Yale University School of Medicine, New Haven, CT 06510.
Stefania Bellone, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06510.
Elena Bonazzoli, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06510.
Luca Zammataro, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06510.
Xiaotong Yao, Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY.
Aditya Deshpande, Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY.
Samir Zaidi, Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065.
Adele Guglielmi, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06510.
Barbara Gnutti, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06510.
Nupur Nagarkatti, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06510.
Joan R. Tymon-Rosario, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06510.
Justin Harold, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06510.
Dennis Mauricio, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06510.
Burak Zeybek, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06510.
Gulden Menderes, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06510.
Gary Altwerger, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06510.
Kyungjo Jeong, Department of Biomedical Sciences, Korea University College of Medicine, 02841 Seoul, Korea.
Siming Zhao, Department of Human Genetics, University of Chicago, Chicago, IL 60637.
Natalia Buza, Department of Pathology, Yale University School of Medicine, New Haven, CT 06510.
Pei Hui, Department of Pathology, Yale University School of Medicine, New Haven, CT 06510.
Antonella Ravaggi, Department of Obstetrics and Gynecology, "Angelo Nocivelli" Institute of Molecular Medicine, University of Brescia, 25100 Brescia, Italy.
Eliana Bignotti, Department of Obstetrics and Gynecology, "Angelo Nocivelli" Institute of Molecular Medicine, University of Brescia, 25100 Brescia, Italy.
Chiara Romani, Department of Obstetrics and Gynecology, "Angelo Nocivelli" Institute of Molecular Medicine, University of Brescia, 25100 Brescia, Italy.
Paola Todeschini, Department of Obstetrics and Gynecology, "Angelo Nocivelli" Institute of Molecular Medicine, University of Brescia, 25100 Brescia, Italy.
Laura Zanotti, Department of Obstetrics and Gynecology, "Angelo Nocivelli" Institute of Molecular Medicine, University of Brescia, 25100 Brescia, Italy.
Franco Odicino, Department of Obstetrics and Gynecology, "Angelo Nocivelli" Institute of Molecular Medicine, University of Brescia, 25100 Brescia, Italy.
Sergio Pecorelli, Department of Obstetrics and Gynecology, "Angelo Nocivelli" Institute of Molecular Medicine, University of Brescia, 25100 Brescia, Italy.
Laura Ardighieri, Department of Pathology, University of Brescia, Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia, 25100 Brescia, Italy.
Kaya Bilguvar, Department of Genetics, Yale University School of Medicine, New Haven, CT 06510.
Charles M. Quick, Department of Pathology, University of Arkansas for Medical sciences, Little Rock, AR 72205.

Document Type

Article

Publication Title

Proceedings of the National Academy of Sciences of the United States of America

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.

DOI

10.1073/pnas.2025182118

Publication Date

4-13-2021

Identifier

33876771 (pubmed); PMC8053980 (pmc); 10.1073/pnas.2025182118 (doi); 2025182118 (pii)

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