Integrated mutational landscape analysis of uterine leiomyosarcomas

Jungmin Choi(Korea University), Aránzazu Manzano(Yale University), Weilai Dong(Yale University), Stefania Bellone(Yale University), Elena Bonazzoli(Yale University), Luca Zammataro(Yale University), Xiaotong Yao(Cornell University), Aditya Deshpande(Cornell University), Samir Zaidi(Memorial Sloan Kettering Cancer Center), Adele Guglielmi(Yale University), Barbara Gnutti(Yale University), Nupur Nagarkatti(Yale University), Joan Tymon‐Rosario(Yale University), Justin Harold(Yale University), Dennis Mauricio(Yale University), Burak Zeybek(Yale University), Gulden Menderes(Yale University), Gary Altwerger(Yale University), Kyungjo Jeong(Korea University), Siming Zhao(University of Chicago), Natália Buza(Yale University), Pei Hui(Yale University), Antonella Ravaggi(University of Brescia), Eliana Bignotti(University of Brescia), Chiara Romani(University of Brescia), Paola Todeschini(University of Brescia), Laura Zanotti(University of Brescia), Franco Odicino(University of Brescia), Sërgio Pecorelli(University of Brescia), Laura Ardighieri(Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia), Kaya Bilgüvar(Yale University), Charles M. Quick(University of Arkansas for Medical Sciences), Dan-Arin Silasi(Mercy Clinic Neurology), Gloria S. Huang(Yale University), Vaagn Andikyan(Yale University), Mitchell Clark(Yale University), Elena Ratner(Yale University), Masoud Azodi(Yale University), Marcin Imieliński(Cornell University), Peter E. Schwartz(Yale University), Ludmil B. Alexandrov(University of California San Diego), Richard P. Lifton(Rockefeller University), Joseph Schlessinger(Yale University), Alessandro D. Santin(Yale University)
Proceedings of the National Academy of Sciences
April 5, 2021
10.1073/pnas.2025182118
Cited by 114Open Access
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Abstract

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.

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