Mutational landscape of primary, metastatic, and recurrent ovarian cancer reveals c-MYC gains as potential target for BET inhibitors

Charles Li, Department of Genetics, Yale School of Medicine, New Haven, CT 06510.
Elena Bonazzoli, Department of Obstetrics, Gynecology & Reproductive Sciences, Yale School of Medicine, New Haven, CT 06510.
Stefania Bellone, Department of Obstetrics, Gynecology & Reproductive Sciences, Yale School of Medicine, New Haven, CT 06510.
Jungmin Choi, Department of Genetics, Yale School of Medicine, New Haven, CT 06510.
Weilai Dong, Department of Genetics, Yale School of Medicine, New Haven, CT 06510.
Gulden Menderes, Department of Obstetrics, Gynecology & Reproductive Sciences, Yale School of Medicine, New Haven, CT 06510.
Gary Altwerger, Department of Obstetrics, Gynecology & Reproductive Sciences, Yale School of Medicine, New Haven, CT 06510.
Chanhee Han, Department of Obstetrics, Gynecology & Reproductive Sciences, Yale School of Medicine, New Haven, CT 06510.
Aranzazu Manzano, Department of Obstetrics, Gynecology & Reproductive Sciences, Yale School of Medicine, New Haven, CT 06510.
Anna Bianchi, Department of Obstetrics, Gynecology & Reproductive Sciences, Yale School of Medicine, New Haven, CT 06510.
Francesca Pettinella, Department of Obstetrics, Gynecology & Reproductive Sciences, Yale School of Medicine, New Haven, CT 06510.
Paola Manara, Department of Obstetrics, Gynecology & Reproductive Sciences, Yale School of Medicine, New Haven, CT 06510.
Salvatore Lopez, Department of Obstetrics, Gynecology & Reproductive Sciences, Yale School of Medicine, New Haven, CT 06510.
Ghanshyam Yadav, Department of Obstetrics, Gynecology & Reproductive Sciences, Yale School of Medicine, New Haven, CT 06510.
Francesco Riccio, Department of Obstetrics, Gynecology & Reproductive Sciences, Yale School of Medicine, New Haven, CT 06510.
Luca Zammataro, Department of Obstetrics, Gynecology & Reproductive Sciences, Yale School of Medicine, New Haven, CT 06510.
Burak Zeybek, Department of Obstetrics, Gynecology & Reproductive Sciences, Yale School of Medicine, New Haven, CT 06510.
Yang Yang-Hartwich, Department of Obstetrics, Gynecology & Reproductive Sciences, Yale School of Medicine, New Haven, CT 06510.
Natalia Buza, Department of Pathology, Yale School of Medicine, New Haven, CT 06510.
Pei Hui, Department of Pathology, Yale School of Medicine, New Haven, CT 06510.
Serena Wong, Department of Pathology, Yale School of Medicine, New Haven, CT 06510.
Antonella Ravaggi, Department of Obstetrics & Gynecology, Angelo Nocivelli Institute of Molecular Medicine, University of Brescia, 25100 Brescia, Italy.
Eliana Bignotti, Department of Obstetrics & Gynecology, Angelo Nocivelli Institute of Molecular Medicine, University of Brescia, 25100 Brescia, Italy.
Chiara Romani, Department of Obstetrics & Gynecology, Angelo Nocivelli Institute of Molecular Medicine, University of Brescia, 25100 Brescia, Italy.
Paola Todeschini, Department of Obstetrics & Gynecology, Angelo Nocivelli Institute of Molecular Medicine, University of Brescia, 25100 Brescia, Italy.
Laura Zanotti, Department of Obstetrics & Gynecology, Angelo Nocivelli Institute of Molecular Medicine, University of Brescia, 25100 Brescia, Italy.
Valentina Zizioli, Department of Obstetrics & Gynecology, Angelo Nocivelli Institute of Molecular Medicine, University of Brescia, 25100 Brescia, Italy.
Franco Odicino, Department of Obstetrics & Gynecology, Angelo Nocivelli Institute of Molecular Medicine, University of Brescia, 25100 Brescia, Italy.
Sergio Pecorelli, Department of Obstetrics & Gynecology, Angelo Nocivelli Institute of Molecular Medicine, University of Brescia, 25100 Brescia, Italy.
Laura Ardighieri, Department of Pathology, University of Brescia, 25100 Brescia, Italy.
Dan-Arin Silasi, Department of Obstetrics, Gynecology & Reproductive Sciences, Yale School of Medicine, New Haven, CT 06510.
Babak Litkouhi, Department of Obstetrics, Gynecology & Reproductive Sciences, Yale School of Medicine, New Haven, CT 06510.

Document Type

Article

Publication Title

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

Abstract

Ovarian cancer remains the most lethal gynecologic malignancy. We analyzed the mutational landscape of 64 primary, 41 metastatic, and 17 recurrent fresh-frozen tumors from 77 patients along with matched normal DNA, by whole-exome sequencing (WES). We also sequenced 13 pairs of synchronous bilateral ovarian cancer (SBOC) to evaluate the evolutionary history. Lastly, to search for therapeutic targets, we evaluated the activity of the Bromodomain and Extra-Terminal motif (BET) inhibitor GS-626510 on primary tumors and xenografts harboring c-MYC amplifications. In line with previous studies, the large majority of germline and somatic mutations were found in BRCA1/2 (21%) and TP53 (86%) genes, respectively. Among mutations in known cancer driver genes, 77% were transmitted from primary tumors to metastatic tumors, and 80% from primary to recurrent tumors, indicating that driver mutations are commonly retained during ovarian cancer evolution. Importantly, the number, mutation spectra, and signatures in matched primary-metastatic tumors were extremely similar, suggesting transcoelomic metastases as an early dissemination process using preexisting metastatic ability rather than an evolution model. Similarly, comparison of SBOC showed extensive sharing of somatic mutations, unequivocally indicating a common ancestry in all cases. Among the 17 patients with matched tumors, four patients gained PIK3CA amplifications and two patients gained c-MYC amplifications in the recurrent tumors, with no loss of amplification or gain of deletions. Primary cell lines and xenografts derived from chemotherapy-resistant tumors demonstrated sensitivity to JQ1 and GS-626510 (P = 0.01), suggesting that oral BET inhibitors represent a class of personalized therapeutics in patients harboring recurrent/chemotherapy-resistant disease.

First Page

619

Last Page

624

DOI

10.1073/pnas.1814027116

Publication Date

1-8-2019

Identifier

30584090 (pubmed); PMC6329978 (pmc); 10.1073/pnas.1814027116 (doi); 1814027116 (pii)

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