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Proc Natl Acad Sci U S A. 2019 Jan 8;116(2):619-624. doi: 10.1073/pnas.1814027116. Epub 2018 Dec 24.

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

Author information

1
Department of Genetics, Yale School of Medicine, New Haven, CT 06510.
2
Department of Obstetrics, Gynecology & Reproductive Sciences, Yale School of Medicine, New Haven, CT 06510.
3
Department of Pathology, Yale School of Medicine, New Haven, CT 06510.
4
Department of Obstetrics & Gynecology, Angelo Nocivelli Institute of Molecular Medicine, University of Brescia, 25100 Brescia, Italy.
5
Department of Pathology, University of Brescia, 25100 Brescia, Italy.
6
Laboratory of Human Genetics and Genomics, The Rockefeller University, New York, NY 10065.
7
Department of Pharmacology, Yale School of Medicine, New Haven, CT 06510 joseph.schlessinger@yale.edu.

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.

KEYWORDS:

BET inhibitors; bilateral ovarian tumors; ovarian carcinoma; whole-exome sequencing

PMID:
30584090
PMCID:
PMC6329978
[Available on 2019-07-08]
DOI:
10.1073/pnas.1814027116
[Indexed for MEDLINE]

Conflict of interest statement

The authors declare no conflict of interest.

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