TY - JOUR
T1 - Mutational landscape of primary, metastatic, and recurrent ovarian cancer reveals c-MYC gains as potential target for BET inhibitors
AU - Li, Charles
AU - Bonazzoli, Elena
AU - Bellone, Stefania
AU - Choi, Jungmin
AU - Dong, Weilai
AU - Menderes, Gulden
AU - Altwerger, Gary
AU - Han, Chanhee
AU - Manzano, Aranzazu
AU - Bianchi, Anna
AU - Pettinella, Francesca
AU - Manara, Paola
AU - Lopez, Salvatore
AU - Yadav, Ghanshyam
AU - Riccio, Francesco
AU - Zammataro, Luca
AU - Zeybek, Burak
AU - Yang-Hartwich, Yang
AU - Buza, Natalia
AU - Hui, Pei
AU - Wong, Serena
AU - Ravaggi, Antonella
AU - Bignotti, Eliana
AU - Romani, Chiara
AU - Todeschini, Paola
AU - Zanotti, Laura
AU - Zizioli, Valentina
AU - Odicino, Franco
AU - Pecorelli, Sergio
AU - Ardighieri, Laura
AU - Silasi, Dan Arin
AU - Litkouhi, Babak
AU - Ratner, Elena
AU - Azodi, Masoud
AU - Huang, Gloria S.
AU - Schwartz, Peter E.
AU - Lifton, Richard P.
AU - Schlessinger, Joseph
AU - Santin, Alessandro D.
N1 - Funding Information:
This work was supported in part by grants from the NIH (U01 CA176067-01A1), the Deborah Bunn Alley Ovarian Cancer Research Foundation, The Honorable Tina Brozman Foundation, the Discovery to Cure Foundation, the Stand Up to Cancer Foundation, and the Guido Berlucchi Foundation (to A.D.S.); and by Gilead Sciences Inc.. This investigation was also supported by the Research Grant CA-16359 from the NIH National Cancer Institute.
Publisher Copyright:
© 2019 National Academy of Sciences. All Rights Reserved.
PY - 2019/1/8
Y1 - 2019/1/8
N2 - 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.
AB - 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.
KW - BET inhibitors
KW - Bilateral ovarian tumors
KW - Ovarian carcinoma
KW - Whole-exome sequencing
UR - http://www.scopus.com/inward/record.url?scp=85059541396&partnerID=8YFLogxK
U2 - 10.1073/pnas.1814027116
DO - 10.1073/pnas.1814027116
M3 - Article
C2 - 30584090
AN - SCOPUS:85059541396
SN - 0027-8424
VL - 116
SP - 619
EP - 624
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 2
ER -
