ADAMTS16 mutations sensitize ovarian cancer cells to platinum-based chemotherapy
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Maya Yasukawa1,5, Yuexin Liu1,7, Limei Hu1, David Cogdell1, Kshipra M. Gharpure2, Sunila Pradeep2, Archana S. Nagaraja2, Anil K. Sood2,3,4 and Wei Zhang1,4,6
1Departments of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
2Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
3Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
4Center for RNA Interference and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
5Department of Obstetrics and Gynecology, Showa University School of Medicine, Shinagawa-ku, Tokyo, Japan
6Department of Cancer Biology, Comprehensive Cancer Center of Wake Forest Baptist Medical Center, Winston-Salem, North Carolina, USA
7Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
Keywords: ovarian cancer, ADAMTS16, chemosensitivity, platinum-based chemotherapy, BRCAness
Received: April 07, 2016 Accepted: July 07, 2016 Published: August 08, 2016
Ovarian cancer is one of the most lethal malignant tumors in women. The prognosis of ovarian cancer patients depends, in part, on their response to platinum-based chemotherapy. Our recent analysis of genomics and clinical data from the Cancer Genome Atlas demonstrated that somatic mutations of ADAMTS 1, 6, 8, 9, 15, 16, 18 and L1 genes were associated with higher sensitivity to platinum and longer progression-free survival, overall survival, and platinum-free survival duration in 512 patients with high-grade serous ovarian carcinoma. Among the ADAMTS mutations, ADAMTS16 is the most commonly affected gene in ovarian cancer. However, the functional role of these mutations in ovarian cancer cells is largely unknown. We performed in vitro studies to compare the functional effects of the six identified ADAMTS missense mutations on the platinum sensitivity of ovarian cancer cells. We also used a well-characterized in vivo mouse model to evaluate the response of ovarian cancer cells with ADAMTS16 mutations to platinum-based therapy. Our results showed that exogenously expressed ADAMTS16 missense mutations inhibited cell growth or sensitized tumor cells to cisplatin and inhibited tumor growth in vivo. Orthotopic xenograft experiments showed that mice injected with ovarian cancer cells that exogenously expressed ADAMTS16 mutations had a better response to cisplatin treatment. Thus, these functional studies provide evidence that mutations of ADAMTS16 actively contribute to therapeutic response in ovarian cancer.
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