ADAMTS16 mutations sensitize ovarian cancer cells to platinum-based chemotherapy.

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 mutations 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 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 mouse model to evaluate the response of ovarian cancer cells with mutations to platinum-based therapy. Our results showed that exogenously expressed missense mutations inhibited cell growth or sensitized tumor cells to cisplatin and inhibited tumor growth . Orthotopic xenograft experiments showed that mice injected with ovarian cancer cells that exogenously expressed mutations had a better response to cisplatin treatment. Thus, these functional studies provide evidence that mutations of actively contribute to therapeutic response in ovarian cancer.