We sequenced primary, synchronous bilateral ovarian cancer (SBOC), metastatic, and recurrent ovarian tumors. effective screening programs, epithelial ovarian cancer (EOC) remains the most lethal gynecologic malignancy, with more than two-thirds of EOC patients diagnosed with advanced-stage disease (i.e., abdominal carcinomatosis) (1). While the majority of patients initially respond to either primary surgical cytoreduction followed by platinum-based chemotherapy or neoadjuvant chemotherapy followed by cytoreduction, the development of chemotherapy-resistant disease results in only a 20 to Rabbit Polyclonal to ZC3H4 30% 5-y survival rate (2). This poor prognosis underscores the need for a better understanding of the molecular drivers contributing to early metastases and chemotherapy resistance. Recent whole-exome sequencing (WES) and whole-genome sequencing (WGS) studies focusing on primary chemonaive high-grade serous carcinoma (HG-SC) (3) and chemotherapy-resistant tumor cells collected from patients developing ascites, demonstrated that HG-SC, the most common histologic type of ovarian cancer (4), is characterized by TP53 mutations in up to 96% of the tumors, by high genomic instability, and by germline or somatic defects in homologous recombination repair (HRR) genes in about 50% of patients. Reversion of BRCA1 or BRCA2 mutations in individual patients and recurrent promoter fusion associated with overexpression of the drug efflux pump MDR1 were also observed in a handful of patients with recurrent chemotherapy-resistant OTS186935 disease (4). WGS results, however, were not able to demonstrate any recurrent event in the over 800 gene fusions potentially capable of producing a fused transcript (4). While extensive genomic data for primary chemonaive ovarian cancer are present in the literature (3), very limited data are currently available for metastatic ovarian cancer or for ovarian tumors exposed to the selective pressure of chemotherapy (4). Accordingly, we used WES of tumor and germline DNA from ovarian cancer patients to evaluate genomic differences among primary, metastatic, and recurrent chemotherapy-resistant tumors obtained from fresh biopsy samples. In addition, to evaluate their evolutionary history, we also performed WES of 13 leftCright synchronous bilateral ovarian cancer (SBOC) pairs from patients with bilateral tumors. Lastly, because recurrent amplifications of chromosome 8q23-24 encompassing c-MYC were frequent in primary and metastatic tumors and enriched in recurrent cancers, we assessed the activity of GS-626510, a novel Bromodomain and Extra-Terminal motif (BET) inhibitor, against primary ovarian cancer cell lines and xenografts derived from chemotherapy-resistant disease. Results The Genetic Landscape of Primary, Metastatic, and Recurrent Ovarian Cancer. We analyzed tumors and matched normal samples from 77 patients. These included 64 unilateral primary tumors and 13 matched pairs of tumors from patients with SBOC. We also sequenced 41 metastatic and 17 recurrent tumors. The majority of patients (55/77) had high-grade serous papillary histology. There were also 5 patients with endometrioid tumors, 5 patients with clear-cell tumors, 2 patients with dedifferentiated tumors, and 10 patients with mixed-histology tumors. The clinical features of these patients are presented in = 0.0033 by Wilcoxon rank test, excluding a single hypermutated tumor) (= 0.048). Two of the five mutations in primaryCmetastatic pairs were present in both tumors. Amplifications were found in 69 to 88% of various tumor classes, and pathogenic somatic SNVs were found in 2 to 18%. Recurrent tumors had the OTS186935 highest burden of both somatic SNVs and copy number gains (= 0.13) (= OTS186935 2.2e-3 for metastatic tumors, = 0.016 for recurrent tumors). There were few somatic mutations in known ovarian cancer genes in metastases (three mutations in 41 patients) and recurrent tumors (five OTS186935 mutations in 16 patients) that were absent in primary tumors ([a gene previously implicated in ovarian cancer (4)] that were not present in primary tumors. Based on the low rate of new mutations in ovarian cancer-implicated genes, this event was unlikely to occur by chance alone (= 0.016). Among two matched metastatic, recurrent, and primary trios, each metastatic and recurrent OTS186935 pair of tumors shared a high proportion of somatic SNVs (83%), again suggesting that key mutations transmitted to metastatic tumors were likely to be retained during tumor recurrence. Germline Analysis. We analyzed normal samples (= 77) from tumorCnormal pairs for germline mutations in known ovarian cancer-predisposition genes. We also ran a parallel analysis on a control panel of 6,226 healthy patient exomes to estimate the baseline prevalence of these mutations in a healthy population. Twenty-five.
