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      The future of cancer treatment using precision oncogenomics

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      Cold Spring Harbor Molecular Case Studies
      Cold Spring Harbor Laboratory Press

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          Abstract

          Clinicians should soon have the opportunity to use precision oncogenomics to tailor the optimal cancer treatment to a specific patient. Precision oncogenomics will incorporate different sequencing platforms depending on the goal of the sequencing result. For example, the sequencing strategy used in immuno-oncology for the design of a tumor-specific vaccine may be different than that used by oncologists following a patient for clearance of mutations from circulating tumor DNA in the peripheral blood. I will provide a broad overview of several of the ways that precision oncogenomics is likely to influence the field of oncology over the next several years building off the experience at the Genomics Tumor Board at Washington University in St. Louis and a case of small-cell neuroendocrine carcinoma of the endometrium as examples.

          Most cited references6

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          Association Between Mutation Clearance After Induction Therapy and Outcomes in Acute Myeloid Leukemia.

          Tests that predict outcomes for patients with acute myeloid leukemia (AML) are imprecise, especially for those with intermediate risk AML.
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            Recurrent SMARCA4 mutations in small cell carcinoma of the ovary.

            Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare, highly aggressive form of ovarian cancer primarily diagnosed in young women. We identified inactivating biallelic SMARCA4 mutations in 100% of the 12 SCCOHT tumors examined. Protein studies confirmed loss of SMARCA4 expression, suggesting a key role for the SWI/SNF chromatin-remodeling complex in SCCOHT.
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              The histone methyltransferase EZH2 is a therapeutic target in small cell carcinoma of the ovary, hypercalcaemic type.

              Small cell carcinoma of the ovary, hypercalcaemic type (SCCOHT) is a rare but aggressive and untreatable malignancy affecting young women. We and others recently discovered that SMARCA4, a gene encoding the ATPase of the SWI/SNF chromatin-remodelling complex, is the only gene recurrently mutated in the majority of SCCOHT. The low somatic complexity of SCCOHT genomes and the prominent role of the SWI/SNF chromatin-remodelling complex in transcriptional control of genes suggest that SCCOHT cells may rely on epigenetic rewiring for oncogenic transformation. Herein, we report that approximately 80% (19/24) of SCCOHT tumour samples have strong expression of the histone methyltransferase EZH2 by immunohistochemistry, with the rest expressing variable amounts of EZH2. Re-expression of SMARCA4 suppressed the expression of EZH2 in SCCOHT cells. In comparison to other ovarian cell lines, SCCOHT cells displayed hypersensitivity to EZH2 shRNAs and two selective EZH2 inhibitors, GSK126 and EPZ-6438. EZH2 inhibitors induced cell cycle arrest, apoptosis, and cell differentiation in SCCOHT cells, along with the induction of genes involved in cell cycle regulation, apoptosis, and neuron-like differentiation. EZH2 inhibitors suppressed tumour growth and improved the survival of mice bearing SCCOHT xenografts. Therefore, our data suggest that loss of SMARCA4 creates a dependency on the catalytic activity of EZH2 in SCCOHT cells and that pharmacological inhibition of EZH2 is a promising therapeutic strategy for treating this disease. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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                Author and article information

                Journal
                Cold Spring Harb Mol Case Stud
                Cold Spring Harb Mol Case Stud
                cshmcs
                cshmcs
                cshmcs
                Cold Spring Harbor Molecular Case Studies
                Cold Spring Harbor Laboratory Press
                2373-2873
                April 2018
                : 4
                : 2
                : a002824
                Affiliations
                Washington University School of Medicine, St. Louis, Missouri 63110, USA
                Author notes
                Corresponding author: lwartman@ 123456wustl.edu
                Article
                MCS002824War
                10.1101/mcs.a002824
                5880270
                29610395
                d2591329-de37-4f02-9ba2-8f3c6a3bc675
                © 2018 Wartman; Published by Cold Spring Harbor Laboratory Press

                This article is distributed under the terms of the Creative Commons Attribution-NonCommercial License, which permits reuse and redistribution, except for commercial purposes, provided that the original author and source are credited.

                History
                Page count
                Pages: 6
                Funding
                Funded by: McDonnell Genome Institute
                Funded by: National Institutes of Health (NIH) , open-funder-registry 10.13039/100000002;
                Award ID: K08 CA166229
                Funded by: National Cancer Institute (NCI) , open-funder-registry 10.13039/100000054;
                Award ID: K08 CA166229
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