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CLINICAL APPLICATION OF WHOLE EXOME SEQUENCING IN A CASE OF METASTASISED LOW GRADE SEROUS OVARIAN CANCER

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ESGO State of the Art 2018 Conference

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CLINICAL APPLICATION OF WHOLE EXOME SEQUENCING IN A CASE OF METASTASISED LOW GRADE SEROUS OVARIAN CANCER Bruce Moran1,3, Michael Wilkinson1, Sudipto Das2, Darran O’Connor2, Jean Murphy3, Kieran Sheahan1,3, Cathy Kelly1, Niall Mulligan1, Brendan Loftus4,5, Donal Brennan1,5,6. 1: Ireland East Hospital Group, Mater Misericordiae University Hospital, Dublin 7. 2: Molecular and Cellular Therapeutics Lab., Royal College of Surgeons Ireland, Dublin 2. 3: Department of Histopathology, St. Vincent’s University Hospital, Dublin 4. 4: Core Sequencing Facility, Conway Institute, University College Dublin, Dublin 4. 5: School of Medicine, University College Dublin, Dublin 4. 6: Cancer Biology and Therapeutics Lab., Conway Institute, University College Dublin, Dublin 4. Background: Low grade serous ovarian cancer (LGSOC) is defined by slow growth, chromosomal stability and resistance to chemotherapy. We report a stage IV LGSOC patient who had extensive cytoreductive surgery in December 2016, completed 6 cycles of adjuvant carboplatinum and paclitaxel and was commenced on maintenance tamoxifen. She developed recurrent disease in her chest and abdominal wall in November 2017. Methods: DNA was extracted from seven FFPE tumour samples (5 from primary surgery and 2 from recurrences) and whole blood. Exomes were sequenced using Illumina’s NextSeq platform. Sequence data was trimmed, aligned and single nucleotide variants (SNVs) and copy number alterations (CNAs) were called. Single gene testing was performed for BRAF V600E, KRAS and ERFR. MSI status was confirmed using immunohistochemistry. Results The tumour had a low mutational burden. Among twenty protein-coding somatic SNVs reported, we identified a class 3 ‘kinase-dead’ BRAF variant, D594G present in 6/7 tumour samples. This mutation is known to inhibit protein activity. Concordant near-whole chromosome 1 amplification in both primary and recurrent samples, covering the NRAS proto-oncogene. Single gene testing confirmed wild type EGFR and KRAS and the tumour is microsatellite stable. Discussion: Class 3 BRAF mutations increase MAPK activity by weakly binding CRAF which increases receptor tyrosine kinase mediated phosphorylation of RAS genes. This is particularly the case in RAS-activated tumours, likely here given NRAS amplification. As a result we have commenced this lady on MEK inhibitor (Trametinib) and she is awaiting restaging. These findings have not been previously described in LGSOC. FFPE = Formalin-Fixed Parafin Embedded

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