A Luscan1, P A Just2, A Briand1, C Burin des Roziers3, P Goussard3, P Nitschké4, M Vidaud1, M F Avril5, B Terris2, E Pasmant1. 1. Service de Biochimie et de Génétique Moléculaire, Assistance Publique-Hôpitaux de Paris, Hôpital Cochin, Paris, France EA7331, Université Paris Descartes, Sorbonne Paris Cité, Faculté des Sciences Pharmaceutiques et Biologiques, Paris, France. 2. INSERM, U1016, Institut Cochin, and CNRS, UMR8104, Université Paris Descartes Sorbonne Paris Cité, Paris, France Service d'Anatomie et Cytologie Pathologiques, AP-HP, Hôpital Cochin, Université Paris Descartes Sorbonne Paris Cité, Paris, France. 3. Service de Biochimie et de Génétique Moléculaire, Assistance Publique-Hôpitaux de Paris, Hôpital Cochin, Paris, France. 4. Plateforme de Bioinformatique, Université Paris Descartes Sorbonne Paris Cité, Institut IMAGINE, Paris, France. 5. Institut Cochin-INSERM U1016, CNRS UMR 8104, Université Paris Descartes Sorbonne Paris Cité, Paris, France APHP, Department of Dermatology, Cochin Hospital, Paris, France.
Abstract
AIMS: Uveal melanoma (UM) is the most common malignant tumour of the eye. Diagnosis often occurs late in the course of disease, and prognosis is generally poor. Recently, recurrent somatic mutations were described, unravelling additional specific altered pathways in UM. Targeted next-generation sequencing (NGS) can now be applied to an accurate and fast identification of somatic mutations in cancer. The aim of the present study was to characterise the mutation pattern of five UM hepatic metastases with well-defined clinical and pathological features. METHODS: We analysed the UM mutation spectrum using targeted NGS on 409 cancer genes. RESULTS: Four previous reported genes were found to be recurrently mutated. All tumours presented mutually exclusive GNA11 or GNAQ missense mutations. BAP1 loss-of-function mutations were found in three UMs. SF3B1 missense mutations were found in the two UMs with no BAP1 mutations. We then searched for additional mutation targets. We identified the Arg505Cys mutation in the tumour suppressor FBXW7. The same mutation was previously described in different cancer types, and FBXW7 was recently reported to be mutated in UM exomes. CONCLUSIONS: Further studies are required to confirm FBXW7 implication in UM tumorigenesis. Elucidating the molecular mechanisms underlying UM tumorigenesis holds the promise for novel and effective targeted UM therapies. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
AIMS: Uveal melanoma (UM) is the most common malignant tumour of the eye. Diagnosis often occurs late in the course of disease, and prognosis is generally poor. Recently, recurrent somatic mutations were described, unravelling additional specific altered pathways in UM. Targeted next-generation sequencing (NGS) can now be applied to an accurate and fast identification of somatic mutations in cancer. The aim of the present study was to characterise the mutation pattern of five UM hepatic metastases with well-defined clinical and pathological features. METHODS: We analysed the UM mutation spectrum using targeted NGS on 409 cancer genes. RESULTS: Four previous reported genes were found to be recurrently mutated. All tumours presented mutually exclusive GNA11 or GNAQ missense mutations. BAP1 loss-of-function mutations were found in three UMs. SF3B1 missense mutations were found in the two UMs with no BAP1 mutations. We then searched for additional mutation targets. We identified the Arg505Cys mutation in the tumour suppressor FBXW7. The same mutation was previously described in different cancer types, and FBXW7 was recently reported to be mutated in UM exomes. CONCLUSIONS: Further studies are required to confirm FBXW7 implication in UM tumorigenesis. Elucidating the molecular mechanisms underlying UM tumorigenesis holds the promise for novel and effective targeted UM therapies. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
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