SFEBES2023 Oral Poster Presentations RET and Endocrine Cancer (4 abstracts)
Investigating the functional kinome in Multiple Endocrine Neoplasia Type 2
Beatrice Rix 1 , Rakhee Chauhan 2 , Caroline Brain 3 , Tom R. Kurzawinski 4 , Olumide K. Ogunbiyi 5 , Katherine Swarbrick 5 , Daisuke Nonaka 6,7 , Paul V. Carroll 8 , Barbara M. McGowan 8 , Benjamin C. Whitelaw 9 , Neil Q. McDonald 2,10 , William Grey 1 & Louise Izatt 11,12
1York Biomedical Research Institute, Department of Biology, University of York, York, United Kingdom. 2Signalling and Structural Biology Laboratory, The Francis Crick Institute, London, United Kingdom. 3Department of Paediatric Endocrinology, Great Ormond Street Hospital for Children NHSFT, London, United Kingdom. 4Department of Endocrine Surgery, University College London Hospitals NHS Foundation Trust, London, United Kingdom. 5Department of Histopathology, Great Ormond Street Hospital for Children NHSFT, London, United Kingdom. 6Department of Pathology, Guy’s and St Thomas’ NHS Foundation Trust, London, United Kingdom. 7Department of Cellular Pathology, King’s College London, London, United Kingdom. 8Clinical Endocrinologist Guy’s and St Thomas’ NHS Foundation Trust, London, United Kingdom. 9Clinical Endocrinologist King’s College Hospital NHS Foundation Trust, London, United Kingdom. 10Institute of Structural and Molecular Biology, Department of Biological Sciences, Birkbeck College, London, United Kingdom. 11Department of Clinical Genetics, Guy’s and St Thomas’ NHS Foundation Trust, London, United Kingdom. 12Department of Medical and Molecular Genetics, King’s College London, London, United Kingdom
Introduction: The age of onset and severity of thyroid disease in MEN2 kindreds can be variable, resulting in wide intrafamilial heterogeneity, despite the same oncogenic driver RET pathogenic variant being present. Our study sought to investigate the RET kinomic landscape in MEN2 to discover new biomarkers and to provide further mechanistic insights into malignant disease progression, focussing on paediatric cases.
Methods: Peripheral blood and thyroid tissue samples were obtained from 23 children and 10 adults diagnosed with different germline RET pathogenic variants (cysteine rich region C609Y, C620G, C634G/R/S, intracellular pathogenic variants V804M, S891A and M918T) and healthy controls. Matching thyroid tissue was obtained from pre-emptive risk-reducing thyroidectomies in children with MEN2A and adult and paediatric patients undergoing primary surgery for medullary thyroid cancer. Kinetics of tyrosine, serine and threonine phosphorylation in protein lysates from peripheral blood mononuclear cells and thyroid cells were analysed using Pamgene technology (PamStation 12).
Results: Functional large scale kinome and integrated analyses revealed differentially active kinases between healthy controls, MEN2A and MEN2B patients. Using network analysis, protein-protein interaction databases and cumulative functionality predictors we generated a range of biomarkers, which imply multi-kinase alterations in a genotype specific manner leading to different disease outcomes. We further validated these markers in primary paediatric patient thyroid tissue excised before frank cancerous transformation. Direct RET kinase activity was comparable between mutation types, but downstream specificity and subsequent kinase activity segregated by mutation type. Interestingly, cysteine rich mutants were more similar to M918T than V804M or S891A, suggesting that genotype-phenotype linkage may be due to substrate specificity rather than standalone RET kinase activity.
Conclusion: Together our data demonstrates that, as a kinase hub, pathogenic variants in RET lead to diverse outcomes in primary patients, providing rationale for targeting RET protein to prevent malignant transformation or disease progression in MEN2A and MEN2B.
Volume 94
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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