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SMAD4 and KCNQ3 alterations are associated with lymph node metastases in oesophageal adenocarcinoma

Foley, Kieran; Shorthouse, David; Rahrmann, Eric; Zhuang, Lizhe; Devonshire, Ginny; Gilbertson, Richard J; OCCAMS consortium; ... Hall, Benjamin A; + view all (2024) SMAD4 and KCNQ3 alterations are associated with lymph node metastases in oesophageal adenocarcinoma. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease , 1870 (1) , Article 166867. 10.1016/j.bbadis.2023.166867. Green open access

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Abstract

Metastasis in oesophageal adenocarcinoma (OAC) is an important predictor of survival. Radiological staging is used to stage metastases in patients, and guide treatment selection, but is limited by the accuracy of the approach. Improvements in staging will lead to improved clinical decision making and patient outcomes. Sequencing studies on primary tumours and pre-cancerous tissue have revealed the mutational landscape of OAC, and increasingly cheap and widespread sequencing approaches offer the potential to improve staging assessment. In this work we present an analysis of lymph node metastases found by radiological and pathological sampling, identifying new roles of the genes SMAD4 and KCNQ3 in metastasis. Through transcriptomic analysis we find that both genes are associated with canonical Wnt pathway activity, but KCNQ3 is uniquely associated with changes in planar cell polaritiy associated with non-canonical Wnt signalling. We go on to validate our observations in KCNQ3 in cell line and xenograph systems, showing that overexpression of KCNQ3 reduces wound closure and the number of metastases observed. Our results suggest both genes as novel biomarkers of metastatic risk and offer new potential routes to drug targeting.

Type: Article
Title: SMAD4 and KCNQ3 alterations are associated with lymph node metastases in oesophageal adenocarcinoma
Location: Netherlands
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.bbadis.2023.166867
Publisher version: https://doi.org/10.1016/j.bbadis.2023.166867
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: Imaging, Metastasis, Mutation, Oesophageal adenocarcinoma, Radiology, Wnt Signalling
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > UCL BEAMS
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Engineering Science
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Engineering Science > Dept of Med Phys and Biomedical Eng
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy > Pharmaceutics
URI: https://discovery.ucl.ac.uk/id/eprint/10176581
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