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., Fitzgerald, Rebecca C. and Hall, Benjamin A. 2024. SMAD4 and KCNQ3 alterations are associated with lymph node metastases in oesophageal adenocarcinoma. BBA - Molecular Basis of Disease 1870 (1) , 166867. 10.1016/j.bbadis.2023.166867

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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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Publisher:	Elsevier
ISSN:	0925-4439
Date of First Compliant Deposit:	16 October 2023
Date of Acceptance:	25 August 2023
Last Modified:	08 Nov 2024 12:45
URI:	https://orca.cardiff.ac.uk/id/eprint/163197

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