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

Kieran Foley; David Shorthouse; Eric Rahrmann; Lizhe Zhuang; Ginny Devonshire; Richard J. Gilbertson; OCCAMS Consortium; Rebecca C. Fitzgerald; Benjamin A. Hall; Russell D. Petty

doi:10.1016/j.bbadis.2023.166867

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

Kieran Foley, David Shorthouse, Eric Rahrmann, Lizhe Zhuang, Ginny Devonshire, Richard J. Gilbertson, OCCAMS Consortium, Rebecca C. Fitzgerald (Lead / Corresponding author), Benjamin A. Hall (Lead / Corresponding author), Russell D. Petty (Research group member)

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Article number	166867
Number of pages	11
Journal	Biochimica et Biophysica Acta - Molecular Basis of Disease
Volume	1870
Issue number	1
Early online date	28 Aug 2023
DOIs	https://doi.org/10.1016/j.bbadis.2023.166867
Publication status	Published - Jan 2024

Keywords

Imaging
Metastasis
Mutation
Oesophageal adenocarcinoma
Radiology
Wnt Signalling

ASJC Scopus subject areas

Molecular Medicine
Molecular Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Foley, K., Shorthouse, D., Rahrmann, E., Zhuang, L., Devonshire, G., Gilbertson, R. J., OCCAMS Consortium, Fitzgerald, R. C., Hall, B. A., & Petty, R. D. (2024). SMAD4 and KCNQ3 alterations are associated with lymph node metastases in oesophageal adenocarcinoma. Biochimica et Biophysica Acta - Molecular Basis of Disease, 1870(1), Article 166867. https://doi.org/10.1016/j.bbadis.2023.166867

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title = "SMAD4 and KCNQ3 alterations are associated with lymph node metastases in oesophageal adenocarcinoma",

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.",

keywords = "Imaging, Metastasis, Mutation, Oesophageal adenocarcinoma, Radiology, Wnt Signalling",

author = "Kieran Foley and David Shorthouse and Eric Rahrmann and Lizhe Zhuang and Ginny Devonshire and Gilbertson, {Richard J.} and {OCCAMS Consortium} and Fitzgerald, {Rebecca C.} and Hall, {Benjamin A.} and Fitzgerald, {Rebecca C.} and Edwards, {Paul A. W.} and Nicola Grehan and Barbara Nutzinger and Elwira Fidziukiewicz and Redmond, {Aisling M.} and Sujath Abbas and Adam Freeman and Smyth, {Elizabeth C.} and Maria O{\textquoteright}Donovan and Ahmad Miremadi and Shalini Malhotra and Monika Tripathi and Calvin Cheah and Hannah Coles and Conor Flint and Matthew Eldridge and Maria Secrier and Ginny Devonshire and Sriganesh Jammula and Jim Davies and Charles Crichton and Nick Carroll and Hardwick, {Richard H.} and Peter Safranek and Andrew Hindmarsh and Vijayendran Sujendran and Hayes, {Stephen J.} and Yeng Ang and Andrew Sharrocks and Preston, {Shaun R.} and Izhar Bagwan and Vicki Save and Skipworth, {Richard J.E.} and Hupp, {Ted R.} and O{\textquoteright}Neill, {J. Robert} and Olga Tucker and Andrew Beggs and Philippe Taniere and Walker, {Robert C.} and Hanna, {George B.} and Petty, {Russell D.}",

note = "Publisher Copyright: {\textcopyright} 2023",

year = "2024",

month = jan,

doi = "10.1016/j.bbadis.2023.166867",

language = "English",

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Foley, K, Shorthouse, D, Rahrmann, E, Zhuang, L, Devonshire, G, Gilbertson, RJ, OCCAMS Consortium, Fitzgerald, RC, Hall, BA & Petty, RD 2024, 'SMAD4 and KCNQ3 alterations are associated with lymph node metastases in oesophageal adenocarcinoma', Biochimica et Biophysica Acta - Molecular Basis of Disease, vol. 1870, no. 1, 166867. https://doi.org/10.1016/j.bbadis.2023.166867

TY - JOUR

T1 - SMAD4 and KCNQ3 alterations are associated with lymph node metastases in oesophageal adenocarcinoma

AU - Foley, Kieran

AU - Shorthouse, David

AU - Rahrmann, Eric

AU - Zhuang, Lizhe

AU - Devonshire, Ginny

AU - Gilbertson, Richard J.

AU - OCCAMS Consortium

AU - Fitzgerald, Rebecca C.

AU - Hall, Benjamin A.

A2 - Fitzgerald, Rebecca C.

A2 - Edwards, Paul A. W.

A2 - Grehan, Nicola

A2 - Nutzinger, Barbara

A2 - Fidziukiewicz, Elwira

A2 - Redmond, Aisling M.

A2 - Abbas, Sujath

A2 - Freeman, Adam

A2 - Smyth, Elizabeth C.

A2 - O’Donovan, Maria

A2 - Miremadi, Ahmad

A2 - Malhotra, Shalini

A2 - Tripathi, Monika

A2 - Cheah, Calvin

A2 - Coles, Hannah

A2 - Flint, Conor

A2 - Eldridge, Matthew

A2 - Secrier, Maria

A2 - Devonshire, Ginny

A2 - Jammula, Sriganesh

A2 - Davies, Jim

A2 - Crichton, Charles

A2 - Carroll, Nick

A2 - Hardwick, Richard H.

A2 - Safranek, Peter

A2 - Hindmarsh, Andrew

A2 - Sujendran, Vijayendran

A2 - Hayes, Stephen J.

A2 - Ang, Yeng

A2 - Sharrocks, Andrew

A2 - Preston, Shaun R.

A2 - Bagwan, Izhar

A2 - Save, Vicki

A2 - Skipworth, Richard J.E.

A2 - Hupp, Ted R.

A2 - O’Neill, J. Robert

A2 - Tucker, Olga

A2 - Beggs, Andrew

A2 - Taniere, Philippe

A2 - Walker, Robert C.

A2 - Hanna, George B.

A2 - Petty, Russell D.

PY - 2024/1

Y1 - 2024/1

N2 - 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.

AB - 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.

KW - Imaging

KW - Metastasis

KW - Mutation

KW - Oesophageal adenocarcinoma

KW - Radiology

KW - Wnt Signalling

UR - http://www.scopus.com/inward/record.url?scp=85169610455&partnerID=8YFLogxK

U2 - 10.1016/j.bbadis.2023.166867

DO - 10.1016/j.bbadis.2023.166867

M3 - Article

C2 - 37648039

AN - SCOPUS:85169610455

SN - 0925-4439

VL - 1870

JO - Biochimica et Biophysica Acta - Molecular Basis of Disease

JF - Biochimica et Biophysica Acta - Molecular Basis of Disease

IS - 1

M1 - 166867

ER -

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

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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