Spatial expression of IKK-alpha is associated with a differential mutational landscape and survival in primary colorectal cancer

Meera Patel,Donald C Mcmillan,Antonia K Roseweir,Hannah Hood,Jean A Quinn,Paul G Horgan,Joanne Edwards,David K Chang,Selma Rebus,Kathryn A F Pennel,Andrew V Biankin,James H Park

doi:10.1038/s41416-022-01729-2

Meera Patel, Donald C Mcmillan + Show 10 more

Open Access

https://doi.org/10.1038/s41416-022-01729-2

Copy DOI

Abstract

BackgroundTo understand the relationship between key non-canonical NF-κB kinase IKK-alpha(α), tumour mutational profile and survival in primary colorectal cancer.MethodsImmunohistochemical expression of IKKα was assessed in a cohort of 1030 patients who had undergone surgery for colorectal cancer using immunohistochemistry. Mutational tumour profile was examined using a customised gene panel. Immunofluorescence was used to identify the cellular location of punctate IKKα expression.ResultsTwo patterns of IKKα expression were observed; firstly, in the tumour cell cytoplasm and secondly as discrete ‘punctate’ areas in a juxtanuclear position. Although cytoplasmic expression of IKKα was not associated with survival, high ‘punctate’ IKKα expression was associated with significantly reduced cancer-specific survival on multivariate analysis. High punctate expression of IKKα was associated with mutations in KRAS and PDGFRA. Dual immunofluorescence suggested punctate IKKα expression was co-located with the Golgi apparatus.ConclusionsThese results suggest the spatial expression of IKKα is a potential biomarker in colorectal cancer. This is associated with a differential mutational profile highlighting possible distinct signalling roles for IKKα in the context of colorectal cancer as well as potential implications for future treatment strategies using IKKα inhibitors.

Highlights

Colorectal cancer (CRC) is the third most common cause of death worldwide
Prognostic analysis of IKKα gene (CHUK) expression in TCGA dataset Somatic mutation data related to the CHUK (IKKα) gene signature was extracted from The Cancer Genome Atlas (TCGA) panCancer atlas colorectal cohort
In this communication we report on the association between protein expression of key non-canonical NF-κB kinase, IKKα, patient and tumour characteristics and the mutational landscape in patients who have undergone surgery for CRC

Summary

Introduction

Colorectal cancer (CRC) is the third most common cause of death worldwide. The heterogeneity observed in CRC is reflected in how patients present, how they respond to treatment and survival outcomes. There has been a widespread expansion in the molecular genetics of CRC, it remains a challenge to translate advances in CRC genomics into clinically relevant prognostic or predictive tests To expand this approach, investigation of molecular pathways and processes downstream of mutational events in patient tissue samples offers an avenue to identify subgroups of patients, identify prognostic or predictive biomarkers whilst simultaneously uncovering novel therapeutic targets. It should be noted that the majority of this evidence originates from studies based on cell lines and animal models [2] with limited understanding of expression in human CRC tissue and how this may be related to patient outcomes These studies focus on the canonical arm of NF-κB signalling which results in recruitment of the IKK complex composed of subunits IκB kinase-alpha (IKKα), IκB kinasebeta (IKKβ) and IκB kinase-gamma (IKKγ)/NEMO and subsequent phosphorylation-induced degradation of IκB inhibitory protein which results in unmasking of the nuclear localising sequence (NLS) of the p50:p65 complex.

Objectives

Results

Conclusion