Clinical and translational radiation oncology · 2026
Pan-cancer analysis of Notch pathway-linked gene expression identifies tumour-specific and sex-stratified prognostic associations.
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O'Hea Helen, Bourbonne V, Marignol Laure
Аннотация
BACKGROUND: The Notch signalling pathway regulates cell fate, proliferation, and differentiation and consists of receptors (Notch1-4), ligands (JAG1-2, DLL1, DLL3-4), and downstream targets. Altered expression of Notch pathway-linked genes has been reported in multiple cancers, although their associations with survival may vary according to tumour type. Their relationship with biological sex and radiotherapy (RT) has been less extensively explored.
PURPOSE: To explore associations between Notch pathway-linked gene expression and overall survival (OS) across multiple cancer types, and to examine whether these associations differ by biological sex or in an RT-treated lung cancer subgroup.
METHODOLOGY: Gene expression and clinical data from patients across nine cancer types were analysed using publicly available datasets derived from The Cancer Genome Atlas (TCGA) and the Kaplan-Meier Plotter platform. Associations between the expression of 14 Notch pathway-linked genes and OS were evaluated using Kaplan-Meier survival analyses. Representative findings were further evaluated using multivariable Cox proportional hazards models incorporating clinical covariates and gene expression × sex interaction terms.
MAIN FINDINGS: Across nine cancer types, 13 of the 14 Notch pathway-linked genes were significantly associated with OS in at least one tumour type. DLL3 and JAG1 demonstrated recurrent associations across multiple cancers, with higher DLL3 expression more frequently associated with poorer OS. Sex-stratified analyses identified additional prognostic associations; however, multivariable interaction analyses did not consistently support biological sex as an effect modifier. In the RT-treated lung adenocarcinoma subgroup, higher JAG1 expression was associated with poorer OS, although this association was not confirmed in an adjusted pan-cancer RT validation cohort.
CONCLUSION: This exploratory pan-cancer analysis identified associations between the expression of several Notch pathway-linked genes and OS, including recurrent associations involving DLL3 and JAG1. Differences observed in sex-stratified analyses and the RT-treated lung adenocarcinoma subgroup warrant further investigation in independent cohorts.
PURPOSE: To explore associations between Notch pathway-linked gene expression and overall survival (OS) across multiple cancer types, and to examine whether these associations differ by biological sex or in an RT-treated lung cancer subgroup.
METHODOLOGY: Gene expression and clinical data from patients across nine cancer types were analysed using publicly available datasets derived from The Cancer Genome Atlas (TCGA) and the Kaplan-Meier Plotter platform. Associations between the expression of 14 Notch pathway-linked genes and OS were evaluated using Kaplan-Meier survival analyses. Representative findings were further evaluated using multivariable Cox proportional hazards models incorporating clinical covariates and gene expression × sex interaction terms.
MAIN FINDINGS: Across nine cancer types, 13 of the 14 Notch pathway-linked genes were significantly associated with OS in at least one tumour type. DLL3 and JAG1 demonstrated recurrent associations across multiple cancers, with higher DLL3 expression more frequently associated with poorer OS. Sex-stratified analyses identified additional prognostic associations; however, multivariable interaction analyses did not consistently support biological sex as an effect modifier. In the RT-treated lung adenocarcinoma subgroup, higher JAG1 expression was associated with poorer OS, although this association was not confirmed in an adjusted pan-cancer RT validation cohort.
CONCLUSION: This exploratory pan-cancer analysis identified associations between the expression of several Notch pathway-linked genes and OS, including recurrent associations involving DLL3 and JAG1. Differences observed in sex-stratified analyses and the RT-treated lung adenocarcinoma subgroup warrant further investigation in independent cohorts.