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Gene expression profile predicts response to antitumor necrosis factor in children with Crohn's disease: A Porto
Ohad Atia1, Asaf Azulay1, Gili Focht1
1Juliet Keidan Institute of Pediatric Gastroenterology and Nutrition, The Eisenberg R&D Authority, Shaare Zedek Medical Center, The Hebrew University of Jerusalem, Jerusalem, Israel.
Insights
Predicting anti-tumor necrosis factor (TNF) response in pediatric Crohn's disease (CD) is challenging. This study identified five key intestinal genes that accurately predict treatment success in children with CD, paving the way for personalized therapy.
Area of Science:
- Pediatric Gastroenterology
- Molecular Biology
- Immunology
Background:
- Predicting response to anti-tumor necrosis factor (TNF) therapy in pediatric Crohn's disease (CD) remains a clinical challenge.
- Validated biomarkers are needed to guide treatment selection and improve outcomes for children with CD.
Purpose of the Study:
- To evaluate the predictive utility of intestinal gene expression for anti-TNF treatment response in pediatric CD.
- To identify specific gene signatures that can predict therapeutic success or failure.
Main Methods:
- A systematic literature review identified candidate genes associated with anti-TNF response.
- Intestinal gene expression was analyzed from biopsies of pediatric CD patients before anti-TNF initiation.
- Machine learning models, including support vector machines, were used to build and validate a predictive signature.
Main Results:
- A panel of five genes (TREM1, IL23R, CCL7, IL17F, and YES1) demonstrated high predictive utility for anti-TNF response in the primary cohort (AUC 0.88).
- The identified genomic signature achieved 82% accuracy in an external validation cohort, correctly classifying most patients, including non-responders.
- The model showed strong performance metrics, including sensitivity (92%) and negative predictive value (83%) in the discovery cohort.
Conclusions:
- Increased expression of a specific five-gene signature is associated with a higher likelihood of response to anti-TNF therapy in pediatric CD.
- These five genes hold potential as predictive biomarkers for guiding anti-TNF treatment selection in children with CD.
- Further prospective studies are recommended to validate these gene biomarkers in clinical practice.
Objectives:
There is a paucity of validated predictors of response to anti-tumor necrosis factor (TNF) in pediatric Crohn's disease (CD). We aimed to evaluate the predictive utility of intestinal gene expression to predict response to anti-TNF in children with CD.
Methods:
We enrolled children with CD before initiating anti-TNF as part of the prospective biobank of the pediatric inflammatory bowel disease Porto group of ESPGHAN. Genes potentially associated with therapeutic response were first preselected from a systematic literature review. Ribonucleic acid was extracted and sequenced from inflamed ileal biopsies of 20 children before initiating anti-TNF (13 with steroid-free remission [SFR] at 12 months, and seven with primary nonresponse [PNR]). An external validation cohort including 22 children (21 SFR, 1 PNR) was enrolled from Germany and Canada. Using maximum relevance-minimum redundancy (mRMR) methods, we constructed a support vector machine-learning model evaluated via leave-one-out cross-validation and permutation testing.
Results:
Of 1799 studies identified in the systematic review, 24 met the inclusion criteria, reporting on 150 genes possibly associated with anti-TNF response in children or adults. In the Porto group cohort, 30 genes were associated with treatment response, of which five (TREM1, IL23R, CCL7, IL17F, and YES1) were most frequently selected. A multivariable model of these genes achieved high predictive utility (area under receiver operating characteristic curve: 0.88 [95% confidence interval: 0.69-1.0], sensitivity/specificity/positive predictive value/negative predictive value: 92%/71%/86%/83%). The same genomic signature in external validation achieved accuracy of 82% (i.e., 18/22 samples were classified correctly, including the single PNR patient).
Conclusion:
Increased expression of five genes is associated with higher rate of anti-TNF response in pediatric CD. Prospective studies are now warranted to validate these genes as biomarkers for treatment selection.
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