Abstract 59P
Background
Although anti-epidermal growth factor receptor (EGFR) therapy has established efficacy in RAS/BRAF wild type (WT) mCRC, 10-20% of WT patients exhibit primary resistance to this treatment. Biomarker discovery has mainly focused on tumor-specific DNA mutations, which suffer from variable mutation frequencies among patients. Epigenetic abnormalities, such as promoter hypermethylation, represent a common and early event in carcinogenesis, making it promising for resistance detection. In fact, several studies have shown an association between DNA methylation patterns and resistance to anti-EGFR therapy in CRC. To validate and build upon these findings, we investigated the methylomes of primary tumors with resistant and responsive phenotypes.
Methods
We isolated DNA from 15 primary CRC tumors. These DNA samples were subjected to Enzymatic Methyl-Sequencing (EMSeq), creating a genome-wide methylation dataset. We calculated methylation levels at CpGs and evaluated their correlation with resistance status. Based on the methylation values, a differential methylation analysis was performed using a modified linear mixed regression model. The CpGs were ranked based on the largest Δmethylation values and most significant p-values across the three patient groups. We performed a false discovery rate (FDR) evaluation, which led to the selection of differentially methylated CpGs (DMCs) with the highest likelihood of being genuine associations. Additionally, the DMCs were used as input for gene set enrichment analysis (GSEA).
Results
The GSEA revealed significant enrichment in 1 KEGG and 8 Reactome pathways, including MAPK-related, Akt and Wnt signaling. A gene ontology (GO) overrepresentation analysis was conducted on the significant genes. Notably, the most prominent GO categories were GTPase activity for molecular function and response to oxidative stress for biological processes.
Conclusions
We have created a comprehensive dataset of methylation sites with a substantial effect on conferring resistance to anti-EGFR therapy in CRC patients. In addition to identifying critical DMCs, the pathways hold potential as a rich source of predictive biomarkers.
Editorial acknowledgement
Clinical trial identification
Legal entity responsible for the study
The authors.
Funding
University of Antwerp.
Disclosure
All authors have declared no conflicts of interest.
Resources from the same session
136P - Molecular correlates of drug response to guide therapy in TNBC
Presenter: Nathan Merrill
Session: Cocktail & Poster Display session
Resources:
Abstract
137P - Event-free survival prediction using lncRNAs in pediatric B-cell acute lymphoblastic leukemia
Presenter: Unai Illarregi
Session: Cocktail & Poster Display session
Resources:
Abstract
138P - Exome sequencing analysis for the identification of actionable mutations related to neoadjuvant chemotherapy response in locally advanced breast cancer
Presenter: Ximena López
Session: Cocktail & Poster Display session
Resources:
Abstract
139P - Genomic prognostic and potential theragnostic factors in anal squamous cell carcinoma treated with abdominoperineal resection
Presenter: Abderaouf Hamza
Session: Cocktail & Poster Display session
Resources:
Abstract
144P - Correlation of EZH2 expression and response to chemoradiotherapy in patients with locally advanced inoperable oral cavity and oropharyngeal squamous cell cancers
Presenter: Soel Ahmed
Session: Cocktail & Poster Display session
Resources:
Abstract
140P - Predictive value of DNA damage response and repair gene alterations and neoscore for neoadjuvant immunotherapies in non-small cell lung cancer
Presenter: Fei Feng
Session: Cocktail & Poster Display session
Resources:
Abstract
141P - Immune-related epigenomic and transcriptomic signatures to predict immunotherapy response in NSCLC
Presenter: María Gallardo-Gómez
Session: Cocktail & Poster Display session
Resources:
Abstract
142P - Role and impact of hypoxia-inducible factor 1-alpha on survival rates in pancreatic cancer: A systematic review and meta-analysis
Presenter: Muhammed Elfaituri
Session: Cocktail & Poster Display session
Resources:
Abstract
143P - Genomic characterization and outcomes of patients with primary sclerosing cholangitis-related cholangiocarcinoma
Presenter: Jaime Haro Silerio
Session: Cocktail & Poster Display session
Resources:
Abstract
145P - Identification of next generation sequencing (NGS)-based genomic signature predicting resistance to immunotherapy (IO) in patients (pts) with metastatic non-small cell lung cancer (mNSCLC): A single-center cohort study
Presenter: Antonio Vitale
Session: Cocktail & Poster Display session
Resources:
Abstract