Genome-wide enriched pathway analysis of acute post-radiotherapy pain in breast cancer patients: a prospective cohort study

Abstract

Background: Adjuvant radiotherapy (RT) can increase the risk of developing pain; however, the molecular mechanisms of RT-related pain remain unclear. The current study aimed to identify susceptibility loci and enriched pathways for clinically relevant acute post-RT pain, defined as having moderate to severe pain (pain score ≥ 4) at the completion of RT. Methods: We conducted a genome-wide association study (GWAS) with 1,344,832 single-nucleotide polymorphisms (SNPs), a gene-based analysis using PLINK set-based tests of 19,621 genes, and a functional enrichment analysis of a gene list of 875 genes with p < 0.05 using NIH DAVID functional annotation module with KEGG pathways and GO terms (n = 380) among 1112 breast cancer patients. Results: About 29% of patients reported acute post-RT pain. None of SNPs nor genes reached genome-wide significant level. Four SNPs showed suggestive associations with post-RT pain; rs16970540 in RFFL or near the LIG3 gene (p = 1.7 × 10 −6), rs4584690, and rs7335912 in ABCC4/MPR4 gene (p = 5.5 × 10 −6 and p = 7.8 × 10 −6 , respectively), and rs73633565 in EGFL6 gene (p = 8.1 × 10 −6). Gene-based analysis suggested the potential involvement of neurotransmitters, olfactory receptors, and cytochrome P450 in post-RT pain, whereas functional analysis showed glucuronidation (FDR-adjusted p value = 9.46 × 10 −7) and olfactory receptor activities (FDR-adjusted p value = 0.032) as the most significantly enriched biological features. Conclusions: This is the first GWAS suggesting that post-RT pain is a complex polygenic trait influenced by many biological processes and functions such as glucuronidation and olfactory receptor activities. If validated in larger populations, the results can provide biological targets for pain management to improve cancer patients' quality of life. Additionally, these genes can be further tested as predictive biomarkers for personalized pain management.

Identification of Candidate Genes and Pathways Associated with Obesity-Related Traits in Canines via Gene-Set Enrichment and Pathway-Based GWAS Analysis

“…The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway database and Gene Ontology (GO) database under biological process and molecular function categories were used for functional annotation and enrichment analyses. Over-representation of genes in every GO terms and pathways were tested using a Fisher's exact test, which was conducted using the web-based gene-enrichment analysis tool, the Database for Annotation, Visualization, and integrated discovery (DAVID, http://david.abcc.ncifcrf.gov/) [32]. False discovery rate (FDR) correction (<0.05) was applied to account for multiple testing [32].…”

“…Over-representation of genes in every GO terms and pathways were tested using a Fisher's exact test, which was conducted using the web-based gene-enrichment analysis tool, the Database for Annotation, Visualization, and integrated discovery (DAVID, http://david.abcc.ncifcrf.gov/) [32]. False discovery rate (FDR) correction (<0.05) was applied to account for multiple testing [32]. The GO terms/KEGG category pathways with more than 10 and less than 1000 genes were analyzed for narrowing down the functional categories.…”

Characteristics of Genomic Mutations and Signaling Pathway Alterations in Thymic Epithelial Tumors

“…It has been reported that the ZNF429 gene is signi cantly associated with acute postoperative pain in breast cancer, whereas ZNF208 polymorphisms are associated with ischemic stroke in a southern Chinese Han population. [40,41] Studies have found that PABPC1 (poly(A) binding protein cytoplasmic 1) is directly involved in the tumorigenesis of gastric cancer through promotion of cell proliferation; consistent with this, down-regulated expression of PABPC1 is associated with tumor progression and a worse prognosis. [42,43] Our analysis of the TCGA-THYM database further showed that the genes with the highest mutation frequency were GTF2I (50%), HRAS (8%), and MUC16 (7%) (Fig.…”

Enterochromaffin Cells: Sentinels to Gut Microbiota in Hyperalgesia?

“…Olfr plays an important role in many physiological and pathological processes such as sensory perception, behavior and emotion regulation, immune system activity and inflammation regulation, tumor growth, and metastasis ( Meijerink, 2021 ). Although there were few studies on its mechanism of action in hyperalgesia, the current research status suggests that it is closely related to hyperalgesia in certain diseases ( Lee et al., 2019 ). The genome-wide association study of blood samples from breast cancer patients showed that the occurrence of pain after adjuvant radiotherapy was significantly associated with the activity of Olfr genes (OR52N1, OR4C12, OR4A47) ( Lee et al., 2019 ).…”