Genome-wide association study identifies genetic susceptibility loci and pathways of radiation-induced acute oral mucositis

Abstract

Background: Radiation-induced oral mucositis (OM) is one of the most common acute complications for head and neck cancer. Severe OM is associated with radiation treatment breaks, which harms successful tumor management. Radiogenomics studies have indicated that genetic variants are associated with adverse effects of radiotherapy.

Methods: A large-scale genome-wide scan was performed in 1467 nasopharyngeal carcinoma patients, including 753 treated with 2D-CRT from Genetic Architecture of the Radiotherapy Toxicity and Prognosis (GARTP) cohort and 714 treated with IMRT (192 from the GARTP and 522 newly recruited). Subgroup analysis by radiotherapy technique was further performed in the top associations. We also performed physical and regulatory mapping of the risk loci and gene set enrichment analysis of the candidate target genes.

Results: We identified 50 associated genomic loci and 64 genes via positional mapping, expression quantitative trait locus (eQTL) mapping, chromatin interaction mapping and gene-based analysis, and 36 of these loci were replicated in subgroup analysis. Interestingly, one of the top loci located in TNKS, a gene relevant to radiation toxicity, was associated with increased OM risk with OR = 3.72 of the lead SNP rs117157809 (95% CI 2.10-6.57; P = 6.33 × 10^-6). Gene set analyses showed that the 64 candidate target genes were enriched in the biological processes of regulating telomere capping and maintenance and telomerase activity (Top P = 7.73 × 10^-7).

Conclusions: These results enhance the biological understanding of radiotherapy toxicity. The association signals enriched in telomere function regulation implicate the potential underlying mechanism and warrant further functional investigation and potential individual radiotherapy applications.

Keywords: Functional mapping; Genome-wide association study; Oral mucositis; Radiation injuries; Radiogenomics.

Fig. 1

Manhattan plot of the genome-wide P-values of associations. Associations were assessed using logistic regression analysis with adjustment for treatment, the radiation technique and the top five principal components of population stratification. The blue line indicates the threshold for suggestive significance: P < 1 × 10⁻⁴

Fig. 2

Regional plot of the association of rs10810756. The -log₁₀P-value (y-axis) of SNPs are presented according to their chromosomal positions (x-axis). The lead SNP (labeled by rs ID) is indicated by a deep purple circle, and the r² values of the rest of the SNPs with the top genotyped SNP are indicated by different colors. SNPs that are not in LD with any of the independent significant SNPs (with r² ≤ 0.4) are gray

Fig. 3

Cross-locus interactions for genomic regions associated with radiation-induced oral mucositis. Circos plots showing genes on chromosome 9 that were implicated through the genomic risk loci (blue areas) by positional mapping, by chromatin interaction mapping (orange font), eQTL mapping (green font), or by both chromatin interaction and eQTL mapping (red font). The outer layer shows a Manhattan plot containing the -log₁₀ P-value of each SNP in the GWAS analysis of radiation-induced oral mucositis (n = 1467 individuals)