A two-stage genome-wide association study to identify novel genetic loci associated with acute radiotherapy toxicity in nasopharyngeal carcinoma

Abstract

Background Genetic variants associated with acute side effects of radiotherapy in nasopharyngeal carcinoma (NPC) remain largely unknown. Methods We performed a two-stage genome-wide association analysis including a total of 1084 patients, where 319 individuals in the discovery stage were genotyped for 688,783 SNPs using whole genome-wide screening microarray. Significant variants were then validated in an independent cohort of 765 patients using the MassARRAY system. Gene mapping, linkage disequilibrium, genome-wide association analysis, and polygenic risk score were conducted or calculated using FUMA, LDBlockShow, PLINK, and PRSice software programs, respectively. Results Five SNPs (rs6711678, rs4848597, rs4848598, rs2091255, and rs584547) showed statistical significance after validation. Radiotherapy toxicity was more serious in mutant minor allele carriers of all five SNPs. Stratified analysis further indicated that rs6711678, rs4848597, rs4848598, and rs2091255 correlated with skin toxicity in patients of EBV positive, late stage (III and IV), receiving both concurrent chemoradiotherapy and induction/adjuvant chemotherapy, and with OR values ranging from 1.92 to 2.66. For rs584547, high occurrence of dysphagia was found in A allele carriers in both the discovery (P = 1.27 × 10− 6, OR = 1.55) and validation (P = 0.002, OR = 4.20) cohorts. Furthermore, prediction models integrating both genetic and clinical factors for skin reaction and dysphagia were established. The area under curve (AUC) value of receiver operating characteristic (ROC) curves were 0.657 (skin reaction) and 0.788 (dysphagia). Conclusions Rs6711678, rs4848597, rs4848598, and rs2091255 on chromosome 2q14.2 and rs584547 were found to be novel risk loci for skin toxicity and dysphagia in NPC patients receiving radiotherapy. Trial registration Chinese Clinical Trial Register (registration number: ChiCTR-OPC-14005257 and CTXY-140007-2).

A pretreatment multiparametric MRI‐based radiomics‐clinical machine learning model for predicting radiation‐induced temporal lobe injury in patients with nasopharyngeal carcinoma

“…39 Therefore, the response of normal tissues after radiotherapy can vary significantly among patients receiving similar treatment. Wang et al 8 found five single nucleotide polymorphisms are risk loci for skin toxicity and dysphagia in patients with NPC receiving radiotherapy. A recent study suggests that genetic susceptibility gene CEP128 affects the occurrence of RTLI.…”

“…[5][6][7] However, despite similar clinical factors, there still exists interindividual variability, implying the existence of other crucial yet undiscovered factors that necessitate consideration. 8 It was reported that each patient's temporal lobe exhibits unique genetic susceptibility to radiation exposure and the genetic susceptibility gene CEP128 involved in RTLI development. 9 Additionally, He et al performed a genome-wide association study and developed a polygenic risk score for RTLI.…”

A two-stage genome-wide association study identifies novel germline genetic variations in CACNA2D3 associated with radiotherapy response in nasopharyngeal carcinoma

“…[ 19 ] Previously, we also performed a GWAS study of multiple acute radiotherapy toxicities in 1084 patients with nasopharyngeal carcinoma. Rs6711678, rs4848597, rs4848598 and rs2091255 on chromosome 2q14.2 and rs5845477 are novel risk loci for skin toxicity and dysphagia [ 20 ]. In this study, we provided the first GWAS study for radiotherapy response in NPC patients.…”

Machine learning in onco-pharmacogenomics: a path to precision medicine with many challenges

“…Clinically relevant predictors of toxicity have also been found in many GWAS studies, e.g., SNPs predicting severe skin toxicity in patients with colorectal carcinoma treated with cetuximab ( Baas et al, 2018 ) or predicting dysphagia in patients with nasopharyngeal carcinoma treated with radiotherapy ( Wang et al, 2022 ) or predicting neurotoxicity and leukoencephalopathy in patients with lymphoblastic leukemia treated with methotrexate ( Bhojwani et al, 2014 ). Many other correlations between SNPs and toxicity can be found in the literature.…”