Polygenic risk scores (PRS) have the potential to identify individuals at risk of diseases, optimizing treatment, and predicting survival outcomes. Here, we construct and validate a genome-wide association study (GWAS) derived PRS for nasopharyngeal carcinoma (NPC), using a multi-center study of six populations (6 059 NPC cases and 7 582 controls), and evaluate its utility in a nested case-control study. We show that the PRS enables effective identification of NPC high-risk individuals (AUC = 0.65) and improves the risk prediction with the PRS incremental deciles in each population (Ptrend ranging from 2.79 × 10−7 to 4.79 × 10−44). By incorporating the PRS into EBV-serology-based NPC screening, the test’s positive predictive value (PPV) is increased from an average of 4.84% to 8.38% and 11.91% in the top 10% and 5% PRS, respectively. In summary, the GWAS-derived PRS, together with the EBV test, significantly improves NPC risk stratification and informs personalized screening.

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.

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Background Nasopharyngeal carcinoma (NPC) is a highly aggressive neoplasm mainly distributed in the eastern and southeastern parts of Asia. NPC has a poor prognosis among head and neck cancers, and molecular-targeted therapies showed limited clinical efficacy. Methods We reviewed publications in the PubMed database and extracted genes associated with NPC. The online tool WebGestalt was used to perform Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis for these genes. Next, the two parameters, Jaccard Coefficient (JC) and Overlap Coefficient (OC), were used to analyze the crosstalk of each pair of selected pathways. The new NPC-related genes were predicted by protein-protein interaction (PPI) network combined with hub genes extraction. Western blotting, qRT-PCR, and immunohistochemistry (IHC) were used to detect the expression of candidate genes in NPC cells and tissues, and cellular function assays were used to explore the effects of genes on NPC cells. Results A total of 552 genes were identified and used to build an NPC-related gene set (NPCgset). Pathways enriched in KEGG pathway analysis were further used for crosstalk analysis and were grouped into two modules: one was related to the carcinogenesis process, and the other was correlated with the immune response. Eight genes from the NPCgset were selected to build a PPI network, and two hub genes PIK3CA and AKT1 were chosen. Proteins interacting with PIK3CA were analyzed; among them, the expression of RRAS was down-regulated in NPC and associated with poor prognosis of NPC patients. Furthermore, RRAS suppressed proliferation, invasion and the epithelial-mesenchymal transformation (EMT) of the HK1 and 5-8F cell lines. Conclusions Our study may help to explore the biological processes underlying NPCgset and suggests that RRAS may act as a tumor suppressor gene in NPC.

Background Nasopharyngeal carcinoma (NPC) is closely associated with genetic factors and Epstein-Barr virus (EBV) infection, showing significant familial aggregation. Individuals with a family history suffer elevated NPC risk, requiring effective genetic counseling for risk stratification and individualized prevention. Methods We performed whole-exome sequencing on 502 familial NPC patients and 404 unaffected relatives and controls. We systematically evaluated the established cancer predisposition genes and investigated novel NPC susceptibility genes, making comparisons with other 21 familial cancers in the UK biobank (N = 5218). Results Rare pathogenic mutations in the established cancer predisposition genes were observed in familial NPC patients, including ERCC2 (1.39%), TP63 (1.00%), MUTYH (0.80%) and BRCA1 (0.80%). Additionally, six novel susceptibility genes were identified. RAD54L involved in DNA repair pathway together with ERCC2, MUTYH, and BRCA1, showed the highest frequency (4.18%) in familial NPC. Enrichment analysis found mutations in TP63 were enriched in familial NPC, while RAD54L and EML2 were enriched in both NPC and other EBV-associated cancers. Besides rare variants, common variants reported in the studies of sporadic NPC were also associated with familial NPC risk. Individuals in the top quantile of common variant-derived genetic risk score (GRSC) while carrying rare variants exhibited increased NPC risk (OR = 13.47, 95% CI: 6.33–28.68, P = 1.48 × 10–11); males in this risk group showed cumulative lifetime risk of 24.19%, much higher than those in the bottom GRSC quantile and without rare variants (2.04%). Conclusions This study expands the catalog of NPC susceptibility genes and provides the potential for risk stratification of individuals with an NPC family history.