Whole-exome sequencing study of familial nasopharyngeal carcinoma and its implication for identifying high-risk individuals
Menée à partir de données de la biobanque britannique portant sur 5 218 patients atteints d'un cancer héréditaire et menée à partir du séquençage du génome entier de 502 patients atteints d'un carcinome rhinopharyngé lié à des gènes de prédisposition et 404 parents ou témoins sains, cette étude identifie 6 nouveaux gènes de susceptibilité à la maladie et met en évidence la performance d'un système de score, basé sur la présence de variants génétiques rares ou communs, pour évaluer le risque de développer un carcinome rhinopharyngé héréditaire
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.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).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%).This study expands the catalog of NPC susceptibility genes and provides the potential for risk stratification of individuals with an NPC family history.
Journal of the National Cancer Institute , article en libre accès, 2021