A two-stage genome-wide association study of radiation-induced acute toxicity in head and neck cancer

Journal of Translational Medicine

Hendrika Marike Boezen¹  Behrooz Ziad Alizadeh¹  Johanna Geertruida Maria van den Hoek²  Anne Petra Gerarda Crijns²  Roel Johannes Henricus Marinus Steenbakkers²  Johannes Albertus Langendijk²  Elnaz Naderi³ 

[1] Department of Epidemiology, University Medical Center Groningen, Groningen, The Netherlands;Department of Radiation Oncology, University Medical Center Groningen, P.O. Box 30 001, Hanzeplein 1, HPC; DA 30, 9700 RB, Groningen, The Netherlands;Department of Radiation Oncology, University Medical Center Groningen, P.O. Box 30 001, Hanzeplein 1, HPC; DA 30, 9700 RB, Groningen, The Netherlands;Department of Epidemiology, University Medical Center Groningen, Groningen, The Netherlands;

关键词: Radiogenomics;    GWAS;    Radiation-induced toxicity;    Head and neck cancer;   

DOI  :  10.1186/s12967-021-03145-1

来源: Springer

【 摘 要 】

BackgroundMost head and neck cancer (HNC) patients receive radiotherapy (RT) and develop toxicities. This genome-wide association study (GWAS) was designed to identify single nucleotide polymorphisms (SNPs) associated with common acute radiation-induced toxicities (RITs) in an HNC cohort.MethodsA two-stage GWAS was performed in 1279 HNC patients treated with RT and prospectively scored for mucositis, xerostomia, sticky saliva, and dysphagia. The area under the curve (AUC) was used to estimate the average load of toxicity during RT. At the discovery study, multivariate linear regression was used in 957 patients, and the top-ranking SNPs were tested in 322 independent replication cohort. Next, the discovery and the replication studies were meta-analyzed.ResultsA region on 5q21.3 containing 16 SNPs showed genome-wide (GW) significance association at P-value < 5.0 × 10–8 with patient-rated acute xerostomia in the discovery study. The top signal was rs35542 with an adjusted effect size of 0.17*A (95% CI 0.12 to 0.23; P-value <  = 3.78 × 10–9). The genome wide significant SNPs were located within three genes (EFNA5, FBXL17, and FER). In-silico functional analysis showed these genes may be involved in DNA damage response and co-expressed in minor salivary glands. We found 428 suggestive SNPs (P-value < 1.0 × 10–5) for other toxicities, taken to the replication study. Eleven of them showed a nominal association (P-value < 0.05).ConclusionsThis GWAS suggested novel SNPs for patient-rated acute xerostomia in HNC patients. If validated, these SNPs and their related functional pathways could lead to a predictive assay to identify sensitive patients to radiation, which may eventually allow a more individualized RT treatment.

【 授权许可】

CC BY