Department of Radiation Oncology, University Medical Center Groningen, Hanzeplein 1, HPC; DA 30, P.O. Box 30 001, 9700 RB, Groningen, The Netherlands.
Department of Epidemiology, University Medical Center Groningen, Groningen, The Netherlands.
J Transl Med. 2021 Nov 27;19(1):481. doi: 10.1186/s12967-021-03145-1.
Most 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.
A 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.
A region on 5q21.3 containing 16 SNPs showed genome-wide (GW) significance association at P-value < 5.0 × 10 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). 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) for other toxicities, taken to the replication study. Eleven of them showed a nominal association (P-value < 0.05).
This 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.
大多数头颈部癌症（HNC）患者接受放射治疗（RT）并产生毒性。本全基因组关联研究（GWAS）旨在鉴定与 HNC 队列中常见急性放射性诱导毒性（RIT）相关的单核苷酸多态性（SNP）。
在接受 RT 治疗的 1279 例 HNC 患者中进行了两阶段 GWAS，并前瞻性地对粘膜炎、口干、粘性唾液和吞咽困难进行评分。使用曲线下面积（AUC）来估计 RT 期间毒性的平均负荷。在发现研究中，对 957 例患者使用多元线性回归，对 322 例独立复制队列中的前排名单 SNP 进行检测。然后，对发现和复制研究进行了荟萃分析。
在发现研究中，位于 5q21.3 上的包含 16 个 SNP 的区域在 P 值 < 5.0 × 10 时与患者自评的急性口干具有全基因组（GW）显著关联。顶级信号是 rs35542，其调整后的效应大小为 0.17*A（95%CI 0.12 至 0.23；P 值 < = 3.78 × 10）。全基因组显著 SNP 位于三个基因（EFNA5、FBXL17 和 FER）内。计算机功能分析表明，这些基因可能参与 DNA 损伤反应，并在小唾液腺中共同表达。我们发现其他毒性的 428 个提示 SNP（P 值 < 1.0 × 10），并将其纳入复制研究。其中 11 个显示出名义关联（P 值 < 0.05）。
本 GWAS 提示了 HNC 患者自评急性口干的新 SNP。如果得到验证，这些 SNP 及其相关功能途径可能会导致一种预测性检测方法来识别对辐射敏感的患者，这最终可能使 RT 治疗更加个体化。
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