State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, 510060, People's Republic of China.
School of Public Health, Sun Yat-sen University, Guangzhou, People's Republic of China.
Hum Genet. 2023 Jun;142(6):759-772. doi: 10.1007/s00439-023-02554-0. Epub 2023 Apr 16.
Chemoradiation-induced hearing loss (CRIHL) is one of the most devasting side effects for nasopharyngeal carcinoma (NPC) patients, which seriously affects survivors' long-term quality of life. However, few studies have comprehensively characterized the risk factors for CRIHL. In this study, we found that age at diagnosis, tumor stage, and concurrent cisplatin dose were positively associated with chemoradiation-induced hearing loss. We performed a genome-wide association study (GWAS) in 777 NPC patients and identified rs1050851 (within the exon 2 of NFKBIA), a variant with a high deleteriousness score, to be significantly associated with hearing loss risk (HR = 5.46, 95% CI 2.93-10.18, P = 9.51 × 10). The risk genotype of rs1050851 was associated with higher NFKBIA expression, which was correlated with lower cellular tolerance to cisplatin. According to permutation-based enrichment analysis, the variants mapping to 149 hereditary deafness genes were significantly enriched among GWAS top signals, which indicated the genetic similarity between hereditary deafness and CRIHL. Pathway analysis suggested that synaptic signaling was involved in the development of CRIHL. Additionally, the risk score integrating genetic and clinical factors can predict the risk of hearing loss with a relatively good performance in the test set. Collectively, this study shed new light on the etiology of chemoradiation-induced hearing loss, which facilitates high-risk individuals' identification for personalized prevention and treatment.
放化疗诱导的听力损失（CRIHL）是鼻咽癌（NPC）患者最具破坏性的副作用之一，严重影响幸存者的长期生活质量。然而，很少有研究全面描述 CRIHL 的危险因素。在这项研究中，我们发现诊断时的年龄、肿瘤分期和同期顺铂剂量与放化疗诱导的听力损失呈正相关。我们在 777 名 NPC 患者中进行了全基因组关联研究（GWAS），并确定了 rs1050851（NFKBIA 外显子 2 内），这是一个具有高致损性评分的变体，与听力损失风险显著相关（HR=5.46，95%CI2.93-10.18，P=9.51×10）。rs1050851 的风险基因型与 NFKBIA 表达升高相关，这与细胞对顺铂的耐受性降低有关。根据基于置换的富集分析，映射到 149 个遗传性耳聋基因的变体在 GWAS 顶级信号中显著富集，这表明遗传性耳聋和 CRIHL 之间存在遗传相似性。通路分析表明，突触信号参与了 CRIHL 的发生。此外，整合遗传和临床因素的风险评分可以在测试集中以相对较好的性能预测听力损失的风险。总的来说，这项研究为放化疗诱导的听力损失的病因学提供了新的见解，有助于识别高危个体，进行个性化的预防和治疗。
