Variants in WFS1 and Other Mendelian Deafness Genes Are Associated with Cisplatin-Associated Ototoxicity.
Variants in WFS1 and Other Mendelian Deafness Genes Are Associated with Cisplatin-Associated Ototoxicity.
复制标题
DOI：
10.1158/1078-0432.ccr-16-2809
复制
发表时间：
2017-07-01
期刊：
影响因子：
--
通讯作者：
Travis LB
中科院分区：
文献类型：
--
作者：
Wheeler HE;Gamazon ER;Frisina RD;Perez-Cervantes C;El Charif O;Mapes B;Fossa SD;Feldman DR;Hamilton RJ;Vaughn DJ;Beard CJ;Fung C;Kollmannsberger C;Kim J;Mushiroda T;Kubo M;Ardeshir-Rouhani-Fard S;Einhorn LH;Cox NJ;Dolan ME;Travis LB
顺铂是世界上最常用的化疗药物之一，也是耳毒性最强的药物之一。我们试图确定调节顺铂相关性耳毒性(CAO)的遗传变异。我们使用定量测听技术(4-12 kHz)对511名有欧洲遗传血统的睾丸癌幸存者进行了CAO的全基因组关联研究。我们使用各种公开可用的数据库进行了多基因建模和功能分析。我们使用了一个电子健康记录队列来复制我们最重要的机械发现。孟德尔耳聋基因wfs1第一内含子的单核苷酸多态rs62283056和wfs1表达的数量性状基因座具有全基因组意义(P=1.4×10−8)。顺铂累积剂量与rs62283056基因型之间存在显著交互作用，提示顺铂剂量越大，携带小等位基因的患者听力损失越重(P=0.035)。在独立的BioVU队列(n=18,620名患者，Bonferroni调整P<；0.05)中重复了WFS1表达降低和听力损失之间的关联。除了这一最高信号外，我们还表明CAO是一个多基因性状，而且84个已知孟德尔耳聋基因及其附近的SNPs在GWA低P值时显著丰富(P=0.048)。我们首次显示了WFS1在CAO中的作用，并记录了累积顺铂剂量增加与rs62283056基因型之间的统计学显著交互作用。我们的临床翻译结果表明，在决定不同累积剂量、疗效相似的顺铂化疗方案时，治疗前对患者进行基因分型以将耳毒性降至最低可能是有用的。
Cisplatin is one of the most commonly used chemotherapy drugs worldwide and one of the most ototoxic. We sought to identify genetic variants that modulate cisplatin-associated ototoxicity (CAO). We performed a genome-wide association study (GWAS) of CAO using quantitative audiometry (4–12 kHz) in 511 testicular cancer survivors of European genetic ancestry. We performed polygenic modeling and functional analyses using a variety of publicly available databases. We used an electronic health record cohort to replicate our top mechanistic finding. One SNP, rs62283056, in the first intron of Mendelian deafness gene WFS1 (wolframin ER transmembrane glycoprotein) and an expression quantitative trait locus (eQTL) for WFS1 met genome-wide significance for association with CAO (P=1.4×10−8). A significant interaction between cumulative cisplatin dose and rs62283056 genotype was evident, indicating that higher cisplatin doses exacerbate hearing loss in patients with the minor allele (P=0.035). The association between decreased WFS1 expression and hearing loss was replicated in an independent BioVU cohort (n=18,620 patients, Bonferroni adjusted P<0.05). Beyond this top signal, we show CAO is a polygenic trait and that SNPs in and near 84 known Mendelian deafness genes are significantly enriched for low P-values in the GWAS (P=0.048). We show for the first time the role of WFS1 in CAO and document a statistically significant interaction between increasing cumulative cisplatin dose and rs62283056 genotype. Our clinical translational results demonstrate that pre-therapy patient genotyping to minimize ototoxicity could be useful when deciding between cisplatin-based chemotherapy regimens of comparable efficacy with different cumulative doses.