Ruan Xianhui, Tian Mengran, Kang Ning, Ma Weike, Zeng Yu, Zhuang Gaojian, Zhang Wei, Xu Guangwei, Hu Linfei, Hou Xiukun, Xie Wenjun, Gao Ming, Piao Yongjun, Guo Shicheng, Zheng Xiangqian
Department of Thyroid and Neck Tumor, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer Tianjin 300060, China.
Department of Thyroid and Breast Tumor, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital Guangzhou 511500, Guangdong, China.
Am J Cancer Res. 2021 Nov 15;11(11):5402-5414. eCollection 2021.
m6A methylation has been demonstrated to be one of the most important epigenetic regulation mechanisms in cell differentiation and cancer development especially m6A derived diagnostic and prognostic biomarkers have been identified in the past several years. However, systemic investigation to the interaction between germline single-nucleotide polymorphisms (SNPs) and m6A has not been conducted yet. In this study, we collected previous identified significant thyroid cancer associated SNPs from UKB cohort (358 cases and 407,399 controls) and ICR cohort (3,001 patients and 287,550 controls) and thyroid eQTL (sample size = 574 from GTEx project) and m6A-SNP (N = 1,678,126) were applied to prioritize the candidate SNPs. Finally, five candidate genes () were identified to be thyroid cancer associated m6A-related genetic susceptibility. Loss and gain function studies of m6A writer proteins confirm that ACSM5 is regulated by m6A methylation of mRNA. Moreover, ACSM5 is downregulated in thyroid cancer and inversely correlated with PTC malignancy and patient survival. Together, our study highlight mRNA-seq and m6A-seq double analysis provided a novel approach to identify cancer biomarkers and understanding the heterogeneity of human cancers.
m6A甲基化已被证明是细胞分化和癌症发展中最重要的表观遗传调控机制之一，尤其是在过去几年中已经鉴定出了m6A衍生的诊断和预后生物标志物。然而，尚未对种系单核苷酸多态性（SNP）与m6A之间的相互作用进行系统研究。在本研究中，我们从英国生物银行队列（358例病例和407399例对照）和ICR队列（3001例患者和287550例对照）中收集了先前鉴定的与甲状腺癌相关的显著SNP，并应用甲状腺表达数量性状基因座（来自GTEx项目的样本量=574）和m6A-SNP（N=1678126）对候选SNP进行优先级排序。最后，鉴定出五个候选基因（）与甲状腺癌相关的m6A相关遗传易感性。m6A书写蛋白的功能丧失和获得研究证实，ACSM5受mRNA的m6A甲基化调控。此外，ACSM5在甲状腺癌中表达下调，与甲状腺乳头状癌的恶性程度和患者生存率呈负相关。总之，我们的研究强调mRNA测序和m6A测序双重分析为鉴定癌症生物标志物和理解人类癌症的异质性提供了一种新方法。
