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中华临床实验室管理电子杂志 ›› 2022, Vol. 10 ›› Issue (02) : 65 -75. doi: 10.3877/cma.j.issn.2095-5820.2022.02.001

论著

基于生物信息学对直肠癌中m6A调节因子介导相关修饰模式的分析
周威1, 胡山2, 柳金强1, 段理理1, 钮瞭然1, 洪流1,†(), 樊代明1   
  1. 1. 710032　陕西西安，空军军医大学第一附属医院消化病医院
    2. 100017　北京，解放军61889部队卫生所
  • 收稿日期:2021-12-31 出版日期:2022-05-28
  • 通信作者: 洪流
  • 基金资助:
    国家自然科学基金(82073210)

Analysis of m6A regulatory factor mediated modification patterns in rectal cancer based on Bioinformatics

Wei Zhou1, Shan Hu2, Jinqiang Liu1, Lili Duan1, Liaoran Niu1, Liu Hong1,†(), Daiming Fan1   

  1. 1. Digestive Hospital, the First Affiliated Hospital, Air Force Medical University, Xi'an Shanxi 710032, China
    2. The Health Center of PLA Unit 61889, Beijing 100017, China
  • Received:2021-12-31 Published:2022-05-28
  • Corresponding author: Liu Hong
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引用本文：

周威, 胡山, 柳金强, 段理理, 钮瞭然, 洪流, 樊代明. 基于生物信息学对直肠癌中m6A调节因子介导相关修饰模式的分析[J]. 中华临床实验室管理电子杂志, 2022, 10(02): 65-75.

Wei Zhou, Shan Hu, Jinqiang Liu, Lili Duan, Liaoran Niu, Liu Hong, Daiming Fan. Analysis of m6A regulatory factor mediated modification patterns in rectal cancer based on Bioinformatics[J]. Chinese Journal of Clinical Laboratory Management(Electronic Edition), 2022, 10(02): 65-75.

目的

探索N6-甲基腺嘌呤（m6A）修饰在肿瘤形成及与肿瘤微环境（TME）形成中的关系。

方法

基于23个m6A调节因子对288例直肠癌标本的m6A修饰模式进行综合评估，以确定直肠癌中m6A修饰模式和m6A相关基因特征，并评估基于PCA算法的m6A评分方案与免疫治疗反应之间的相关性。

结果

本研究分析了23个m6A调节因子在直肠癌中的表达和突变情况，及其与患者预后的关系，进一步在直肠癌样本中确定了三种不同的m6A修饰模式，分析其与不同的临床特征有关，并且证明m6A评分可以预测患者对抗PD-1/PD-L1免疫治疗的临床反应。

结论

m6A修饰异常与肿瘤的发生发展密切相关，并且在TME多样性和复杂性的形成中起着重要作用，评估肿瘤中的m6A修饰模式将有助于指导更有效的免疫治疗策略。

关键词: 直肠肿瘤, 肿瘤微环境, 预后, m6A修饰
Objective

To explore the relationship between m6A modification and tumor microenvironment (TME).

Methods

The m6A modification pattern of 288 rectal cancer specimens was comprehensively evaluated based on 23 m6A regulators (RC) to determine the m6A modification pattern and m6A related gene characteristics in RC, and to evaluate the correlation between m6A scoring scheme based on PCA algorithm and immunotherapy response.

Results

This study analyzed the expression and mutation of 23 m6A regulatory factors in RC and their relationship with the prognosis of patient. Further, three different m6A modification modes were identified in RC samples, which were related to different clinical characteristics. It was proved that m6A score could predict the clinical response of patients to PD-1/PD-L1 immunotherapy.

Conclusions

This study showed that the abnormal m6A modification was closely related to the occurrence and development of tumors, and played an important role in the formation of diversity and complexity of TME. Evaluating the m6A modification mode in tumors will help to guide more effective immunotherapy strategies.

Key words: Rectal cancer, Tumor microenvironment, Prognosis, m6A modification
图1 直肠癌中m6A调节因子的遗传变异注：1A为23个m6A调控因子的PPI网络；1B为23个m6A调节因子的CNV突变频率；1C为染色体上m6A调节因子CNV改变的位置；1D为正常和直肠癌样本之间23种m6A调节因子mRNA表达水平的差异；1E为直肠癌中23个m6A甲基化修饰调节因子的相关性；1F为23种m6A调节因子在136例直肠癌患者中的突变频率；1G为m6A基因在ZC3H13基因不同突变组之间的差异情况
表1 直肠癌中m6A调节因子与直肠癌患者生存的关系
m6A调节因子 HR HR.95L HR.95H P值
IGFBP1 0.839 649 0.755 171 0.933 577 0.000 087
YTHDF3 1.332 288 0.924 868 1.919 184 0.000 246
HNRNPA2B1 0.378 774 0.246 117 0.582 935 0.000 421
VIRMA 0.595 351 0.419 923 0.844 065 0.000 789
YTHDC2 1.732 703 1.249 126 2.403 488 0.000 956
YTHDF1 0.604 633 0.430 435 0.849 330 0.001 221
IGFBP2 0.923 730 0.845 738 1.008 914 0.004 226
METTL14 1.146 693 0.806 679 1.630 023 0.005 431
FMR1 0.683 866 0.503 849 0.928 202 0.005 470
LRPPRC 0.773 795 0.581 259 1.030 108 0.008 567
RBM15 0.682 198 0.481 666 0.966 217 0.012 177
IGFBP3 1.109 171 0.950 080 1.294 901 0.014 037
YTHDC1 1.268 771 1.005 214 1.601 431 0.028 030
METTL16 0.688 606 0.454 288 1.043 782 0.029 306
图2 直肠癌中m6A调节因子与生存的关系注：2A为直肠癌患者预后相关的m6A调节因子；2B为直肠癌中m6A调节因子的表达相互作用
图3 m6A修饰模式的确定注：3A通过m6A调节因子的表达相似性将直肠癌分为三型；3B为三个m6A分型的直肠癌患者生存曲线图；3C为三个m6A分型患者的临床症状热图；3D为23个m6A调节因子在三个基因分型中的表达。aP<0.05；bP<0.01；cP<0.001
图4 基于m6A分组间的DEGs构建基因分型注：4A通过m6A表型相关标记基因将直肠癌分为三型；4B为三个基因分型的直肠癌患者生存曲线图；4C为不同基因分型患者的临床症状热图；4D为23个m6A调节因子在三个基因分型中的表达。aP＜0.05；bP＜0.01；cP＜0.001
图5 m6A评分预测免疫治疗的获益注：5A为m6A评分与免疫细胞的相关性；5B为低或高m6A评分组中5年内存活或死亡的患者比例；5C为存活和死亡患者的m6A评分；5D为低或高m6A评分组之间PD-L1表达的差异；5E为低或高m6A评分组在CTLA4抗体和PD-1抗体表达阳性（pos）和阴性（neg）时的表达水平
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