Identification of the prognostic signature based on genomic instability-related alternative splicing in colorectal cancer and its regulatory network

作者全名："Ding, Qiuying; Hou, Zhengping; Zhao, Zhibo; Chen, Yao; Zhao, Lei; Xiang, Yue"

作者地址："[Ding, Qiuying; Hou, Zhengping; Chen, Yao; Zhao, Lei; Xiang, Yue] Chongqing Med Univ, Affiliated Hosp 2, Inst Viral Hepatitis, Ctr Lipid Res,Key Lab Mol Biol Infect Dis,Minist E, Chongqing, Peoples R China; [Zhao, Zhibo] Chongqing Med Univ, Dept Hepatobiliary Surg, Affiliated Hosp 2, Chongqing, Peoples R China"

通信作者："Chen, Y; Zhao, L; Xiang, Y (通讯作者)，Chongqing Med Univ, Affiliated Hosp 2, Inst Viral Hepatitis, Ctr Lipid Res,Key Lab Mol Biol Infect Dis,Minist E, Chongqing, Peoples R China."

来源：FRONTIERS IN BIOENGINEERING AND BIOTECHNOLOGY

ESI学科分类：Multidisciplinary

WOS号：WOS:000834576800001

JCR分区：Q1

影响因子：5.7

年份：2022

卷号：10

期号：　

开始页：　

结束页：　

文献类型：Article

关键词：colorectal cancer; genomic instability; alternative splicing; splicing factor; overall survival

摘要："Background: Colorectal cancer (CRC) is a heterogeneous disease with many somatic mutations defining its genomic instability. Alternative Splicing (AS) events, are essential for maintaining genomic instability. However, the role of genomic instability-related AS events in CRC has not been investigated. Methods: From The Cancer Genome Atlas (TCGA) program, we obtained the splicing profiles, the single nucleotide polymorphism, transcriptomics, and clinical information of CRC. Combining somatic mutation and AS events data, a genomic instability-related AS signature was constructed for CRC. Mutations analyses, clinical stratification analyses, and multivariate Cox regression analyses evaluated this signature in training set. Subsequently, we validated the sensitivity and specificity of this prognostic signature using a test set and the entire TCGA dataset. We constructed a nomogram for the prognosis prediction of CRC patients. Differentially infiltrating immune cells were screened by using CIBERSORT. Inmmunophenoscore (IPS) analysis was used to evaluate the response of immunotherapy. The AS events-related splicing factors (SF) were analyzed by Pearson's correlation. The effects of SF regulating the prognostic AS events in proliferation and migration were validated in Caco2 cells. Results: A prognostic signature consisting of seven AS events (PDHA1-88633-ES, KIAA1522-1632-AP, TATDN1-85088-ES, PRMT1-51042-ES, VEZT-23786-ES, AIG1-77972-AT, and PHF11-25891-AP) was constructed. Patients in the high-risk score group showed a higher somatic mutation. The genomic instability risk score was an independent variable associated with overall survival (OS), with a hazard ratio of a risk score of 1.537. The area under the curve of receiver operator characteristic curve of the genomic instability risk score in predicting the OS of CRC patients was 0.733. Furthermore, a nomogram was established and could be used clinically to stratify patients to predict prognosis. Patients defined as high-risk by this signature showed a lower proportion of eosinophils than the low-risk group. Patients with low risk were more sensitive to anti-CTLA4 immunotherapy. Additionally, HSPA1A and FAM50B were two SF regulating the OS-related AS. Downregulation of HSPA1A and FAM50B inhibited the proliferation and migration of Caco2 cells. Conclusion: We constructed an ideal prognostic signature reflecting the genomic instability and OS of CRC patients. HSPA1A and FAM50B were verified as two important SF regulating the OS-related AS."

基金机构："National Natural Science Foundation of China [81970510, 31971084]; Chongqing Natural Science Foundation [cstc2021ycjh-bgzxm0146, cstc2019jcyj-msxmX0336]; Talent Project of Chongqing [CQYC2019050790]; Science and Technology Research Program of Chongqing Municipal Education Commission [KJQN201900438]"

基金资助正文："This study was funded by the National Natural Science Foundation of China (Grant No. 81970510 and No. 31971084), Chongqing Natural Science Foundation (cstc2021ycjh-bgzxm0146, cstc2019jcyj-msxmX0336), Talent Project of Chongqing (CQYC2019050790) and the Science and Technology Research Program of Chongqing Municipal Education Commission (KJQN201900438)."