Identification of the prognostic signature based on genomic instability-related alternative splicing in colorectal cancer and its regulatory network.
Identification of the prognostic signature based on genomic instability-related alternative splicing in colorectal cancer and its regulatory network.
复制标题
基于基因组不稳定性相关的结直肠癌选择性剪接及其调控网络的预后特征鉴定。
DOI：
10.3389/fbioe.2022.841034
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发表时间：
2022
影响因子：
5.7
通讯作者：
Xiang, Yue
中科院分区：
文献类型：
--
作者：
Ding, Qiuying;Hou, Zhengping;Zhao, Zhibo;Chen, Yao;Zhao, Lei;Xiang, Yue
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.
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影响因子：
12.8
作者：
Kagoya, Yuki;Saijo, Hiroshi;Hirano, Naoto
通讯作者：
Hirano, Naoto
影响因子：
13.6
作者：
El Marabti E;Abdel-Wahab O
通讯作者：
Abdel-Wahab O
影响因子：
6.4
作者：
Eilertsen IA;Sveen A;Strømme JM;Skotheim RI;Nesbakken A;Lothe RA
通讯作者：
Lothe RA
影响因子：
3.7
作者：
Alholle, Abdullah;Brini, Anna T.;Latif, Farida
通讯作者：
Latif, Farida
DOI：
10.1038/nrm.2017.27
发表时间：
2017-07
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
Baralle FE;Giudice J
通讯作者：
Giudice J