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

Abstract

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.

Alternative Splicing Events and Their Clinical Significance in Colorectal Cancer: Targeted Therapeutic Opportunities

“…Amongst pool of PRMT1 variants, two splice variants of PRMT1 (variants v.1 and v.2) (show Figure 5) were reported to be significantly upregulated in CRC and their overexpress was associated with the nodal status and histological grade of tumors in colon cancer [ 83]. The AS event PRMT1-51042-ES, reported to be highly expressed by cytotoxic helper cells, was identified as an independent predictor of overall survival, genomic stability, and poor prognosis in CRC [84]. PRMT1∆arm, a variant of PRMT1, is miss exons crucial for organizing the dimerization domain necessary for enzymatic activity a result, PRMT1∆arm is unable to methylate arginines, but retains the chromatin-bind capacity, competitively limiting the binding of active PRMT1 and ultimately leadin increased chances of malignancy [85].…”

“…The AS event PRMT1-51042-ES, reported to be highly expressed by cytotoxic T-helper cells, was identified as an independent predictor of overall survival, genomic instability, and poor prognosis in CRC [84]. PRMT1∆arm, a variant of PRMT1, is missing exons crucial for organizing the dimerization domain necessary for enzymatic activity.…”

Prognostic and immunological analysis of METTL16 in pan-cancer

“…Figure 5F showed a positive correlation between the expression of neoantigen and METTL16 in COAD, KICH, and UCEC. In addition to simple deoxyribonucleic acid sequence alterations, genomic instability encompasses chromosomal aberrations [59]. METTL16 was positively correlated with MESO, OV, LIHC, and LUSC in ploidy analysis, and negatively correlated with THYM, DLBC, PRAD, and UCEC (Fig.…”

“…Maintaining genomic instability requires AS [59]. By conducting an analysis of the NCBI database, we discovered that METTL16 contains numerous variable splices (Fig.…”