Splice-disrupt genomic variants in prostate cancer

Abstract

Background Splice-disrupt genomic variants are one of the causes of cancer-causing errors in gene expression. Little is known about splice-disrupt genomic variants. Methods and results Here, pattern of splice-disrupt variants was investigated using 21,842,764 genomic variants in different types of prostate cancer. A particular attention was paid to genomic locations of splice-disrupt variants on target genes. HLA-A in prostate cancer, MSR1 in familial prostate cancer, and EGFR in both castration-resistant prostate cancer and metastatic castration-resistant had the highest allele frequencies of splice-disrupt variations. Some splice-disrupt variants, located on coding sequences of NCOR2, PTPRC, and CRP, were solely present in the advanced metastatic castration-resistant prostate cancer. High-risk splice-disrupt variants were identified based on computationally calculated Polymorphism Phenotyping (PolyPhen), Sorting Intolerant From Tolerant (SIFT), and Genomic Evolutionary Rate Profiling (GERP) + + scores as well as the recorded clinical significance in dbSNP database of NCBI. Functional annotation of damaging splice-disrupt variants highlighted important cancer-associated functions, including endocrine resistance, lipid metabolic process, steroid metabolic process, regulation of mitotic cell cycle, and regulation of metabolic process. This is the first study that profiles the splice-disrupt genomic variants and their target genes in prostate cancer. Literature mining based variant analysis highlighted the importance of rs1800716 variant, located on the CYP2D6 gene, involved in a range of important functions, such as RNA spicing, drug interaction, death, and urotoxicity. Conclusions This is the first study that profiles the splice-disrupt genomic variants and their target genes in different types of prostate cancer. Unravelling alternative splicing opens a new avenue towards the establishment of new diagnostic and prognostic markers for prostate cancer progression and metastasis.

Alternative splicing in prostate cancer progression and therapeutic resistance

“…Only one study so far has profiled the different splice-disrupt genomic variants in CaP and reported HLA-A in primary CaP, MSR1 in familial CaP, and EGFR in both CRPC and metastatic CRPC with the highest allele frequencies of splice-disrupt variations [ 133 ]. Nonetheless, several splice-disrupting genomic variants have been predicted during different stages of CaP progression, which impact cancer-relevant genes such as EGFR [ 133 ]. The extent to which these predictions hold true is yet to be fully determined.…”