Splice-disrupt genomic variants in prostate cancer

Ibrahim O Alanazi; Salman F Alamery; Esmaeil Ebrahimie; Manijeh Mohammadi-Dehcheshmeh

doi:10.1007/s11033-022-07257-9

Splice-disrupt genomic variants in prostate cancer

Mol Biol Rep. 2022 Jun;49(6):4237-4246. doi: 10.1007/s11033-022-07257-9. Epub 2022 Mar 14.

Authors

Ibrahim O Alanazi^#¹, Salman F Alamery^#², Esmaeil Ebrahimie^{3

4

5}, Manijeh Mohammadi-Dehcheshmeh^{6

7}

Affiliations

¹ National Center for Biotechnology, Life Science and Environment Research Institute, King Abdulaziz City for Science and Technology (KACST), Riyadh, Saudi Arabia.
² Department of Biochemistry, College of Science, King Saud University, Riyadh, Saudi Arabia.
³ Genomics Research Platform, School of Life Sciences, La Trobe University, Melbourne, VIC, 3086, Australia. E.Ebrahimie@latrobe.edu.au.
⁴ School of Animal and Veterinary Sciences, The University of Adelaide, Adelaide, 5371, Australia. E.Ebrahimie@latrobe.edu.au.
⁵ School of BioSciences, The University of Melbourne, Melbourne, VIC, 3010, Australia. E.Ebrahimie@latrobe.edu.au.
⁶ Genomics Research Platform, School of Life Sciences, La Trobe University, Melbourne, VIC, 3086, Australia.
⁷ School of Animal and Veterinary Sciences, The University of Adelaide, Adelaide, 5371, Australia.

^# Contributed equally.

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.

Keywords: Genomic mutation; Prostate cancer; Splicing; Systems biology; Variant discovery.

MeSH terms

Alternative Splicing / genetics
Genomics
Humans
Male
Prostate / metabolism
Prostatic Neoplasms, Castration-Resistant* / genetics
Prostatic Neoplasms, Castration-Resistant* / metabolism
Prostatic Neoplasms, Castration-Resistant* / pathology
Receptors, Androgen* / metabolism

Substances

Receptors, Androgen