Splice-disrupt Genomic Variants in Prostate Cancer

Overview

Journal Mol Biol Rep

Specialty Molecular Biology

Date 2022 Mar 14

PMID 35286517

Authors

Ibrahim O Alanazi

Salman F Alamery

Esmaeil Ebrahimie

Manijeh Mohammadi-Dehcheshmeh

Affiliations

Soon will be listed here.

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.

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References

Pajares M, Ezponda T, Catena R, Calvo A, Pio R, Montuenga L . Alternative splicing: an emerging topic in molecular and clinical oncology. Lancet Oncol. 2007; 8(4):349-57. DOI: 10.1016/S1470-2045(07)70104-3. View

Baharlou Houreh M, Ghorbani Kalkhajeh P, Niazi A, Ebrahimi F, Ebrahimie E . SpliceDetector: a software for detection of alternative splicing events in human and model organisms directly from transcript IDs. Sci Rep. 2018; 8(1):5063. PMC: 5864913. DOI: 10.1038/s41598-018-23245-1. View

Stamm S, Ben-Ari S, Rafalska I, Tang Y, Zhang Z, Toiber D . Function of alternative splicing. Gene. 2005; 344:1-20. DOI: 10.1016/j.gene.2004.10.022. View

Pan Q, Shai O, Lee L, Frey B, Blencowe B . Deep surveying of alternative splicing complexity in the human transcriptome by high-throughput sequencing. Nat Genet. 2008; 40(12):1413-5. DOI: 10.1038/ng.259. View

Wang E, Sandberg R, Luo S, Khrebtukova I, Zhang L, Mayr C . Alternative isoform regulation in human tissue transcriptomes. Nature. 2008; 456(7221):470-6. PMC: 2593745. DOI: 10.1038/nature07509. View

Oltean S, Bates D . Hallmarks of alternative splicing in cancer. Oncogene. 2013; 33(46):5311-8. DOI: 10.1038/onc.2013.533. View

Ebrahimie E, Rahimirad S, Tahsili M, Mohammadi-Dehcheshmeh M . Alternative RNA splicing in stem cells and cancer stem cells: Importance of transcript-based expression analysis. World J Stem Cells. 2021; 13(10):1394-1416. PMC: 8567453. DOI: 10.4252/wjsc.v13.i10.1394. View

Anna A, Monika G . Splicing mutations in human genetic disorders: examples, detection, and confirmation. J Appl Genet. 2018; 59(3):253-268. PMC: 6060985. DOI: 10.1007/s13353-018-0444-7. View

Wang L, Duke L, Zhang P, Arlinghaus R, Fraser Symmans W, Sahin A . Alternative splicing disrupts a nuclear localization signal in spleen tyrosine kinase that is required for invasion suppression in breast cancer. Cancer Res. 2003; 63(15):4724-30. View

10.

Lastella P, Resta N, Miccolis I, Quagliarella A, Guanti G, Stella A . Site directed mutagenesis of hMLH1 exonic splicing enhancers does not correlate with splicing disruption. J Med Genet. 2004; 41(6):e72. PMC: 1735798. DOI: 10.1136/jmg.2003.016659. View

11.

Agiannitopoulos K, Papadopoulou E, Tsaousis G, Pepe G, Kampouri S, Kocdor M . Characterization of the c.793-1G > A splicing variant in CHEK2 gene as pathogenic: a case report. BMC Med Genet. 2019; 20(1):131. PMC: 6660672. DOI: 10.1186/s12881-019-0862-3. View

12.

Gorlov I, Gorlova O, Frazier M, Amos C . Missense mutations in hMLH1 and hMSH2 are associated with exonic splicing enhancers. Am J Hum Genet. 2003; 73(5):1157-61. PMC: 1180494. DOI: 10.1086/378819. View

13.

Hecker M, Ruge A, Putscher E, Boxberger N, Rommer P, Fitzner B . Aberrant expression of alternative splicing variants in multiple sclerosis - A systematic review. Autoimmun Rev. 2019; 18(7):721-732. DOI: 10.1016/j.autrev.2019.05.010. View

14.

Rius R, Riley L, Guo Y, Menezes M, Compton A, Van Bergen N . Cryptic intronic NBAS variant reveals the genetic basis of recurrent liver failure in a child. Mol Genet Metab. 2018; 126(1):77-82. DOI: 10.1016/j.ymgme.2018.12.002. View

15.

Raud L, Ka C, Gourlaouen I, Callebaut I, Ferec C, Le Gac G . Functional analysis of novel RHD variants: splicing disruption is likely to be a common mechanism of variant D phenotype. Transfusion. 2019; 59(4):1367-1375. DOI: 10.1111/trf.15210. View

16.

Tavian D, Maggi L, Mora M, Morandi L, Bragato C, Missaglia S . A novel mutation causing total loss of RNA and protein expression in two NLSDM siblings with early onset but slowly progressive severe myopathy. Genes Dis. 2021; 8(1):73-78. PMC: 7859421. DOI: 10.1016/j.gendis.2019.07.006. View

17.

Alanazi I, Al Shehri Z, Ebrahimie E, Giahi H, Mohammadi-Dehcheshmeh M . Non-coding and coding genomic variants distinguish prostate cancer, castration-resistant prostate cancer, familial prostate cancer, and metastatic castration-resistant prostate cancer from each other. Mol Carcinog. 2019; 58(6):862-874. DOI: 10.1002/mc.22975. View

18.

Sherry S, Ward M, Kholodov M, Baker J, Phan L, Smigielski E . dbSNP: the NCBI database of genetic variation. Nucleic Acids Res. 2000; 29(1):308-11. PMC: 29783. DOI: 10.1093/nar/29.1.308. View

19.

Liu X, Jian X, Boerwinkle E . dbNSFP v2.0: a database of human non-synonymous SNVs and their functional predictions and annotations. Hum Mutat. 2013; 34(9):E2393-402. PMC: 4109890. DOI: 10.1002/humu.22376. View

20.

Liu X, Jian X, Boerwinkle E . dbNSFP: a lightweight database of human nonsynonymous SNPs and their functional predictions. Hum Mutat. 2011; 32(8):894-9. PMC: 3145015. DOI: 10.1002/humu.21517. View