Association between single nucleotide polymorphisms of X-ray repair cross-complementing protein 4 gene and development of pancreatic cancer

Ding, Yanbing; Ln, Li

doi:10.4238/2015.august.14.25

Cited by 12 publications

(7 citation statements)

References 21 publications

(25 reference statements)

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“…The splicing impact of XRCC4 rs1805377 has been noted previously (Nalla and Rogan, 2005). This SNP has been implicated with an increased risk of gastric cancer (Chiu et al, 2008), pancreatic cancer (Ding and Li, 2015) and glioma (Zhao et al, 2013b). Similarly, the potential impact of rs1893592 in UBASH3A has been recognized (Kim et al, 2015) and is associated with arthritis (Liu et al, 2017) and type 1 diabetes (Ge and Concannon, 2018).…”

Section: Discussionmentioning

confidence: 88%

Expression Changes Confirm Genomic Variants Predicted to Result in Allele-Specific, Alternative mRNA Splicing

Mucaki

Shirley

2020

Front. Genet.

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Splice isoform structure and abundance can be affected by either noncoding or masquerading coding variants that alter the structure or abundance of transcripts. When these variants are common in the population, these nonconstitutive transcripts are sufficiently frequent so as to resemble naturally occurring, alternative mRNA splicing. Prediction of the effects of such variants has been shown to be accurate using information theory-based methods. Single nucleotide polymorphisms (SNPs) predicted to significantly alter natural and/or cryptic splice site strength were shown to affect gene expression. Splicing changes for known SNP genotypes were confirmed in HapMap lymphoblastoid cell lines with gene expression microarrays and custom designed q-RT-PCR or TaqMan assays. The majority of these SNPs (15 of 22) as well as an independent set of 24 variants were then subjected to RNAseq analysis using the ValidSpliceMut web beacon (http:// validsplicemut.cytognomix.com), which is based on data from the Cancer Genome Atlas and International Cancer Genome Consortium. SNPs from different genes analyzed with gene expression microarray and q-RT-PCR exhibited significant changes in affected splice site use. Thirteen SNPs directly affected exon inclusion and 10 altered cryptic site use. Homozygous SNP genotypes resulting in stronger splice sites exhibited higher levels of processed mRNA than alleles associated with weaker sites. Four SNPs exhibited variable expression among individuals with the same genotypes, masking statistically significant expression differences between alleles. Genome-wide information theory and expression analyses (RNAseq) in tumor exomes and genomes confirmed splicing effects for 7 of the HapMap SNP and 14 SNPs identified from tumor genomes. q-RT-PCR resolved rare splice isoforms with read abundance too low for statistical significance in ValidSpliceMut. Nevertheless, the web-beacon provides evidence of unanticipated splicing outcomes, for example, intron retention due to compromised recognition of constitutive splice sites. Thus, ValidSpliceMut and q-RT-PCR represent complementary resources for identification of allele-specific, alternative splicing.

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Section: Discussionmentioning

confidence: 88%

Expression Changes Confirm Genomic Variants Predicted to Result in Allele-Specific, Alternative mRNA Splicing

Mucaki

Shirley

2020

Front. Genet.

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“…The pathogenesis of pancreatic cancer involves many environmental and genetic factors, and it is reported that environmental chemicals exposure, heavy metals, and obesity contribute to the susceptibility of pancreatic cancer (Antwi et al, 2015;Kim and Ahuja, 2015;Zheng et al, 2015). Many studies have shown that genetic factors, such as E-cadherin gene, X-ray repair cross-complementing protein 4 gene, cyclooxygenase-2 gene, and DNA repair genes (Ding and Li, 2015;Shen et al, 2015;Wang et al, 2015;Zhao et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Association between ERCC1 and ERCC2 gene polymorphisms and susceptibility to pancreatic cancer

He¹,

Zheng²,

Tan³

et al. 2016

Genet. Mol. Res.

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ABSTRACT. We conducted a study to investigate the association between ERCC1 (rs3212986) and ERCC2 (rs13181) gene polymorphisms and the risk of pancreatic cancer in a Chinese population. A total of 217 pancreatic cancer patients and 244 control subjects were recruited from the Nuclear Industry 215 Hospital of Shaanxi Province between February 2013 and December 2014. Genomic DNA was extracted from peripheral blood samples using a TIANamp Blood DNA Kit (Tiangen, Beijing, China) according to the manufacturer's instructions. The ERCC1 rs3212986 and ERCC2 rs13181 polymorphisms were genotyped by polymerase chain reaction-restriction fragment length of polymorphism. Unconditional logistic regression analyses showed that subjects with the CC genotype of ERCC1 rs3212986 were susceptible to the development of pancreatic cancer when compared with subjects with the AA genotype (OR = 2.57, 95%CI = 1.34-5.02). The ERCC1 rs3212986 gene polymorphism was associated with increased risk of pancreatic cancer in the dominant (OR = 1.54, 95%CI = 1.05-2.28) and recessive (OR = 2.22, 95%CI = 1.20-4.19) models. However, no significant difference was found between the ERCC2 rs13181 polymorphism and the risk of pancreatic cancer in the codominant, dominant, and recessive models. We suggest that the ERCC1 rs3212986 polymorphism increases susceptibility to pancreatic cancer in the codominant, dominant, and recessive models, although further studies are needed to confirm our findings.

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“…The splicing impact of XRCC4 rs1805377 has been noted previously (Nalla and Rogan 2005). This SNP has been implicated with an increased risk of gastric cancer (Chiu et al 2008), pancreatic cancer (Ding and Li, 2015) and glioma (Zhao et al 2013 [b]). Similarly, the potential impact of rs1893592 in UBASH3A has been recognized (Kim et al 2015) and is associated with arthritis (Liu et al 2017) and type 1 diabetes (Ge and Concannon, 2018).…”

Section: Discussionmentioning

confidence: 99%

Expression changes confirm genomic variants predicted to result in allele-specific, alternative mRNA splicing

Mucaki

2019

Preprint

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Splice isoform structure and abundance can be affected by either non-coding or masquerading coding variants that alter the structure or abundance of transcripts. When these variants are common in the population, these non-constitutive transcripts are sufficiently frequent so as to resemble naturally occurring, alternative mRNA splicing. Prediction of the effects of such variants has been shown to be accurate using information theory-based methods. Single nucleotide polymorphisms (SNPs) predicted to significantly alter natural and/or cryptic splice site strength were shown to affect gene expression. Splicing changes for known SNP genotypes were confirmed in HapMap lymphoblastoid cell lines with gene expression microarrays and custom designed q-RT-PCR or TaqMan assays. The majority of these SNPs (15 of 22) as well as an independent set of 24 variants were then subjected to RNAseq analysis using the ValidSpliceMut web beacon (http://validsplicemut.cytognomix.com), which is based on data from the Cancer Genome Atlas and International Cancer Genome Consortium. SNPs from different genes analyzed with gene expression microarray and q-RT-PCR exhibited significant changes in affected splice site use. Thirteen SNPs directly affected exon inclusion and 10 altered cryptic site use. Homozygous SNP genotypes resulting in stronger splice sites exhibited higher levels of processed mRNA than alleles associated with weaker sites. Four SNPs exhibited variable expression among individuals with the same genotypes, masking statistically significant expression differences between alleles. Genome-wide information theory and expression analyses (RNAseq) in tumour exomes and genomes confirmed splicing effects for 7 of the HapMap SNP and 14 SNPs identified from tumour genomes. q-RT-PCR resolved rare splice isoforms with read abundance too low for statistical significance in ValidSpliceMut.Nevertheless, the web-beacon provides evidence of unanticipated splicing outcomes, for example, intron retention due to compromised recognition of constitutive splice sites. Thus, ValidSpliceMut and q-RT-PCR represent complementary resources for identification of allelespecific, alternative splicing. KeywordsAllele-specific gene expression, mRNA splicing, RT-PCR, gene expression microarray, RNAseq, single nucleotide polymorphism, mutation, cryptic splicing; intron retention; alternative splicing, information theory Accurate and comprehensive methods are needed for predicting impact of non-coding mutations, in particular, mRNA splicing defects, which are prevalent in genetic disease (Krawczak et al. 1992;Teraoka et al. 1999;Ars et al. 2003;Spielmann and Mundlos, 2016;Gloss and Dinger, 2018). This class of mutations may account for as much as 62% of point mutations (López-Bigas et al. 2005). Large transcriptome studies have suggested that a large fraction of genome-wide association studies (GWAS) signals for disease and complex traits are due to SNPs affecting mRNA splicing (Park et al. 2018). ValidSpliceMut (Shirley et al. 2019) presents evidence of altere...

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Association between single nucleotide polymorphisms of X-ray repair cross-complementing protein 4 gene and development of pancreatic cancer

Cited by 12 publications

References 21 publications

Expression Changes Confirm Genomic Variants Predicted to Result in Allele-Specific, Alternative mRNA Splicing

Expression Changes Confirm Genomic Variants Predicted to Result in Allele-Specific, Alternative mRNA Splicing

Association between ERCC1 and ERCC2 gene polymorphisms and susceptibility to pancreatic cancer

Expression changes confirm genomic variants predicted to result in allele-specific, alternative mRNA splicing

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