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Multiple breast cancer risk variants are associated with differential transcript isoform expression in tumors.

Caswell JL, Camarda R, Zhou AY, Huntsman S, Hu D, Brenner SE, Zaitlen N, Goga A, Ziv E - Hum. Mol. Genet. (2015)

Bottom Line: A subset of these SNPs are associated with quantitative expression of nearby genes, but the functional effects of the majority remain unknown.Six SNPs were associated with differential transcript expression of seven nearby genes at FDR < 0.05 (BABAM1, DCLRE1B/PHTF1, PEX14, RAD51L1, SRGAP2D and STXBP4).Lastly, at two loci, we identified the likely causal SNP for the alternative splicing event, and at one, functionally validated the effect of that SNP on alternative splicing using a minigene reporter assay.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Institute for Human Genetics, Helen Diller Family Comprehensive Cancer Center and, Department of Medicine, Division of Medical Oncology, Stanford University, Stanford, CA, USA and caswell@stanford.edu.

No MeSH data available.


Related in: MedlinePlus

Alternative splice site usage in STXBP4 exon 6 based on rs6504950 genotype. (A) With the rs6504950 risk allele, virtually all STXBP4 exon 5–6 junction reads map to one junction, whereas with the non-risk allele, virtually all map to the other. (B) LocusZoom plot (23) displaying −log10P-values for the association of each SNP within the window with STXBP4 exon 5–6 junction 1 by position. (C) The locus of rs11658717, the presumed causal SNP. The two alternative 3′ splice sites are highlighted in red. The minor allele of rs11658717 (G) is in high LD with the risk allele of rs6504950 (A). Screenshot from http://genome.ucsc.edu (24).
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DDV432F2: Alternative splice site usage in STXBP4 exon 6 based on rs6504950 genotype. (A) With the rs6504950 risk allele, virtually all STXBP4 exon 5–6 junction reads map to one junction, whereas with the non-risk allele, virtually all map to the other. (B) LocusZoom plot (23) displaying −log10P-values for the association of each SNP within the window with STXBP4 exon 5–6 junction 1 by position. (C) The locus of rs11658717, the presumed causal SNP. The two alternative 3′ splice sites are highlighted in red. The minor allele of rs11658717 (G) is in high LD with the risk allele of rs6504950 (A). Screenshot from http://genome.ucsc.edu (24).

Mentions: After excluding the six problematic associations, six raSNPs were associated with exon, junction or whole-transcript expression of seven genes (Table 1). Four of the six loci replicated at P < 0.05 in the smaller set of 109 ER-negative tumors from TCGA (Table 1), three at FDR < 0.05. We identified one SNP associated with exon skipping (rs11552449-DCLRE1B), two SNPs associated with alternative splice site usage (rs6504950-STXBP4 and rs8170-BABAM1) (Figs 2 and 3), three SNPs associated with more complex exon usage patterns (rs11552449-PHTF1, rs616488-PEX14 and rs999737-RAD51L1) and one SNP associated only with an exon–exon junction, which could represent an unannotated alternative splice site or other unannotated pattern of exon usage (rs11249433-SRGAP2D).Table 1.


Multiple breast cancer risk variants are associated with differential transcript isoform expression in tumors.

Caswell JL, Camarda R, Zhou AY, Huntsman S, Hu D, Brenner SE, Zaitlen N, Goga A, Ziv E - Hum. Mol. Genet. (2015)

Alternative splice site usage in STXBP4 exon 6 based on rs6504950 genotype. (A) With the rs6504950 risk allele, virtually all STXBP4 exon 5–6 junction reads map to one junction, whereas with the non-risk allele, virtually all map to the other. (B) LocusZoom plot (23) displaying −log10P-values for the association of each SNP within the window with STXBP4 exon 5–6 junction 1 by position. (C) The locus of rs11658717, the presumed causal SNP. The two alternative 3′ splice sites are highlighted in red. The minor allele of rs11658717 (G) is in high LD with the risk allele of rs6504950 (A). Screenshot from http://genome.ucsc.edu (24).
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4664170&req=5

DDV432F2: Alternative splice site usage in STXBP4 exon 6 based on rs6504950 genotype. (A) With the rs6504950 risk allele, virtually all STXBP4 exon 5–6 junction reads map to one junction, whereas with the non-risk allele, virtually all map to the other. (B) LocusZoom plot (23) displaying −log10P-values for the association of each SNP within the window with STXBP4 exon 5–6 junction 1 by position. (C) The locus of rs11658717, the presumed causal SNP. The two alternative 3′ splice sites are highlighted in red. The minor allele of rs11658717 (G) is in high LD with the risk allele of rs6504950 (A). Screenshot from http://genome.ucsc.edu (24).
Mentions: After excluding the six problematic associations, six raSNPs were associated with exon, junction or whole-transcript expression of seven genes (Table 1). Four of the six loci replicated at P < 0.05 in the smaller set of 109 ER-negative tumors from TCGA (Table 1), three at FDR < 0.05. We identified one SNP associated with exon skipping (rs11552449-DCLRE1B), two SNPs associated with alternative splice site usage (rs6504950-STXBP4 and rs8170-BABAM1) (Figs 2 and 3), three SNPs associated with more complex exon usage patterns (rs11552449-PHTF1, rs616488-PEX14 and rs999737-RAD51L1) and one SNP associated only with an exon–exon junction, which could represent an unannotated alternative splice site or other unannotated pattern of exon usage (rs11249433-SRGAP2D).Table 1.

Bottom Line: A subset of these SNPs are associated with quantitative expression of nearby genes, but the functional effects of the majority remain unknown.Six SNPs were associated with differential transcript expression of seven nearby genes at FDR < 0.05 (BABAM1, DCLRE1B/PHTF1, PEX14, RAD51L1, SRGAP2D and STXBP4).Lastly, at two loci, we identified the likely causal SNP for the alternative splicing event, and at one, functionally validated the effect of that SNP on alternative splicing using a minigene reporter assay.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Institute for Human Genetics, Helen Diller Family Comprehensive Cancer Center and, Department of Medicine, Division of Medical Oncology, Stanford University, Stanford, CA, USA and caswell@stanford.edu.

No MeSH data available.


Related in: MedlinePlus