Abstract P2-03-13: Multiple breast cancer risk variants are associated with differential transcript isoform expression in tumors
Authors: Caswell Jennifer L , Huntsman Scott , Hu Donglei , Ziv Elad 
Published: May 2015

Abstract
Introduction: Genome-wide association studies have identified over seventy single-nucleotide polymorphisms (SNPs) associated with breast cancer. A subset of these SNPs regulate expression of nearby genes, but the functional effects of the majority remain unknown. We hypothesized that some breast cancer risk SNPs may regulate alternative splicing of nearby genes.
Methods: We used RNA sequencing data and matched germline genotypes from The Cancer Genome Atlas for 358 estrogen receptor (ER)-positive and 109 ER-negative breast tumors. For each risk SNP, we tested the association between genotype and exon-, junction-, and transcript-specific expression of genes within 500 kilobases, adjusting for overall gene expression. We excluded associations potentially related to error in mapping to pseudogenes or bias in mapping to the reference genome.
Results: Six breast cancer risk SNPs were associated with differential isoform expression of seven nearby genes at FDR &lt; 0.05 in ER-positive tumors; five of these associations replicated (P-value &lt; 0.05) in ER-negative tumors (Table 1). At five loci, the pattern of association with alternative splicing mirrored the pattern of association with breast cancer. Of these five, two SNPs were associated with alternative splice site usage in nearby genes (STXBP4, BABAM1), one with exon skipping (DCLRE1B), and two with more complex exon usage patterns (PEX14, RAD51L1).
Associations between breast cancer risk SNPs and transcripts identified in ER-positive tumors at FDR &lt; 0.05SNP rsIDSNP LocationGeneSNP Distance from Geneβ (ER+)P-value (ER+)FDR (ER+)P-value (ER-) Component rs6504950chr17:53,056,571STXBP4In gene: intron 1 Exon 5:6 junction 1 0.591.5E-232.6E-193.1E-07 Exon 5:6 junction 2 -0.722.5E-232.6E-192.3E-10 Transcript uc010dcc -0.421.5E-112.6E-08 rs11552449*chr1:114,448,389DCLRE1BIn gene: exon 1 Transcript uc001eei -0.635.7E-131.4E-09 Transcript uc001eeg 0.268.0E-101.2E-06 Exon 1:3 junction -0.481.3E-071.3E-044.7E-03 Exon 2 0.241.2E-069.1E-041.0E-04rs8170chr19:17,389,704BABAM1In gene: exon 8 Transcript uc002nfv 0.476.1E-086.5E-055.3E-05 Transcript uc002nfu -0.275.3E-063.3E-036.3E-03rs11249433†chr1:121,280,613SRGAP2D151 kB Exon 2:3 junction -0.451.4E-077.3E-061.5E-02rs11552449*†chr1:114,448,389PHTF1146 kB Exon 1:2 junction 0.501.6E-071.5E-04 Exon 2 0.343.5E-062.3E-03 rs616488chr1:10,566,215PEX14In gene: intron 2 Exon 7 -0.391.1E-068.8E-042.9E-02 Transcript uc001arm -0.391.1E-068.1E-04 rs999737chr14:69,034,682RAD51L1In gene: intron 13 Exon 15 -0.336.2E-053.4E-02 Location is for hg19 build. β is for effect of the breast cancer risk allele. FDR is when all exon, junction, and transcript tests are considered together. P-values for ER- shown when &lt; 0.05. * SNP is associated with transcript expression of two different genes. † Pattern of association with transcript does not correspond to pattern of association with breast cancer.
Conclusion: Regulation of differential transcript expression appears to be an important functional mechanism of breast cancer risk SNPs. These associations allow us to identify likely candidate causal genes, and also specific exons and transcripts that may mediate breast cancer risk, opening a new window into the link between risk variants, gene function, and outcome.
Citation Format: Jennifer L Caswell, Scott Huntsman, Donglei Hu, Elad Ziv. Multiple breast cancer risk variants are associated with differential transcript isoform expression in tumors [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P2-03-13.