Background Family history is a risk factor of many diseases. Genome-wide sequencing efforts have identified naturally occurring genetic variations such as copy number variations (CNV) and single nucleotide polymorphisms (SNPs) across the human genome that could account for the risk associated with family history (1). In fact, genome-wide association studies (GWAS) have linked numerous SNPs with an increased risk of developing specific diseases, such as breast and prostate cancer (2-13). Interestingly, most risk-associated SNPs (raSNPs) map to non-coding genomic regions, which excludes their role in protein sequence/structure alterations (2-13). This has significantly complicated the understanding of how SNPs can contribute to cancer development and has hindered the development of therapeutic strategies based on SNP profiling. Genome-wide assays revealed the preferential recruitment of transcription factors to non-coding regions surrounding actively transcribed genes in breast and prostate cancer cells (14-17). In addition, changes to the genomic distribution of these transcription factors directly impacts transcriptional programs (18, 19). Hypothesis We hypothesize that raSNPs associate with cancer development by promoting transcriptional programs favorable to oncogenesis by altering transcription factor recruitment. Approach Combining multiple genomics datasets from different cancer types, we will determine the role of breast and prostate cancer raSNPs on transcription factor activity by 1) determining the cancer type- specificity of raSNPs and transcription factor recruitment, 2) defining the role of raSNPs on transcription factor recruitment and by 3) determining how raSNPs modulating transcription factor recruitment affects transcriptional programs. Relevance to the mission While breast and prostate cancer raSNPs serve important diagnostic and prognostic purposes, they lack therapeutic value. Defining the function of these raSNPs, as we currently propose, will reveal the therapeutic applicability of SNP profiling in breast and prostate cancer. Hence, our research will be of direct and rapid benefit to the clinic.

Public Health Relevance

While single nucleotide polymorphism (SNP) profiling has identified specific genetic variations as risk factors for cancer development, the mechanisms responsible for the increased risk are ill defined. This hinders the therapeutic value of SNP profiling. Therefore, by defining the mechanism driving the risk associated with SNPs in breast and prostate cancer, as we currently propose, we will identify the therapeutic benefit of SNP profiling.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA155004-05
Application #
8598078
Study Section
Cancer Genetics Study Section (CG)
Program Officer
Mietz, Judy
Project Start
2011-01-12
Project End
2015-12-31
Budget Start
2014-01-01
Budget End
2014-12-31
Support Year
5
Fiscal Year
2014
Total Cost
$201,690
Indirect Cost
$14,940
Name
University Health Network
Department
Type
DUNS #
208469486
City
Toronto
State
ON
Country
Canada
Zip Code
M5 2-M9
Bailey, Swneke D; Desai, Kinjal; Kron, Ken J et al. (2016) Noncoding somatic and inherited single-nucleotide variants converge to promote ESR1 expression in breast cancer. Nat Genet 48:1260-6
Zhou, Stanley; Treloar, Aislinn E; Lupien, Mathieu (2016) Emergence of the Noncoding Cancer Genome: A Target of Genetic and Epigenetic Alterations. Cancer Discov 6:1215-1229
Bailey, Swneke D; Virtanen, Carl; Haibe-Kains, Benjamin et al. (2015) ABC: a tool to identify SNVs causing allele-specific transcription factor binding from ChIP-Seq experiments. Bioinformatics 31:3057-9
Bailey, Swneke D; Zhang, Xiaoyang; Desai, Kinjal et al. (2015) ZNF143 provides sequence specificity to secure chromatin interactions at gene promoters. Nat Commun 2:6186
Chahar, Sanjay; Gandhi, Vishal; Yu, Shiyan et al. (2014) Chromatin profiling reveals regulatory network shifts and a protective role for hepatocyte nuclear factor 4α during colitis. Mol Cell Biol 34:3291-304
Corradin, Olivia; Saiakhova, Alina; Akhtar-Zaidi, Batool et al. (2014) Combinatorial effects of multiple enhancer variants in linkage disequilibrium dictate levels of gene expression to confer susceptibility to common traits. Genome Res 24:1-13
Ghoussaini, Maya; Edwards, Stacey L; Michailidou, Kyriaki et al. (2014) Evidence that breast cancer risk at the 2q35 locus is mediated through IGFBP5 regulation. Nat Commun 4:4999
Zhang, Xiaoyang; Bailey, Swneke D; Lupien, Mathieu (2014) Laying a solid foundation for Manhattan--'setting the functional basis for the post-GWAS era'. Trends Genet 30:140-9
Magnani, Luca; Stoeck, Alexander; Zhang, Xiaoyang et al. (2013) Genome-wide reprogramming of the chromatin landscape underlies endocrine therapy resistance in breast cancer. Proc Natl Acad Sci U S A 110:E1490-9
Cowper-Sal lari, Richard; Zhang, Xiaoyang; Wright, Jason B et al. (2012) Breast cancer risk-associated SNPs modulate the affinity of chromatin for FOXA1 and alter gene expression. Nat Genet 44:1191-8

Showing the most recent 10 out of 14 publications