Evaluation of non-protein coding breast cancer risk regions discovered through genome wide association studies

• Applicant: Dr. Michelle Rath
• Subject Area: Gynaecology and Obstetrics
• Term: from 2011 to 2013
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 210339680

A primary goal of genetic association studies is to elucidate genes and biological mechanisms involved in disease. Genome-wide association studies have identified many common genetic variants that are significantly associated with complex diseases such as cancer. Most of the variants are situated in non-protein coding genomic regions, which presents one of the next major challenges in human genetics; to understand the functional consequences of inheriting these loci. The primary hypotheses are that many of these risk regions contain as yet unannotated transcripts and/or are regulatory elements. Studying the biology and function of these poorly understood regions may offer new insights into the prevention and/or treatment of breast cancer. The overall objective of this project would be to systematically evaluate the non-protein coding regions of the genome and their role in breast tumorigenesis using an integrative approach. The first aim will be the evaluation of breast risk regions for signatures of regulatory elements. We plan to perform chromatin immunoprecipiation followed by high throughput sequencing (ChIP-seq) to annotate regulatory elements. A set of epigenetic marks will be tested on breast cell lines enabling the characterization of these regions as promoters and/or enhancers. The second aim is the functional characterization of breast cancer risk regions, where we will employ techniques to functionally identify candidate genes influenced by breast cancer risk loci. We will perform HI-C and SureSelect to reveal loci that are physically interacting with each of the risk regions. Furthermore we plan to evaluate the association between the risk alleles and transcript abundance in the candidate genes located in the surrounding of each risk locus. Successful completion of the aims will lead to an increasingly understanding of biological mechanisms underlying genetic associations with breast cancer risk.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Dr. Matthew Freedman