Functional synonymous variants and variants in splicing regulatory regions in breast cancer

The purpose of this project is to understand how specific types of genetic variants, which traditionally have not been extensively studied, can affect breast cancer risk and tumour characteristics through effects on the transcriptome and proteome. This includes variants in sequences that regulate messenger RNA (mRNA) splicing and synonymous variants that lead to a change between two codons for the same amino acid, thereby not directly altering the protein-coding sequence. Synonymous variants can still be functional, e.g. through effects on mRNA splicing and stability, as well as the speed of translation and protein folding. Our main aims are to 1) provide a detailed understanding of how variants in regulatory motifs control alternative splicing and intron retention, and 2) develop accurate methods for identification of functional synonymous variants. We study this in both sporadic and familial breast cancer, where our work can lead to improvements in the interpretation of clinical sequencing data. Especially in familial breast cancer we believe that the chances of finding previously overlooked variants in known high-risk genes are higher than to find new, rare risk loci. Our results will however have implications and applications in all life sciences where genetic information is interpreted.