Periodic Report Summary 1 - GENCAR (Genetic Control of Gene Expression in Cancer Risk) Human beings share 99.9% of their DNA sequence. The secret behind our species variability is in the 0.1% of DNA sequence which is made of variants. Each person is born with a unique set of these variants, inherited from mother and father. They can have powerful effects depending on where in the genome they occur, and are designated cis-regulatory. And just like they can occur in loci that can make us fatter, slimmer, taller or shorter, they can also occur in places in which they affect genes important for cancer. Consequently, each person’s unique set of variants will determine their individual risk to develop cancer, as well as their response to therapy. The identification of these risk variants is paramount to a better estimation of individual risk, will aid in the stratification of the population at risk, and contribute to targeted screening, prevention and treatment management.My laboratory uses the latest genomic sequencing techniques to develop a new method capable of identifying new risk loci, to help identify the approximately 60-70% of cases which are still unexplained by current susceptibility knowledge. We are functionally characterising three risk loci identified in GWAS for breast cancer, for which we have strong evidence of a cis-regulation mechanism. Our previous data on genome-wide differential allelic expression (DAE) provided the initial evidence and we are now performing the functional assays for validation and full characterisation. These results strongly support our hypothesis that unidentified risk loci will predominantly be cis-regulatory. Next we will perform the first genome-wide case-control study in breast cancer using DAE as a quantitative trait. DAE being the most robust method to read-out cis-regulatory loci effects, will allow us to focus our search strictly on variants with regulatory potential.We are also investigating the interaction between cis-regulatory variants and mutations, both germline and somatic. We have evidence that common BRCA2 and TP53 haplotypes correlate with different levels of gene expression. Now we are interested in: understanding how these modulate the variable penetrance of BRCA2 mutations that we see in germline mutation carriers; and the differences in clinical characteristics of tumours harbouring somatic TP53 mutations. We are applying state-of-the-art genomic techniques such as RNA-seq, Methyl-seq, Chromosome Conformation Capture and others to perform functional analysis of these candidate genes, in normal breast and tumours.We have thus far found significant links between the balance of expression of the mutated and wild-type alleles with susceptibility to cancer (BRCA2) and clinical characteristics of tumours (TP53). We are expanding our TP53 studies to ovarian cancer.My studies will impact both (1) on breast cancer incidence (currently the most common cancer in women in the Western World) and (2) on our understanding of tumour biology (in breast and ovarian tissues). The award of the Marie Curie - Career Integration Grant was essential for my establishment as an independent group leader, and is fundamental in supporting my appointment as Assistant Professor at University of Algarve and my bid for tenure due in 2016. Other report summaries Periodic Report Summary 2 - GENCAR (Genetic Control of Gene Expression in Cancer Risk)
