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Genetic Control of Gene Expression in Cancer Risk

Periodic Report Summary 2 - GENCAR (Genetic Control of Gene Expression in Cancer Risk)

better estimation of individual risk, will aid in the stratification of the population at risk, and contribute to targeted screening, prevention and treatment management.
Approximately 50% of breast cancer cases are still unexplained by current susceptibility knowledge. Additionally, identified variants are surrogate markers of the actual causal variants, which are impossible to detect using the current approach to risk studies.
GenCaR, Genetic Control of Gene Expression in Cancer Risk, was a project designed with two main objectives: (1) Identify new regulatory loci implicated in cancer susceptibility through innovative studies using allelic expression as a quantitative trait; (2) understand the role of cis-regulatory variants in tumour biology and their implication in treatment response.
In our studies we have used both microarray and RNA-seq approaches to measure allelic expression in normal breast tissue of healthy women and patients, as well as in tumours. Through analysis of differential allelic expression data in normal breast we found that over 70% of our genes are regulated by these genetic variants, and we developed analysis methods to map cis-regulatory variants. Overlapping this knowledge with loci known to be associated with risk, we have been able to identify the potential causal variants for risk to breast cancer. We are currently finalizing the first case-control study using allelic expression as a quantitative trait, which will help us identify new risk loci.
Furthermore, our analyses of tumour data have allowed us to unravel the role of normal genetic variants in the expression of somatic mutations, namely in the genes TP53 and PIK3CA genes. We have dissected common haplotypes correlated with different levels of gene expression of the genes targeted by these mutations, and have found that they correlate with different clinical characteristics of tumours. The potential impact of these results is mainly focused on the improvement of patient treatment management in the clinic.
From an impact point of view, this project has enabled the establishment of a new research laboratory at University of Algarve, which is today composed of seven researchers, conducting computational biology work. During its duration the PI mentoring was as follows: supervision of two post-doctoral fellows (one who earned an Individual Fellowship from FCT in 2015), supervision of two PhD students (one on-going, and one as co-supervisor, who graduated in 2017), supervision of six MSc students as supervisor and another eight as co-supervisor, supervision of five undergraduate students, plus another five for the short-term Medical projects. During this period as well the GenCaR contributed to the attendance of various scientific conferences where our results have been disseminated, as well as support publication fees.
Most importantly, it produced the data to support continuing external funding of our group, which includes one grant, in this grant period, from the main national funding body in Portugal, the Foundation for Science and Technology (FCT) (~139k€), one post-doctoral fellowship for thee years (~58k€), one PhD fellowship for four years (~40k€), one 1st Prize of Maratona da Saúde (25k€), and several smaller conference awards. The funding of this project has also been crucial for the PI to get Tenure, and to be a strong candidate for an Associate Professor position in forthcoming opportunities. GenCaR had a significant role in permitting outreach activities of the group, which ranged from seminars to activities with the general public and schools, and personal development courses for the PI, namely in team management and grant writing.
Additional information on our activities and research, including publications for the grant period, can be found in our group website