IP: Dr. Ángel Carracedo Álvarez

Resumen del proyecto: Traditionally, it has been postulated that the causes that explain the genetic component of colorrectal cancer (CRC), particularly sporadic and familial forms, are based on a polygenic inheritance where the combination of common variants of low / moderate penetrance define the susceptibility to neoplastic transformation, while environmental factors modulate this susceptibility. GWAS studies have identified 20 genetic variants that account for approximately 8% of the risk associated with CRC. The success of GWAS in CRC, is a result in part due to the creation of national and international consortia, because only with a large number of well-characterized cases and controls can be found alleles that confer relatively low risks. However, despite the huge efforts invested, GWAS are not expected to be able to reach more than 12% at most to the common variability contributing to the risk. Our hypothesis is based on that much of the genetic variability that explains the disease is concentrated in rare germinal variants exhibiting moderate effects and which can confer significant effect on individual risk. Specifically, this rare variation is largely dependent to each population, and has been insufficiently studied. It is therefore intended, to create an array that includes functional variation in exomes, taking as a base exome sequencing data from Spanish population. The aforementioned array will be validated in 1000 controls, to then be applied as a proof of concept to the specific search for genes involved in CRC, as well as biomarkers of response to chemotherapy (FOLFOX and FOLFIRI). This array will be subsequently applied to analyze 2000 cases and 2000 controls, to be combined with an analysis of interactions of variants in candidate routes. Findings will be subsequently validated and replicated into international consortia (concretely in COGENT).

Entidad financiadora: Ministerio de Economía y Competitividad