Genetic Epidemiology

Identification of genetic polymorphisms as markers of cancer susceptibility.

We have completed several studies on candidate genes in known pathways of colorectal carcinogenesis: DNA repair, metabolism, cell cycle and cellular inflammation This was the goal of a project funded by the FIS (Spanish Government) during the period 2004-06. We examined 150 polymorphisms in 50 candidate genes and published new candidates identified. This study was done in collaboration with Drs. Federico Canzian, Stefano Landi and Federica Gemignani, IARC researchers during that time. As a continuation of this study we have established a co-operation with Dr. Gruber at the University of Michigan and we are conducting a whole genome association study to identify markers of susceptibility not necessarily in genes. We are also working closely with Malcolm Dunlop group at the University of Edinburgh for the validation of markers found in their studies within the COGENT group.

Risk associated with the consumption of drugs: statins, NSAIDs.

It is known that the CRC risk decreases with the regular consumption of aspirin, other NSAIDs and statins. We are working in co-operation with the group of Dr. Stephen Lipkin (University of South California Irvine) and Dr. Stephen Gruber (University of Michigan) in the identification of polymorphisms in genes of lipid metabolism that can participate in the mechanism of action of statins. We found an interesting polymorphism in the gene HMGCR and have submitted a patent for the possible use to select patients who would most likely benefit from the protective effect of statins. We have also identified genes modifying the protective effect of NSAID-related pathways of inflammation and want to extend this search to a wider set of candidate genes.

Design of a new case-control study of colorectal cancer in a large scale (2000 cases and 2000 controls)

The sample size of the study conducted during 1996-98, about 400 cases are allowed to generate and verify other hypotheses proposed by other researchers, but is insufficient to assess genetic and environmental interactions. We have identified the need to expand the bank of tumors and the basis of previous studies. In 2007 we initiated a new multicenter epidemiological study with the aim of recruiting 2000 cases and 2000 controls, with collection of epidemiological information and biological samples quality. The initial funding was a project of the European FP6 STREP in co-operation with the group of Dr. Manolis Kogevinas and Cristina Villanueva's from CREAL and Dr. Carlo LaVeccia from Milan. Since 2008 the study was extended to 6 Spanish centers in the context of the action cross CIBER Epidemiology and Public Health. We are participating actively ICO-HUB in recruiting cases and in co-operation with L'Hospitalet ambulatory for the inclusion of population controls. In late 2008 have included approximately 300 cases and 300 controls. This study will provide a platform for generating new hypotheses and validate others that we are generating. One of the specific objectives is to assess whether exposure to chlorination byproducts in water is a risk factor for colorectal cancer and identify polymorphisms that alter the metabolic risk.

Develop a predictor of individual risk based on the combination of multiple genetic polymorphisms shown to be associated with the disease.

Several global genome association studies are providing markers with potential predictive value of susceptibility. The risk for each marker is very low, with an increase no more than 20%, but the combination of markers in a person could be a much more significant increase in risk. We have succeeded in financing the FIS Spanish population to assess whether the combination of multiple genetic polymorphisms are predictive enough to be used in selection strategies of people who would benefit from more intensive screening.