IMPPC Fundación Institut de Medicina Predictiva i Personalitzada del Càncer

Dr Perucho studies tumours from the intestinal tract (i.e. colon, and stomach) that sometimes develop when the cell machinery preserving the integrity of the genome, rather like computer spelling programs that detect errors and correct them, is not working properly. When these corrector genes (mutators) are inactivated, the mutations that occur in all normal cells accumulate in large numbers because they are not repaired. This originates a remarkable genomic instability and cancer eventually develops when mutations occur in some cancer genes, such as the oncogenes and tumour suppressor genes. Recently, it has become clear that some of the mutator genes are not inactivated by mutations (mutator mutations) but by epigenetic silencing. This results as a consequence of the disintegration of the epigenetic code, an unexplored process that is strongly associated to aging. These studies have clinical applications. For instance, many hereditary colon tumours originate by mutations in mutator genes that are transmitted from generation to generation. Molecular diagnosis of the deficient mutator genes determines which members of these families will be affected in the future. Identification of tumours with this kind of genomic instability is also useful to detect familial cancer patients and to predict survival.

-Ionov, Y., Peinado, M.A., Malkhosyan, S., Shibata, D. and Perucho, M. Ubiquitous somatic mutations in simple repeated sequences reveal a new mechanism for colonic carcinogenesis. Nature 363:558-561, 1993.
-Ionov, Y., Yamamoto, H. Krajewski, S. Reed, J. and Perucho M. Mutational inactivation of the pro-apoptotic gene BAX confers selective advantage during tumor clonal evolution. Proc. Natl. Acad. Sci. USA 97:10872-10877, 2000.
-Yamashita, K., Dai, T., Dai, Y., Yamamoto, F., and Perucho, M. Genetics supersedes epigenetics in colon cancer phenotype. Cancer Cell 4: 121-131, 2003.
- Suzuki K, Suzuki I, Leodolter A, Alonso S, Horiuchi S, Yamashita K, Perucho M. Global DNA demethylation in gastrointestinal cancer is age dependent and precedes genomic damage. Cancer Cell. 9:199-207. 2006.