Investigación de las bases moleculares del cáncer colorrectal familiar tipo x: análisis de ligamiento en 22 familias y caracterización de los tumores asociados

Resumen

Familial Colorectal Cancer Type X (FCCTX) is an entity with an incomplete clinical definition and unknown molecular origin. Since FCCTX families fulfill the Amsterdam criteria, they display an autosomal dominant pattern of inheritance, but the etiology of this syndrome remains unexplained and there is little evidence of the involvement of the common colorectal cancer (CRC) carcinogenetic pathways. In the aim of better characterize this disease we performed a linkage analysis in 22 FCCTX families using 6056 genomewide SNPs. We found four linkage suggestive regions in 2p24.3, 4q13.1, 4q31.21 and 12q21.2¿q21.31, and selected the last one like the best candidate region. Subsequently we screened the genes contained in this candidate region and, regarding the literature, two genes, RASSF9 and NTS, were chosen being the most probably related with carcinogenic processes. We sequenced both genes in our families and two non described changes were found in NTS, although they were ruled out after discard a role in CRC mechanisms. In the last years, several linkage studies have been performed by other authors in the search for highly penetrant mutations implicated in the CRC etiology in FCCTX families, and several genomic regions have been associated, including 3q21-24, 7q31, 9q22.2-31.2, 11.23.2, 11q13.4, 14q24.2 and 22q12.1. But to date, none of these studies has identified novel CRC susceptibility genes. Probably FCCTX is a complex disease not depending on only one major gene but on the interaction between multiple genetic factors that can¿t be detected with the resolution of a linkage analysis. It has been suggested that factors other than high risk susceptibility genes, like low or moderate risk factors, would be implicated in this pathology. Furthermore we constructed a tissue microarray to trait to define an immunohistochemical pattern of our FCCTX cases through comparisons with other three CCR types (samples from individuals carrying mutations in the MLH1 or MSH2 genes, samples from CRC cases diagnosed before the age of 45 and samples from sporadic cases of CRC). And also we screened BRAF and KRAS mutations and CpG island methylator phenotype (CIMP) status in our FCCTX cases. Results of this study suggest that it seems to be a percentage of the FCCTX cases (30.43% of our cases) arising through the CIMP pathway, while there is a percentage arising through the chromosomal instability (CIN) pathway (at least the 26.08% of our cases). The remaining cases (43.47%) don¿t seem to fit to any of the known carcinogenic routes challenging future investigations for the characterization of this subgroup.