Identificació de nous gens implicats en predisposició germinal al càncer colorectal

Colorectal cancer (CRC) is the most frequent neoplasia in both sexes in Spain. It may be sporadic (65%) as well as familial (35%). In the majority of cases the cause of familial CCR remains unknown. However, a 5% is due to high penetrance germline mutations which are characterised as hereditary Mendelian syndromes, such as Lynch syndrome, familial adenomatous polyposis and the poliposis associated with MUTHY and POLE/POLD1. Nowadays using next generation sequencing techniques, new genes associated with germline predisposition to CRC such as NTHL1 or FAN1, have been identified. The main objective of this study is the identification of new genes related to germline predisposition to CRC. Families with a strong aggregation for the disease and the selection of variants shared by different individuals in each family were studied. Germline DNA samples used for the whole exome sequencing by Illumina method were obtained from peripheral blood of patients with CCR belonging to 16 unrelated families. A bioinformatic analysis was performed for reducing the number of encountered variants and selecting those with a high probability to cause a change in the gene function. The candidate genes in each family have been selected considering several functional parameters. Finally, a validation of the variants was carried out (Integrative Genomics Viewer and Sanger sequencing). Twenty-seven variants were selected and 24 of them validated by Sanger sequencing. Segregation studies from additional family members who presented advanced adenomas or other neoplasms as well as somatic studies with tumour DNA to determine the loss of heterozygosity (LOH), were also performed. The most remarkable results were found in 9 genes: LOXL4, GEMIN5, UTP11L, MUC6, HIST1H4, GSK3A, SPLIT2, CIDEB and MCM3. According their function or previous relation with cancer LOXL4, HIST1H4, GSK3A and MCM3 have been considered the most relevant. We identified new possible germinal predisposition variants associated to CCR in genes that play a role in cell cycle, apoptosis and DNA repair., Furthermore, LOXL4, which is associated with head and neck cancer, is also related to CCR. Similarly, MCM and SLIT gene families could participate in genetic CCR predispositio