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Anna Abuli, Ceres Fernandez-Rozadilla, Virginia Alonso-Espinaco, Maria DoloresGiraldez, Jenifer Munoz, Xavier Bessa, Xavier Llor, Rodrigo Jover, Luis Carvajal-Carmona,Ian Tomlinson, Victor Moreno, Angel Carracedo, Antoni Castells, Montserrat Andreu,Clara Ruiz-Ponte, Sergi Castellvi-BelColorectal cancer (CRC) is the second most common cancer in Spain. Although the majorityof CRC is sporadic, inherited susceptibility is relevant in about 30-35% of cases, being dueto hereditary mutations in less than 5%. Much of the remaining genetic risk may beattributabletoalarge numberofcommon,low-penetrancegeneticvariants. ThereispreviousevidenceingeneticsusceptibilitytoCRCoftheinvolvementofgenesthatbelongtocolorectalcarcinogenesis pathways, genes involved in CRC susceptibility by studies in mice, and geneslocated on chromosomal regions (9q22 and 3q22) identified by genetic linkage analysis inCRC families. Objectives. To select genes from CRC pathways, mouse susceptibility studiesor chromosomal regions 9q22 and 3q22 with potential implications in CRC and its poly-morphisms with a putative functional effect, and to assess their implication in geneticsusceptibility toCRC by acase-control associationstudy. Patients andmethods. Case-controlgenetic association study in 2 stages in the EPICOLON cohort (stage 1, 515 cases vs.515 controls; replication stage 2, 900 cases vs. 900 controls). Results. We assessed 400polymorphisms in stage 1. Ten per cent showed significant association with CRC. In orderto validated these statistically significant associations, we replicated 42 polymorphisms inan independent cohort (stage 2), and 5 of them showed significant findings in both stages:[rs1444601, OR=0,85 (0,75-0,95, p=0,006); rs2071387, OR=0,56 (0,36-0,88, p=0,009);rs13088006, OR=0,67 (0,48-0,93, p=0,017); rs2297155, OR=0,35 (0,14-0,9, p=0,019);rs939453,OR=0,89(0,81-0,99,p=0,038)].Conclusions.Fivepolymorphismsshowedstatist-ically significant differences in both independent CRC cohorts, and they may correspondto new low-penetrance genetic components for CRC.