Clinical relevance of 8q23, 15q13 and 18q21 SNP genotyping to evaluate colorectal cancer risk

Stéphanie Baert-Desurmont, Françoise Charbonnier, Estelle Houivet, Lorena Ippolito, Jacques Mauillon, Marion Bougeard, Caroline Abadie, David Malka, Jacqueline Duffour, Françoise Desseigne, Chrystelle Colas, Pascal Pujol, Sophie Lejeune, Catherine Dugast, Bruno Buecher, Laurence Faivre, Dominique Leroux, Paul Gesta, Isabelle Coupier, Rosine Guimbaud, Pascaline Berthet, Sylvie Manouvrier, Estelle Cauchin, Fabienne Prieur, Pierre Laurent-Puig, Marine Lebrun, Philippe Jonveaux, Jean Chiesa, Olivier Caron, Marie-Emmanuelle Morin-Meschin, Florence Polycarpe-Osaer, Sophie Giraud, Aziz Zaanan, Delphine Bonnet, Ludovic Mansuy, Valérie Bonadona, Salima El Chehadeh, François Duhoux, Marion Gauthier-Villars, Jean-Christophe Saurin, Marie- Agnès Collonge-Rame, Laurence Brugières, Qing Wang, Brigitte Bressac-de Paillerets, Jean-Marc Rey, Christine Toulas, Marie-Pierre Buisine, Myriam Bronner, Joanna Sokolowska, Agnès Hardouin, Anne-Françoise Cailleux, Hakim Sebaoui, Julien Blot, Julie Tinat, Jacques Benichou, Thierry Frebourg

To determine if the at-risk single-nucleotide polymorphism (SNP) alleles for colorectal cancer (CRC) could contribute to clinical situations suggestive of an increased genetic risk for CRC, we performed a prospective national case-control study based on highly selected patients (CRC in two first-degree relatives, one before 61 years of age; or CRC diagnosed before 51 years of age; or multiple primary CRCs, the first before 61 years of age; exclusion of Lynch syndrome and polyposes) and controls without personal or familial history of CRC. SNPs were genotyped using SNaPshot, and statistical analyses were performed using Pearson's χ(2) test, Cochran-Armitage test of trend and logistic regression. We included 1029 patients and 350 controls. We confirmed the association of CRC risk with four SNPs, with odds ratio (OR) higher than previously reported: rs16892766 on 8q23.3 (OR: 1.88, 95% confidence interval (CI): 1.30-2.72; P=0.0007); rs4779584 on 15q13.3 (OR: 1.42, CI: 1.11-1.83; P=0.0061) and rs4939827 and rs58920878/Novel 1 on 18q21.1 (OR: 1.49, CI: 1.13-1.98; P=0.007 and OR: 1.49, CI: 1.14-1.95; P=0.0035). We found a significant (P<0.0001) cumulative effect of the at-risk alleles or genotypes with OR at 1.62 (CI: 1.10-2.37), 2.09 (CI: 1.43-3.07), 2.87 (CI: 1.76-4.70) and 3.88 (CI: 1.72-8.76) for 1, 2, 3 and at least 4 at-risk alleles, respectively, and OR at 1.71 (CI: 1.18-2.46), 2.29 (CI: 1.55-3.38) and 6.21 (CI: 2.67-14.42) for 1, 2 and 3 at-risk genotypes, respectively. Combination of SNPs may therefore explain a fraction of clinical situations suggestive of an increased risk for CRC.European Journal of Human Genetics advance online publication, 15 April 2015; doi:10.1038/ejhg.2015.72.