Colorectal cancer genetic variants are also associated with serrated polyposis syndrome susceptibility

Coral Arnau-Collell1, Yasmin Soares de Lima1, Marcos Díaz-Gay1, Jenifer Muñoz1, Sabela Carballal1, Laia Bonjoch1, Leticia Moreira1, Juan José Lozano2, Teresa Ocaña1, Miriam Cuatrecasas3, Aránzazu Díaz de Bustamante4, Antoni Castells1, Gabriel Capellà5, Luis Bujanda6, Joaquín Cubiella7, Daniel Rodríguez-Alcalde8, Francesc Balaguer9, Clara Ruiz-Ponte10, Laura Valle5, Victor Moreno11, Sergi Castellví-Bel1

1Gastroenterology Department, IDIBAPS, CIBEREHD, Hospital Clínic, Barcelona, Spain. 2Bioinformatics Platform, CIBEREHD, Barcelona, Spain. 3Pathology Department and Tumor Bank-Biobank, IDIBAPS, CIBEREHD, Hospital Clínic, Barcelona, Spain. 4Genetics Unit, Hospital Universitario de Móstoles, Madrid, Spain. 5Hereditary Cancer Program, IDIBELL, CIBERONC, Barcelona, Spain. 6Gastroenterology Department, Hospital Donostia-Instituto Biodonostia, CIBEREHD, UPV/EHU, San Sebastián, Spain. 7Gastroenterology Department, Complexo Hospitalario Universitario de Ourense, Instituto de Investigación Sanitaria Galicia Sur, CIBEREHD, Ourense, Spain. 8Digestive Disease Section, Hospital Universitario de Móstoles, Móstoles, Spain. 9. Gastroenterology Department, IDIBAPS, CIBEREHD, Hospital Clínic, Barcelona, Spain. 10Fundación Pública Galega de Medicina Xenómica, Grupo de Medicina Xenómica_USC, IDIS, CIBERER, Santiago de Compostela, Spain. 11Unit of Biomarkers and Susceptibility, ICO, IDIBELL, CIBERESP, University of Barcelona, Barcelona, Spain


Objective: Serrated polyposis syndrome (SPS) is a clinical entity characterized by multiple serrated polyps throughout the colon and increased risk for colorectal cancer (CRC). The basis for SPS genetic predisposition is largely unknown. Common, low-penetrance genetic variants have been consistently associated with CRC susceptibility, however, their role in SPS genetic predisposition has not been yet explored. According to this evidence, the aim of this study was to evaluate if common low-penetrance genetic variants for CRC risk are also implicated in SPS genetic susceptibility.

Methods: A case-control study was performed in 220 SPS patients and 548 asymptomatic controls analysing 65 CRC susceptibility variants. A risk prediction model for SPS predisposition was developed.

Results: Statistically significant associations with SPS were found for 7 genetic variants (rs4779584-GREM1, rs16892766-EIF3H, rs3217810-CCND2, rs992157-PNKD1/TMBIM1, rs704017-ZMIZ1, rs11196172-TCF7L2, rs6061231-LAMA5). The GREM1 risk allele was remarkably overrepresented in SPS cases compared to controls (OR=1.583; 95%CI 1.22-2.05, P-value=0.0005). A 5-fold increase in SPS risk was observed when comparing subjects within the highest decile of variants (≥ 62) with those in the first decile (≤ 48).

Conclusions: Genetic variants for CRC risk are also involved in SPS susceptibility, being the most relevant ones rs4779584 (GREM1), rs16892766 (EIF3H) and rs3217810 (CCND2).