Colorectal cancer susceptibility quantitative trait loci in mice as a novel approach to detect low-penetrance variants in humans: a two-stage case-control study.
Thirty-five percent of colorectal cancer (CRC) susceptibility is thought to be attributable to genetics, but only a small proportion of the cases (<6%) can be explained by highly penetrant mutations. The rest of the susceptibility could be explained by a number of low-penetrance variants following a polygenic model of inheritance. Genetic modeling in rodents has been a successful tool for the unraveling of the genetic basis of diseases. The investigation of mouse quantitative trait loci led to the discovery of 15 "susceptibility to colorectal cancer" (Scc) loci. Thus, we aimed to analyze the human-mouse syntenic regions defined by these Scc loci and select human candidate genes within. Twenty-one genes were chosen and their single-nucleotide polymorphisms were tested as possible low-penetrance variants predisposing to CRC risk. Our most strongly associated single-nucleotide polymorphism, rs954353, seems to be in the 5' region of the CYR61 gene, which could implicate it in terms of the cis-regulation of the gene. CYR61 has been proposed as a connection point among signaling pathways and a probable marker for early CRC detection. However, we could not replicate the association. Despite our negative results, we believe that our candidate gene selection strategy could be quite useful in the future determination of variants predisposing to disease.
Galician Public Foundation of Genomic Medicine (FPGMX), CIBERER, Genomics Medicine Group, Hospital Clínico, Santiago de Compostela, University of Santiago de Compostela, Galicia, Spain.
Ceres
C
Fernández-Rozadilla
Rosa
R
Tarrío
Juan
J
Clofent
Luisa
L
de Castro
Alejandro
A
Brea-Fernández
Xavier
X
Bessa
Anna
A
Abulí
Montserrat
M
Andreu
Rodrigo
R
Jover
Rosa
R
Xicola
Xavier
X
Llor
Antoni
A
Castells
Sergi
S
Castellví-Bel
Angel
A
Carracedo
Clara
C
Ruiz-Ponte
D000818:Animals; D016022:Case-Control Studies; D015179:Colorectal Neoplasms / Q000235:genetics*; D004195:Disease Models, Animal; D020022:Genetic Predisposition to Disease; D005821:Genetic Techniques; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D051379:Mice; D019683:Penetrance; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci