Low-penetrance alleles predisposing to sporadic colorectal cancers: a French case-controlled genetic association study.
BACKGROUND
Sporadic colorectal cancers (CRC) are multifactorial diseases resulting from the combined effects of numerous genetic, environmental and behavioral risk factors. Genetic association studies have suggested low-penetrance alleles of extremely varied genes to be involved in susceptibility to CRC in Caucasian populations.


METHODS
Through a large genetic association study based on 1023 patients with sporadic CRC and 1121 controls, we tested a panel of these low-penetrance alleles to find out whether they could determine "genotypic profiles" at risk for CRC among individuals of the French population. We examined 52 polymorphisms of 35 genes - drawn from inflammation, xenobiotic detoxification, one-carbon, insulin signaling, and DNA repair pathways - for their possible contribution to colorectal carcinogenesis. The risk of cancer associated with these polymorphisms was assessed by calculation of odds ratios (OR) using multivariate analyses and logistic regression.


RESULTS
Whereas all these polymorphisms had previously been found to be associated with CRC risk, especially in Caucasian populations, we were able to replicate the association for only five of them. Three SNPs were shown to increase CRC risk: PTGS1 c.639C>A (p.Gly213Gly), IL8 c.-352T>A, and MTHFR c.1286A>C (p.Ala429Glu). On the contrary, two other SNPs, PLA2G2A c.435+230C>T and PPARG c.1431C>T (p.His477His), were associated with a decrease in CRC risk. Further analyses highlighted genotypic combinations having a greater predisposing effect on CRC (OR 1.97, 95%CI 1.31-2.97, p = 0.0009) than the allelic variants that were examined separately.


CONCLUSIONS
The identification of CRC-predisposing combinations, composed of alleles PTGS1 c.639A, PLA2G2A c.435+230C, PPARG c.1431C, IL8 c.-352A, and MTHFR c.1286C, highlights the importance of inflammatory processes in susceptibility to sporadic CRC, as well as a possible crosstalk between inflammation and one-carbon pathways.
Küry
Sébastien
S
Service de Génétique Médicale, Pôle de Biologie, CHU de Nantes, 9 quai Moncousu, Nantes, 44093 cedex 1, France. sebastien.kury@chu-nantes.fr
Buecher
Bruno
B
Robiou-du-Pont
Sébastien
S
Scoul
Catherine
C
Colman
Hélène
H
Le Neel
Tanguy
T
Le Houérou
Claire
C
Faroux
Roger
R
Ollivry
Jean
J
Lafraise
Bernard
B
Chupin
Louis-Dominique
LD
Sébille
Véronique
V
Bézieau
Stéphane
S
D000328:Adult; D000368:Aged; D000483:Alleles; D016022:Case-Control Studies; D015179:Colorectal Neoplasms / Q000235:genetics*; D005260:Female; D005602:France; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D008957:Models, Genetic; D019683:Penetrance; D020641:Polymorphism, Single Nucleotide