NOD2 3020insC Alone Is Not Sufficient for Colorectal Cancer Predisposition

Abstract

Mutations in NOD2 have been shown to associate with increased susceptibility to Crohn's disease. A recent Polish study linked the truncating NOD2 3020insC variant with an increased risk of colorectal cancer (CRC) at an older age (>50 years) of disease onset, with an odds ratio of 2.23. We studied the possible contribution of the 3020insC variant to CRC risk in a series of 1,042 Finnish population-based patients from which 926 samples were successfully analyzed and in 348 anonymous cancer-free controls. The frequency of the 3020insC mutation was 3.7% in both CRC patients (34 of 926, including 1 homozygote) and cancer-free controls (13 of 348; odds ratio, 0.98; confidence interval, 0.51-1.88). Contrary to the Polish study, there was no significant difference in the mutation rates between CRC patients > 50 years of age (25 of 576; 4.3%) and controls in the present series. We studied respective tumor tissue DNAs of all patients displaying heterozygous 3020insC changes for loss of heterozygosity. Loss of heterozygosity at NOD2 was observed in only 1 of the 33 CRC samples. Our results suggest that NOD2 3020insC alone does not contribute to CRC risk. If this variant predisposes to CRC, additional factors not present in the Finnish population need to be involved.

No evidence for association of NOD2 R702W and G908R with colorectal cancer

“…Very low penetrance effects cannot be excluded without larger materials. If the data from the 4 previous studies [12][13][14][15] and this study is combined to increase the sample size, the mutation frequencies of R702W, G908R and 3020insC do not significantly differ between CRC patients and controls; R702W, p 5 0.17; G908R, p 5 0.12; 3020insC, p 5 0.06 (Table III). If data on all variants (R702W/G908R/3020insC) were pooled, a significant difference is observed between cases and controls (p 5 0.008).…”

“…14 In the current study we have extended our efforts to characterize NOD2 as a candidate susceptibility gene for CRC, and screened the R702W and the G908R variants in the same population-based series of 1,042 CRC patients, in addition to 508 healthy controls. On the basis of these studies, no significant differences in the frequencies of R702W, G908R and 3020insC between CRC patients and controls could be detected (Table I).…”

“…The study from New Zealand prompted us to extend our previous work 14 and to examine, whether occurrence of the 2 NOD2 variants (R702W or G908R) would associate with CRC. An extensive population-based series of Finnish CRC patients as well as 508 healthy blood donors were screened for R702W and G908R to derive a comprehensive picture of NOD2 variants and possible CRC predisposition in Finns.…”

Common NOD2/CARD15 variants are not associated with susceptibility or clinicopathologic characteristics of sporadic colorectal cancer in Hungarian patients

“…Kurzawski et al [25] found that the presence of 3020insC mutation increased the risk of developing CRC by 2.23-fold in Polish patients with an older average age at diagnosis. This was however not confirmed in a Finnish study by Alhopuro et al [26]. Noteworthy, in the most recent Greek study, all three common variants were found to be associated with an increased risk for CRC (OR: 2.4-5.2) [27].…”

NOD2/CARD15 variants in Malaysian patients with sporadic colorectal cancer

“…Among the IBD-related genes, the genetic variants of nucleotide oligomerization domain 2/caspase activating recruitment domain 15 (NOD2/CARD15) are the most extensively studied with respect to their association to CRC susceptibility, notwithstanding various conflicting findings among different populations (Alhopuro et al, 2004;Kurzawski et al, 2004;Papaconstantinou et al, 2005;Roberts et al, 2006;Lakatos et al, 2007;Szeliga et al, 2008). Therefore, in this study, we aimed to investigate the frequency of five genetic variants of NOD2/CARD15 and their potential association to CRC susceptibility in Malaysian patients.…”