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• W1995508764 abstract "The natural killer (NK) cell receptor G2D (NKG2D), officially named killer cell lectin-like receptor subfamily K, member 1 (KLRK1), is involved in the activation of NK cells.1 NKG2D plays an important role in tumor surveillance by NK-cells,2 and increased expression of ligands for NKG2D is detected in colorectal tumor tissue.3 Polymorphisms in the NKG2D gene have been found to be associated with peripheral blood cytotoxicity and cancer development in a Japanese cohort,4 and we recently identified single nucleotide polymorphisms (SNP) in the NKG2D gene associated with cholangiocarcinoma development in patients with primary sclerosing cholangitis.5 Because of the potential importance of inflammatory pathogenesis in colorectal cancer (CRC),6 we aimed to clarify the impact of NKG2D polymorphisms on this phenotype by investigating a large cohort of 1072 German patients with sporadic CRC and 760 healthy controls. Patients with histologically proven CRC from 21 surgical departments in Northern Germany were included, patients fulfilling the clinical Amsterdam or Bethesda criteria for hereditary nonpolyposis colon cancer were excluded. An earlier study in the same cohort has analyzed polymorphisms in DNA repair pathway genes without finding any association.7 The tumors were found in the rectum in 485 patients (45%) and in the colon in 469 patients (44%), for 118 (11%) the tumor localization was unknown. The median age of the patients at diagnosis was 59 years (range: 18–74 years). One hundred ninety-two (18%) of the patients had a first degree relative diagnosed with CRC. Controls were taken from the control-pool of the POPGEN project,8 their median age at recruitment was 68 years (range 48–81 years). The male to female ratios were similar in the cases (1.01) and controls (1.04). Three NKG2D SNPs; rs11053781 and rs2617167 which were associated with cholangiocarcinoma in our previous study,5 and rs2255336 which is a coding SNP (Thr→Ala), were included. The power to detect an association (α = 0.05) with an OR = 2.0 were 100% for all three SNPs, while the power to detect an association with an OR = 1.3 were 90, 97 and 93% for rs2255336, rs11053781 and rs2617167, respectively. Genotyping was performed with TaqMan Assays-on-Demand® (Applied Biosystems, Foster City, CA) for rs2255336 and rs11053781, and with a TaqMan Assay-By-Design® (Applied Biosystems) for rs2617167. The χ2 test was used for association analyses for both alleles and genotypes. No significant differences in allele frequencies were seen for any of the genotyped SNPs when CRC patients were compared against healthy controls with allelic tests (Table I). With genotype based tests (prs2255336 = 0.88, prs11053781 = 0.045 and prs2617167 = 0.71) borderline significance for rs11053781 was seen, however this was not robust to correction for multiple comparison. When the subgroup of patients with a family history of CRC were compared against the healthy controls slight significance were observed with the A-allele at rs11053781 and G-allele at rs2617167 (Allelic tests: prs2255336 = 0.72, prs11053781 = 0.047 and prs2617167 = 0.011; Genotype tests: prs2255336 = 0.87, prs11053781 = 0.021 and prs2617167 = 0.041), only the allelic test of rs2617167 was robust to correction with Bonferronis method with a factor of 3, corrected p-value = 0.034. Furthermore no associations were detected when the subgroup of CRC cases <55 years (n = 256), in which genetics is believed to play a more important role,9 were compared against healthy controls (Allelic tests: prs2255336 = 0.88, prs11053781 = 0.61 and prs2617167 = 0.63; Genotype tests: prs2255336 = 0.49, prs11053781 = 0.49 and prs2617167 = 0.76). The present study demonstrates that NKG2D polymorphisms previously associated with cholangiocarcinoma do not seem to confer risk of sporadic CRC. It should be noted that slight significance were observed after correction at the rs2617167 locus, correction of the p-values were only performed according to the number of SNPs tested and not according to the number of sub-groups tested. This finding probably represents a false positive finding because of multiple comparisons especially since the involved allele is the opposite of that observed in the original study of Scandinavian cholangiocarcinoma patients.5 Taken together, our findings suggest that different mechanisms may be involved in the immune-mediated protection against different malignancies. Tumor surveillance by NK-cells might be especially important in inflammation based cancers like cholangiocarcinoma and further studies on NKG2D polymorphisms in such cancers seem warranted. Although the present study was well powered to detect an effect from the genotyped SNPs on risk of CRC, it should be stated that we cannot formally rule out that other NKG2D polymorphisms not genotyped in the present study may be of importance. Yours sincerely, Espen Melum, Stephan Buch, Clemens Schafmayer, Holger Kalthoff, Jürgen Tepel, Stefan Schreiber, Tom H. Karlsen, Jochen Hampe" @default.
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• W1995508764 date "2008-01-01" @default.
• W1995508764 modified "2023-09-23" @default.
• W1995508764 title "Investigation of cholangiocarcinoma associatedNKG2D polymorphisms in colorectal carcinoma" @default.
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• W1995508764 doi "https://doi.org/10.1002/ijc.23517" @default.
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