Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, Georgia.
Mol Carcinog. 2014 Feb;53 Suppl 1:E187-92. doi: 10.1002/mc.22047. Epub 2013 Jun 18.
Three polymorphic sites at chromosome 8q24 (rs7837328, rs10808555, rs6983267) have been associated with risk for colorectal adenomas. It was also previously reported that the single nucleotide polymorphism (SNP) rs6983267 may enhance Wnt signaling, which regulates cell proliferation. To investigate associations between the 8q24 variants and colorectal epithelial cell proliferation in the normal-appearing colorectal mucosa, as well as with colorectal adenoma, we analyzed data from a previously conducted pilot, colonoscopy-based case-control study of incident, sporadic colorectal adenoma (n = 90 cases, 132 controls). Proliferation was measured in biopsies of the normal-appearing mucosa of the rectum, sigmoid colon, and cecum using immunohistochemistry for proliferating cell nuclear antigen (PCNA). The direct associations of each SNP with colorectal adenoma were consistent with those in previous reports. For all three SNPs, proliferation tended to be higher among those homozygous for the risk alleles compared to those heterozygous or homozygous for the nonrisk alleles combined; among the controls, proliferation was 32.1% higher (P = 0.23) for those with the rs10808555 GG genotype, 16.4% higher (P = 0.16) for those with the rs7837328 AA genotype, and 6.5% higher (P = 0.52) for those with the rs6983267 GG genotype. These preliminary findings, which are consistent with previously reported direct associations between genetic variants at chromosome 8q24 and risk for colorectal adenoma, suggest that the genetic variants may also be associated with higher levels of colorectal epithelial cell proliferation, thus providing support for further investigation of the hypothesis that 8q24 variants may increase risk via enhanced Wnt signaling.
三个位于 8q24 染色体上的多态性位点（rs7837328、rs10808555、rs6983267）与结直肠腺瘤的风险相关。先前也有报道称，单核苷酸多态性（SNP）rs6983267 可能增强 Wnt 信号，从而调节细胞增殖。为了研究 8q24 变异与正常结直肠黏膜中的结直肠上皮细胞增殖以及结直肠腺瘤之间的关系，我们分析了先前进行的一项基于结肠镜的偶发性散发性结直肠腺瘤（n = 90 例病例，132 例对照）的先导、病例对照研究的数据。使用增殖细胞核抗原（PCNA）的免疫组织化学法测量直肠、乙状结肠和盲肠正常外观黏膜的活检标本中的增殖情况。每个 SNP 与结直肠腺瘤的直接关联与先前的报告一致。对于所有三个 SNP，与非风险等位基因杂合或纯合相比，风险等位基因纯合的个体中增殖倾向于更高；在对照组中，rs10808555 GG 基因型个体的增殖率高出 32.1%（P = 0.23），rs7837328 AA 基因型个体的增殖率高出 16.4%（P = 0.16），rs6983267 GG 基因型个体的增殖率高出 6.5%（P = 0.52）。这些初步发现与先前报道的染色体 8q24 上遗传变异与结直肠腺瘤风险之间的直接关联一致，表明遗传变异也可能与结直肠上皮细胞增殖水平升高有关，从而为进一步研究假设提供了支持，即 8q24 变异可能通过增强 Wnt 信号增加风险。
