Cicek Mine S, Slager Susan L, Achenbach Sara J, French Amy J, Blair Hilary E, Fink Stephanie R, Foster Nathan R, Kabat Brian F, Halling Kevin C, Cunningham Julie M, Cerhan James R, Jenkins Robert B, Boardman Lisa A, Petersen Gloria M, Sargent Daniel J, Alberts Steven R, Limburg Paul J, Thibodeau Stephen N
Department of Laboratory Medicine and Pathology, Mayo Clinic, 200 First Street Southwest, 920 Hilton Building, Rochester, MN 55905, USA.
Cancer Epidemiol Biomarkers Prev. 2009 Sep;18(9):2492-500. doi: 10.1158/1055-9965.EPI-09-0362. Epub 2009 Aug 18.
Multiple genome-wide association studies have identified several susceptibility variants for colon cancer at 8q24. However, the functional roles of these variants have yet to be elucidated. Here, we evaluated the potential role of these markers in tumor progression and examined association with commonly observed structural abnormalities in this region, c-MYC amplification and chromosome fragility at FRA8C and FRA8D. We first replicated the previously reported association by testing 1,178 cases and 1,009 clinic-based controls with eight markers localized to three specific regions at 8q24. We observed significant associations with colon cancer risk with markers rs13254738 (ordinal odds ratio, 0.82; 95% confidence interval, 0.072-0.94; P(trend) = 0.0037) and rs6983267 (ordinal odds ratio, 1.17; 95% confidence interval, 1.03-1.32, P(trend) = 0.013). Survival analysis was done using a separate set of 460 cases to evaluate the clinical significance of these markers. Overall, univariate analysis did not detect survival differences for any of the markers. We also tested a subset of the 460 cases (n = 380) for structural abnormalities at or near the c-MYC locus using fluorescence in situ hybridization analysis. Furthermore, we evaluated a small number of cases homozygous for the rs6983267 alleles to test for differences in fragile site induction. None of the 8q markers correlated with amplification at the c-MYC locus as detected by fluorescence in situ hybridization, and no clear pattern of breakage was observed at the FRA8C and FRA8D sites. In this study, we confirm the association for several single nucleotide polymorphisms at 8q24 in colon cancer but have not detected any structural role relating to c-MYC amplification or chromosomal fragility. Finally, these risk alleles do not seem to be associated with survival.
多项全基因组关联研究已在8q24区域鉴定出多个结肠癌易感变异。然而，这些变异的功能作用尚未阐明。在此，我们评估了这些标记物在肿瘤进展中的潜在作用，并研究了其与该区域常见结构异常、c-MYC扩增以及FRA8C和FRA8D处染色体脆性的关联。我们首先通过对1178例病例和1009例基于临床的对照进行检测，使用位于8q24三个特定区域的八个标记物，重复了先前报道的关联研究。我们观察到标记物rs13254738（有序优势比，0.82；95%置信区间，0.072 - 0.94；P趋势 = 0.0037）和rs6983267（有序优势比，1.17；95%置信区间，1.03 - 1.32，P趋势 = 0.013）与结肠癌风险存在显著关联。使用另一组460例病例进行生存分析，以评估这些标记物的临床意义。总体而言，单变量分析未检测到任何标记物的生存差异。我们还使用荧光原位杂交分析对460例病例中的一个子集（n = 380）进行了c-MYC基因座或其附近的结构异常检测。此外，我们评估了少量rs6983267等位基因纯合的病例，以测试脆性位点诱导的差异。荧光原位杂交检测未发现8q标记物与c-MYC基因座扩增相关，且在FRA8C和FRA8D位点未观察到明确的断裂模式。在本研究中，我们证实了8q24区域的几个单核苷酸多态性与结肠癌的关联，但未检测到与c-MYC扩增或染色体脆性相关的任何结构作用。最后，这些风险等位基因似乎与生存无关。
