Department of Oncology and Experimental Medicine, "G. d'Annunzio" University, Chieti-Pescara, Chieti, Italy.
Gastroenterology. 2012 Jan;142(1):71-77.e1. doi: 10.1053/j.gastro.2011.09.048. Epub 2011 Oct 10.
BACKGROUND & AIMS: Germline variations in allele-specific expression (ASE) are associated with highly penetrant familial cancers, but their role in common sporadic cancers is unclear. ASE of adenomatous polyposis coli (APC) is associated with pathogenesis of familial adenomatous polyposis. We investigated whether moderate variations in ASE of APC contribute to common forms of colorectal cancer (CRC).
Denaturing high-performance liquid chromatography was used to analyze germline ASE of APC in blood samples from patients with CRC (cases, n = 53) and controls (n = 68). Means, medians, and variances of ASE were compared. Variants in the APC gene region also were analyzed.
The distribution of ASE differed significantly between groups; cases had significantly larger amounts of variance than controls (P = .0004). Risk for CRC increased proportionally with the degree of deviation from the mean. The odds ratio for individuals with levels of ASE that deviated more than 1 standard deviation from the mean was 3.97 (95% confidence interval, 1.71-9.24; P = .001); for those with levels greater than 1.645 standard deviations, the odds ratio was 13.46 (95% confidence interval, 1.76-609.40; P = .005). Sequence analysis revealed that a patient with a high level of ASE who did not have a family history of CRC carried a nonsense mutation in APC (p.Arg216X). Genotype analysis of APC associated multiple single-nucleotide polymorphisms with ASE values and/or variance among cases, but not controls. Cis variants, therefore, might account for some of the variance in ASE of APC.
Patients with CRC have a larger variance in germline levels of ASE in APC than controls; large distances from the mean ASE were associated with risk for common forms of CRC.
等位基因特异性表达（ASE）的种系变异与高外显率的家族性癌症有关，但它们在常见的散发性癌症中的作用尚不清楚。腺瘤性结肠息肉病（APC）的 ASE 与家族性腺瘤性息肉病的发病机制有关。我们研究了 APC 的 ASE 中度变异是否会导致常见形式的结直肠癌（CRC）。
使用变性高效液相色谱法分析 CRC 患者（病例，n=53）和对照组（n=68）血液样本中的 APC 种系 ASE。比较 ASE 的均值、中位数和方差。还分析了 APC 基因区域的变异。
两组间 ASE 的分布差异有统计学意义；病例组的方差明显大于对照组（P=0.0004）。CRC 的风险与偏离均值的程度成比例增加。ASE 水平偏离均值超过 1 个标准差的个体的比值比为 3.97（95%置信区间，1.71-9.24；P=0.001）；ASE 水平大于 1.645 个标准差的个体的比值比为 13.46（95%置信区间，1.76-609.40；P=0.005）。序列分析显示，一名无 CRC 家族史的 ASE 水平较高的患者携带 APC 中的无义突变（p.Arg216X）。多核苷酸多态性与病例组而非对照组的 ASE 值和/或方差相关的 APC 基因型分析。因此，顺式变异可能解释了 APC 的 ASE 部分变异。
CRC 患者 APC 的种系 ASE 水平变异较大；与 ASE 均值的较大距离与常见形式的 CRC 风险相关。
