Increased variance in germline allele-specific expression of APC associates with colorectal cancer.
Increased variance in germline allele-specific expression of APC associates with colorectal cancer.
复制标题
DOI：
10.1053/j.gastro.2011.09.048
复制
发表时间：
2012-01
期刊：
影响因子：
29.4
通讯作者：
Cama A
中科院分区：
文献类型：
--
作者：
Curia MC;De Iure S;De Lellis L;Veschi S;Mammarella S;White MJ;Bartlett J;Di Iorio A;Amatetti C;Lombardo M;Di Gregorio P;Battista P;Mariani-Costantini R;Williams SM;Cama A
等位基因特异性表达（ASE）的种系变异与高度外显的家族性癌症相关，但其在常见散发性癌症中的作用尚不清楚。腺瘤性结肠息肉病（APC）基因的ASE在家族性腺瘤性结肠息肉病中起作用。我们假设APC中的中度ASE变异有助于常见形式的结直肠癌（CRC）。采用变性高效液相色谱法（DHPLC）对53例结直肠癌患者和68例对照者的生殖系APC ASE进行分析。比较ASE的平均值、中位数和方差。进行突变分析和SNP基因分型。ASE分布组间差异显着;病例组的方差显着大于对照组（p = 0.0004）。重要的是，CRC风险随着偏离平均值的程度成比例增加。ASE与平均值偏离超过1个SD的个体的比值比（OR）为3.97（1.71，9.24 95% CI; p = 0.001）;偏离超过1.645个SD的个体的OR为13.46（1.76，609.40 95% CI; p = 0.005）。为了支持这些发现，序列分析显示，一名有明显ASE的患者，CRC家族史阴性，携带无义APC突变（p.Arg216X）。此外，APC基因分型表明，多个SNPs与ASE值和/或ASE方差的情况下，但在对照组中不相关。因此，顺式变体可以解释至少部分ASE结果。我们的研究结果表明，APC的不平衡生殖系ASE在CRC患者中比对照组更常见，并且代表了常见形式CRC的风险指标。
Germline variation in allele-specific expression (ASE) is associated with highly penetrant familial cancers, but its role in common sporadic cancers is unclear. ASE of the adenomatous polyposis coli (APC) gene plays a role in familial adenomatous polyposis coli. We hypothesized that moderate ASE variation in APC contributes to common forms of colorectal cancer (CRC). Denaturing high performance liquid chromatography (DHPLC) was employed for germline APC ASE analysis in CRC cases (n=53) and controls (n=68). Means, medians, and variances of ASE were compared. Mutation analysis and SNP genotyping were performed. ASE distributions differed significantly between groups; cases had a significantly larger variance than controls (p = 0.0004). Importantly, CRC risk increased proportionally with the degree of deviation from the mean. Individuals with ASE deviating more than 1 SD from the mean had an odds ratio (OR) of 3.97 (1.71, 9.24 95% CI; p = 0.001); those deviating more than 1.645 SDs had an OR of 13.46 (1.76, 609.40 95% CI; p = 0.005). In support of these findings, sequence analysis revealed that a patient with marked ASE, who was negative for CRC family history, carried a nonsense APC mutation (p.Arg216X). Furthermore, APC genotyping showed that multiple SNPs were associated with ASE values and/or ASE variance in cases, but not in controls. Thus, cis variants may explain at least some of the ASE results. Our results indicate that imbalanced germline ASE of APC is more frequent in CRC patients than controls, and represents an indicator of risk for common forms of CRC.
登录
查看更多内容
影响因子：
8.8
作者：
通讯作者：
--
影响因子：
4.7
作者：
Tomsic J;Guda K;Liyanarachchi S;Hampel H;Natale L;Markowitz SD;Tanner SM;de la Chapelle A
通讯作者：
de la Chapelle A
影响因子：
9.7
作者：
Popat, S;Stone, J;Houlston, R
通讯作者：
Houlston, R
影响因子：
7
作者：
Lo, HS;Wang, ZN;Lee, MP
通讯作者：
Lee, MP
影响因子：
11.2
作者：
Guda, Kishore;Natale, Leanna;Markowitz, Sanford D.
通讯作者：
Markowitz, Sanford D.