APC promoter hypermethylation contributes to the loss of APC expression in colorectal cancers with allelic loss on 5q
APC promoter hypermethylation contributes to the loss of APC expression in colorectal cancers with allelic loss on 5q
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DOI：
10.4161/cbt.3.10.1113
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发表时间：
2004-10-01
影响因子：
3.6
通讯作者：
Boland, CR
中科院分区：
文献类型：
--
作者：
Arnold, CN;Goel, A;Boland, CR
简介：APC基因的种系突变与家族性腺瘤性息肉病有关，体细胞突变在散发性结直肠癌中经常发生。然而，要消除 APC 功能，必须使两个等位基因失活。最近，已经证明 APC 启动子的表观遗传修饰会影响 APC 沉默。在这里，我们检查了 APC 甲基化对 APC 基因座上有或没有 LOH 的肿瘤中 APC 表达的影响。材料和方法：对 137 例散发性结直肠癌标本的 5q 基因座上的 LOH 进行了研究。 APC 启动子的甲基化状态通过甲基化特异性 PCR 测定。通过免疫组织化学检测APC表达。结果：137个肿瘤中的110个（80%）表达减少或缺失，132个肿瘤中的13个（10%）发现5q处的LOH。有或没有完整 APC 表达的肿瘤之间 5q LOH 没有差异。反之亦然，具有 5q LOH 的肿瘤中 APC 表达没有差异。在所研究的 118 个肿瘤中，有 33 个 (28%) 检测到异常的 APC 启动子甲基化。在有甲基化数据的 5q LOH 肿瘤中，11 个中有 4 个 (36%) 被甲基化，而在 105 个无 LOH 的肿瘤中，105 个中有 28 个 (27%) 被甲基化。在没有 5q LOH 和正常 APC 表达的肿瘤以及没有 5q LOH 和减少或缺失的 APC 表达的肿瘤中，没有观察到甲基化差异。重要的是，具有 5q LOH 和正常 APC 染色的肿瘤均未出现异常甲基化，而 50% 具有 5q LOH 且染色减少或缺失的癌症呈高甲基化。 结论：本报告表明，与具有 5q LOH 和正常 APC 表达的肿瘤相比，具有 5q LOH 和 APC 表达减少的肿瘤在 APC 启动子处更频繁地发生高甲基化。 APC 启动子甲基化状态、5q LOH 与 APC 表达减少或丢失之间的关联表明，从头甲基化在结直肠肿瘤中 APC 表达沉默中发挥着重要作用，作为“第二次打击”。
Introduction: Germ-line mutations of the APC gene are associated with familial adenomatous polyposis, and somatic mutations occur frequently in sporadic colorectal cancer. However, to abrogate APC function, both alleles must be inactivated. Recently, it has been demonstrated that epigenetic modification of the APC promoter influences APC silencing. Here we examined the influence of APC methylation on APC expression in tumors with and without LOH at the APC locus.Material and Methods: 137 sporadic colorectal cancer specimens were investigated for LOH at the 5q locus. The methylation status of the APC promoter was determined by methylation-specific PCR. APC expression was performed by immunohistochemistry.Results: expression was reduced or lost in 110 of 137 (80%) tumors and LOH at 5q was found in 13 of 132 (10%) tumors. There was no difference in 5q LOH between tumors with or without intact APC expression. Vice versa, there was no difference in the APC expression in tumors with 5q LOH. Aberrant APC promoter methylation was detected in 33 of 118 (28%) tumors investigated. Of the tumors with 5q LOH for which methylation data were available, 4 of 11 (36%) were methylated versus 28 of 105 (27%) of those without LOH. No difference in methylation was observed in tumors without 5q LOH and normal APC expression and those without 5q LOH and reduced or missing APC expression. Importantly, none of the tumors with 5q LOH and normal APC staining were aberrantly methylated, whereas 50% of the cancers with LOH at 5q and reduced or absent staining were hypermethylated.Conclusions: This report suggests that tumors with 5q LOH and reduced APC expression are more frequently hypermethylated at the APC promoter compared to those tumors with 5q LOH and normal APC expression. The association among APC promoter methylation status, 5q LOH, and reduced or lost APC expression suggests that de novo methylation plays an important role as a "second hit" in silencing APC expression in colorectal neoplasia.