The frequency of promoter DNA hypermethylation is decreased in colorectal neoplasms of familial adenomatous polyposis.
The frequency of promoter DNA hypermethylation is decreased in colorectal neoplasms of familial adenomatous polyposis.
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DOI：
10.18632/oncotarget.25987
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发表时间：
2018-08-24
期刊：
影响因子：
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通讯作者：
Kaneda A
中科院分区：
文献类型：
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作者：
Takane K;Fukuyo M;Matsusaka K;Ota S;Rahmutulla B;Matsushita K;Miyauchi H;Nakatani Y;Matsubara H;Kaneda A
家族性腺瘤性息肉病（FAP）是一种遗传性疾病，其特征是大量结直肠腺瘤性息肉，具有发生结直肠癌（CRC）的倾向。在这里，我们使用Infinium 450 K BeadArray对FAP肿瘤进行了全基因组DNA甲基化分析，包括7个癌症样本和16个腺瘤样本。作为散发性结直肠肿瘤和粘膜的对照，我们参考癌症基因组图谱和其他数据库，使用来自297个CRC样本、45个结直肠腺瘤样本和37个正常粘膜样本的Infinium 450 k数据。FAP和散发性CRC/腺瘤的无监督双向分层聚类分析显示，CRC可分为4种DNA甲基化表型（ME）：高ME（HME）、中等ME（IME）、低ME（LME）和正常样ME（NME）。5例FAP肿瘤（2例癌和3例腺瘤）与IME聚类，而18例FAP肿瘤（5例癌和13例腺瘤）与NME聚类。IME FAP肿瘤与KRAS突变显著相关，类似于散发性CRC。然而，在IME病例中，FAP肿瘤中异常DNA甲基化的频率明显低于散发性肿瘤，这些未甲基化的基因包括WNT家族基因和几种类型的癌基因。总之，FAP肿瘤分为至少两种分子亚型，即，在大多数情况下，NME显示大多数没有异常甲基化，在一些情况下IME伴随KRAS突变，但异常DNA甲基化的频率低于散发性肿瘤，这表明FAP可能遵循与散发性CRC不同的肿瘤发生途径。
Familial adenomatous polyposis (FAP) is an inherited disorder characterized by numerous colorectal adenomatous polyps with predisposition to the development of colorectal cancer (CRC). Here, we conducted genome-wide DNA methylation analysis of FAP neoplasms, including seven cancer samples and 16 adenoma samples, using an Infinium 450K BeadArray. As controls for sporadic colorectal neoplasms and mucosae, we used Infinium 450k data from 297 CRC samples, 45 colorectal adenoma samples, and 37 normal mucosa samples with reference to The Cancer Genome Atlas and other databases. Unsupervised two-way hierarchical clustering analysis of FAP and sporadic CRC/adenoma revealed that CRC was classified into four DNA methylation epigenotypes (MEs): high-ME (HME), intermediate-ME (IME), low-ME (LME), and normal-like ME (NME). Five FAP neoplasms (two cancer and three adenoma) were clustered with IME, whereas 18 FAP neoplasms (five cancer and 13 adenoma) were clustered into NME. IME FAP neoplasms significantly correlated with KRAS mutations, similar to sporadic CRC. Within IME cases, however, aberrant DNA methylation was significantly less frequent in FAP neoplasms than sporadic neoplasms, and these unmethylated genes included WNT family genes and several types of oncogenes. In summary, FAP neoplasms were classified into at least two molecular subtypes, i.e., NME in the majority of cases showing mostly no aberrant methylation and IME in some cases accompanied by KRAS mutations but less frequent aberrant DNA methylation than sporadic neoplasms, suggesting that FAP may follow a tumorigenesis pathway different from that of sporadic CRC.