Research Papers:

The frequency of promoter DNA hypermethylation is decreased in colorectal neoplasms of familial adenomatous polyposis

Kiyoko Takane, Masaki Fukuyo, Keisuke Matsusaka, Satoshi Ota, Bahityar Rahmutulla, Kazuyuki Matsushita, Hideaki Miyauchi, Yukio Nakatani, Hisahiro Matsubara and Atsushi Kaneda _

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Oncotarget. 2018; 9:32653-32666. https://doi.org/10.18632/oncotarget.25987

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Kiyoko Takane1, Masaki Fukuyo1,2, Keisuke Matsusaka1, Satoshi Ota3, Bahityar Rahmutulla1, Kazuyuki Matsushita4, Hideaki Miyauchi5, Yukio Nakatani3,6, Hisahiro Matsubara5 and Atsushi Kaneda1

1Department of Molecular Oncology, Graduate School of Medicine, Chiba University, Chiba, Japan

2Department of Genome Research and Development, Kazusa DNA Research Institute, Chiba, Japan

3Department of Pathology, Chiba University Hospital, Chiba, Japan

4Department of Laboratory Medicine and Division of Clinical Genetics and Proteomics, Chiba University Hospital, Chiba, Japan

5Department of Frontier Surgery, and Graduate School of Medicine, Chiba University, Chiba, Japan

6Department of Diagnostic Pathology, Graduate School of Medicine, Chiba University, Chiba, Japan

Correspondence to:

Atsushi Kaneda, email: [email protected]

Keywords: familial adenomatous polyposis (FAP); colorectal cancer; colorectal adenoma; DNA methylation

Received: June 18, 2018     Accepted: July 31, 2018     Published: August 24, 2018


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.

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