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

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

doi:10.18632/oncotarget.25987

Kiyoko Takane, Kazuyuki Matsushita + Show 8 more

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https://doi.org/10.18632/oncotarget.25987

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Abstract

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.

Highlights

Sporadic colorectal cancer (CRC) is a major cause of death and is associated with high incidence and mortality rates [1]
IME Familial adenomatous polyposis (FAP) neoplasms significantly correlated with KRAS mutations, similar to sporadic CRC
Some protocols have been reported to improve quality of FFPE DNA samples and achieve robust array results [19, 20]. Because both frozen and FFPE samples were analyzed in this study, probes that were not significantly influenced by FFPE were extracted to exclude the effects of the FFPE procedure for Infinium analysis

Summary

Introduction

Sporadic colorectal cancer (CRC) is a major cause of death and is associated with high incidence and mortality rates [1]. Some genes were commonly hypermethylated in most CRC cases, two groups of classifier genes (Group-1 and Group-2 markers) were established to classify sporadic CRC into three distinct DNA methylation epigenotypes (MEs): high-ME (HME), intermediate-ME (IME), and low-ME (LME) [8]. HME/CIMP-high sporadic CRC showed hypermethylation of both Group-1 and Group-2 markers and was strongly correlated with BRAF mutations. IME/ CIMP-low sporadic CRC showed methylation of Group-2, but not Group-1 markers, and was strongly correlated with KRAS mutations. LME sporadic CRC showed aberrant hypermethylation of commonly methylated genes, but no methylation of Group-1/Group-2 markers, and did not correlate with BRAF or KRAS mutations, as reported by other groups [9, 10]

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