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2016 ; 11
(8
): 588-602
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Aberrant DNA methylation of WNT pathway genes in the development and progression
of CIMP-negative colorectal cancer
#MMPMID27245242
Galamb O
; Kalmár A
; Péterfia B
; Csabai I
; Bodor A
; Ribli D
; Krenács T
; Patai ÁV
; Wichmann B
; Barták BK
; Tóth K
; Valcz G
; Spisák S
; Tulassay Z
; Molnár B
Epigenetics
2016[Aug]; 11
(8
): 588-602
PMID27245242
show ga
The WNT signaling pathway has an essential role in colorectal carcinogenesis and
progression, which involves a cascade of genetic and epigenetic changes. We aimed
to analyze DNA methylation affecting the WNT pathway genes in colorectal
carcinogenesis in promoter and gene body regions using whole methylome analysis
in 9 colorectal cancer, 15 adenoma, and 6 normal tumor adjacent tissue (NAT)
samples by methyl capture sequencing. Functional methylation was confirmed on
5-aza-2'-deoxycytidine-treated colorectal cancer cell line datasets. In parallel
with the DNA methylation analysis, mutations of WNT pathway genes (APC,
?-catenin/CTNNB1) were analyzed by 454 sequencing on GS Junior platform. Most
differentially methylated CpG sites were localized in gene body regions (95% of
WNT pathway genes). In the promoter regions, 33 of the 160 analyzed WNT pathway
genes were differentially methylated in colorectal cancer vs. normal, including
hypermethylated AXIN2, CHP1, PRICKLE1, SFRP1, SFRP2, SOX17, and hypomethylated
CACYBP, CTNNB1, MYC; 44 genes in adenoma vs. NAT; and 41 genes in colorectal
cancer vs. adenoma comparisons. Hypermethylation of AXIN2, DKK1, VANGL1, and
WNT5A gene promoters was higher, while those of SOX17, PRICKLE1, DAAM2, and MYC
was lower in colon carcinoma compared to adenoma. Inverse correlation between
expression and methylation was confirmed in 23 genes, including APC, CHP1,
PRICKLE1, PSEN1, and SFRP1. Differential methylation affected both canonical and
noncanonical WNT pathway genes in colorectal normal-adenoma-carcinoma sequence.
Aberrant DNA methylation appears already in adenomas as an early event of
colorectal carcinogenesis.
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