Global hypomethylation of genomic DNA in cancer-associated myofibroblasts.
Global hypomethylation has long been recognized as a feature of the malignant epithelial component in human carcinomas. Here we show evidence for this same type of epigenetic alteration in cancer-associated stromal myofibroblasts. We used methylation-sensitive SNP array analysis (MSNP) to profile DNA methylation in early-passage cultures of stromal myofibroblasts isolated from human gastric cancers. The MSNP data indicated widespread hypomethylation in these cells, with rare focal gains of methylation, conclusions that were independently validated by bisulfite sequencing and by a methylation-sensitive cytosine incorporation assay. Immunohistochemistry with anti-5-methylcytosine (anti-5-methyl-C) in a series of gastrectomy specimens showed frequent loss of methylation in nuclei of both the malignant epithelial cells and alpha-smooth muscle actin (ASMA)-positive stromal myofibroblasts of both intestinal-type and diffuse carcinomas. We confirmed this phenomenon and established its onset at the stage of noninvasive dysplastic lesions by immunohistochemistry for anti-5-methyl-C in a transgenic mouse model of multistage gastric carcinogenesis. These findings indicate similar general classes of epigenetic alterations in carcinoma cells and their accompanying reactive stromal cells and add to accumulating evidence for biological differences between normal and cancer-associated myofibroblasts.
Jiang
Le
L
Institute for Cancer Genetics and Department of Medicine, Columbia University, New York, New York 10032, USA.
Gonda
Tamas A
TA
Gamble
Mary V
MV
Salas
Martha
M
Seshan
Venkatraman
V
Tu
Shuiping
S
Twaddell
William S
WS
Hegyi
Peter
P
Lazar
Gyorgy
G
Steele
Islay
I
Varro
Andrea
A
Wang
Timothy C
TC
Tycko
Benjamin
B
D000818:Animals; D043171:Chromosomal Instability; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000096:biosynthesis / Q000235:genetics; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000235:genetics* / Q000378:metabolism; D003845:Deoxycytosine Nucleotides / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D020641:Polymorphism, Single Nucleotide; D013274:Stomach Neoplasms / Q000235:genetics* / Q000473:pathology; D017154:Stromal Cells / Q000473:pathology
D004273:DNA, Neoplasm; D003845:Deoxycytosine Nucleotides; C024107:2'-deoxycytidine 5'-triphosphate; D004248:DNA (Cytosine-5-)-Methyltransferases