Promoter CpG island hypermethylation during breast cancer progression.
This study was designed to evaluate the changes in promoter CpG islands hypermethylation during breast cancer progression from pre-invasive lesions [flat epithelial atypia (FEA), atypical ductal hyperplasia (ADH), and ductal carcinoma in situ (DCIS)] to invasive ductal carcinoma (IDC). We performed MethyLight analysis for the methylation status of 57 promoter CpG island loci in 20 IDCs and their paired normal breast tissues. After selecting 15 CpG island loci showing breast cancer-specific DNA methylation, another set of normal breast tissue (n = 10), ADH/FEA (n = 30), DCIS (n = 35), and IDC (n = 30) of the breast were analyzed for these loci. We found six new methylation markers of breast cancer, namely DLEC1, GRIN2B, HOXA1, MT1G, SFRP4, and TMEFF2, in addition to APC, GSTP1, HOXA10, IGF2, RARB, RASSF1A, RUNX3, SCGB3A1 (HIN-1), and SFRP1. The number of methylated genes increased stepwise from normal breast to ADH/FEA and DCIS, while IDC did not differ from DCIS. Methylation levels and frequencies of APC, DLEC1, HOXA1, and RASSF1A promoter CpG islands were significantly higher in ADH/FEA than in normal breast tissue. GRIN2B, GSTP1, HOXA1, RARB, RUNX3, SFRP1, and TMEFF2 showed higher methylation levels and frequencies in DCIS than in ADH/FEA. DICS and IDC did not differ in the methylation levels or frequencies for most CpG island loci except SFRP1 and HOXA10. Our findings showed that promoter CpG island methylation changed significantly in pre-invasive lesions, and was similar in IDC and DCIS, suggesting that CpG island methylation of tumor-related genes is an early event in breast cancer progression.
Department of Pathology, Seoul National University College of Medicine, 28 Yongon-dong, Chongno-gu, Seoul, 110-744, South Korea.
So Yeon
SY
Park
Hyeong Ju
HJ
Kwon
Hee Eun
HE
Lee
Han Suk
HS
Ryu
Sung-Won
SW
Kim
Jee Hyun
JH
Kim
In Ah
IA
Kim
Namhee
N
Jung
Nam-Yun
NY
Cho
Gyeong Hoon
GH
Kang
D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000378:metabolism; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D018270:Carcinoma, Ductal, Breast / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002285:Carcinoma, Intraductal, Noninfiltrating / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D018899:CpG Islands / Q000235:genetics*; D019175:DNA Methylation / Q000235:genetics / Q000502:physiology*; D004273:DNA, Neoplasm / Q000235:genetics / Q000378:metabolism*; D018450:Disease Progression; D005260:Female; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D006965:Hyperplasia / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008565:Membrane Proteins / Q000378:metabolism; D008668:Metallothionein / Q000378:metabolism; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D012189:Retrospective Studies; D014157:Transcription Factors / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D000099261:Homeobox A1 Protein; D000094742:Secreted Frizzled-Related Proteins
D014408:Biomarkers, Tumor; D004273:DNA, Neoplasm; D018398:Homeodomain Proteins; D008565:Membrane Proteins; D008668:Metallothionein; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; D016194:Receptors, N-Methyl-D-Aspartate; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D000099261:Homeobox A1 Protein; C119064:DLEC1 protein, human; C499629:MT1G protein, human; C121001:NR2B NMDA receptor; C118723:SFRP4 protein, human; D000094742:Secreted Frizzled-Related Proteins; C423567:TMEFF2 protein, human