Comprehensive DNA Methylation Analysis Reveals a Common Ten-Gene Methylation Signature in Colorectal Adenomas and Carcinomas.
Microarray analysis of promoter hypermethylation provides insight into the role and extent of DNA methylation in the development of colorectal cancer (CRC) and may be co-monitored with the appearance of driver mutations. Colonic biopsy samples were obtained endoscopically from 10 normal, 23 adenoma (17 low-grade (LGD) and 6 high-grade dysplasia (HGD)), and 8 ulcerative colitis (UC) patients (4 active and 4 inactive). CRC samples were obtained from 24 patients (17 primary, 7 metastatic (MCRC)), 7 of them with synchronous LGD. Field effects were analyzed in tissues 1 cm (n = 5) and 10 cm (n = 5) from the margin of CRC. Tissue materials were studied for DNA methylation status using a 96 gene panel and for KRAS and BRAF mutations. Expression levels were assayed using whole genomic mRNA arrays. SFRP1 was further examined by immunohistochemistry. HT29 cells were treated with 5-aza-2' deoxycytidine to analyze the reversal possibility of DNA methylation. More than 85% of tumor samples showed hypermethylation in 10 genes (SFRP1, SST, BNC1, MAL, SLIT2, SFRP2, SLIT3, ALDH1A3, TMEFF2, WIF1), whereas the frequency of examined mutations were below 25%. These genes distinguished precancerous and cancerous lesions from inflamed and healthy tissue. The mRNA alterations that might be caused by systematic methylation could be partly reversed by demethylation treatment. Systematic changes in methylation patterns were observed early in CRC carcinogenesis, occuring in precursor lesions and CRC. Thus we conclude that DNA hypermethylation is an early and systematic event in colorectal carcinogenesis, and it could be potentially reversed by systematic demethylation therapy, but it would need more in vitro and in vivo experiments to support this theory.
2nd Department of Medicine, Semmelweis University, Budapest, Hungary.
Árpád V
ÁV
Patai
Molecular Medicine Research Group, Hungarian Academy of Sciences, Budapest, Hungary.
Gábor
G
Valcz
1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary; Tumor Progression Research Group, Hungarian Academy of Sciences, Budapest, Hungary.
Péter
P
Hollósi
2nd Department of Medicine, Semmelweis University, Budapest, Hungary.
Alexandra
A
Kalmár
Molecular Medicine Research Group, Hungarian Academy of Sciences, Budapest, Hungary.
Bálint
B
Péterfia
Department of Gastroenterology and Medicine, Markusovszky University Teaching Hospital, Szombathely, Hungary.
Árpád
Á
Patai
Molecular Medicine Research Group, Hungarian Academy of Sciences, Budapest, Hungary.
Barnabás
B
Wichmann
Molecular Medicine Research Group, Hungarian Academy of Sciences, Budapest, Hungary; Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, United States of America.
Sándor
S
Spisák
2nd Department of Medicine, Semmelweis University, Budapest, Hungary.
Barbara Kinga
BK
Barták
2nd Department of Medicine, Semmelweis University, Budapest, Hungary.
Katalin
K
Leiszter
2nd Department of Medicine, Semmelweis University, Budapest, Hungary.
Kinga
K
Tóth
2nd Department of Medicine, Semmelweis University, Budapest, Hungary.
Ferenc
F
Sipos
1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary.
Ilona
I
Kovalszky
2nd Department of Medicine, Semmelweis University, Budapest, Hungary.
Zoltán
Z
Péter
2nd Department of Medicine, Semmelweis University, Budapest, Hungary.
Pál
P
Miheller
2nd Department of Medicine, Semmelweis University, Budapest, Hungary; Molecular Medicine Research Group, Hungarian Academy of Sciences, Budapest, Hungary.
Zsolt
Z
Tulassay
2nd Department of Medicine, Semmelweis University, Budapest, Hungary; Molecular Medicine Research Group, Hungarian Academy of Sciences, Budapest, Hungary.
Béla
B
Molnár
D000236:Adenoma / Q000235:genetics*; D000293:Adolescent; D002277:Carcinoma / Q000235:genetics*; D045744:Cell Line, Tumor; D003093:Colitis, Ulcerative / Q000235:genetics; D015179:Colorectal Neoplasms / Q000235:genetics*; D019175:DNA Methylation / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D019073:HT29 Cells; D006801:Humans; D009154:Mutation / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D059467:Transcriptome / Q000235:genetics*
D012333:RNA, Messenger