Comprehensive DNA Methylation Analysis Reveals a Common Ten-Gene Methylation Signature in Colorectal Adenomas and Carcinomas

被引：40

作者：

Patai, Arpad V. ^{[1
]}

Valcz, Gabor ^{[2
]}

Hollosi, Peter ^{[3
,4
]}

Kalmar, Alexandra ^{[1
]}

Peterfia, Balint ^{[2
]}

Patai, Arpad ^{[5
]}

Wichmann, Barnabas ^{[2
]}

Spisak, Sandor ^{[2
,6
]}

Bartak, Barbara Kinga ^{[1
]}

Leiszter, Katalin ^{[1
]}

Toth, Kinga ^{[1
]}

Sipos, Ferenc ^{[1
]}

Kovalszky, Ilona ^{[3
]}

Peter, Zoltan ^{[1
]}

Miheller, Pal ^{[1
]}

Tulassay, Zsolt ^{[1
,2
]}

Molnar, Bela ^{[1
,2
]}

机构：

[1] Semmelweis Univ, Dept Med 2, H-1085 Budapest, Hungary

[2] Hungarian Acad Sci, Mol Med Res Grp, Budapest, Hungary

[3] Semmelweis Univ, Dept Pathol & Expt Canc Res 1, H-1085 Budapest, Hungary

[4] Hungarian Acad Sci, Tumor Progress Res Grp, Budapest, Hungary

[5] Markusovszky Univ Teaching Hosp, Dept Gastroenterol & Med, Szombathely, Hungary

[6] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA

来源：

PLOS ONE | 2015年 / 10卷 / 08期

基金：

匈牙利科学研究基金会;

关键词：

FREQUENT EPIGENETIC INACTIVATION; CANCER; GENE; COLON; MARKER; HYPERMETHYLATION; IDENTIFICATION; PROGRESSION; MUTATIONS; PHENOTYPE;

D O I：

10.1371/journal.pone.0133836

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：19