Identification of GABRA1 and LAMA2 as new DNA methylation markers in             colorectal cancer.
Aberrant methylation of CpG islands in the promoter region of genes is a             common epigenetic phenomenon found in early cancers. Therefore conducting genome-scale             methylation studies will enhance our understanding of the epigenetic etiology             behind carcinogenesis by providing reliable biomarkers for early detection of             cancer. To discover novel hypermethylated genes in colorectal cancer by genome-wide             search, we first defined a subset of genes epigenetically reactivated in colon             cancer cells after treatment with a demethylating agent. Next, we identified another             subset of genes with relatively down-regulated expression patterns in colorectal             primary tumors when compared with normal appearing-adjacent regions. Among 29 genes             obtained by cross-comparison of the two gene-sets, we subsequently selected, through             stepwise subtraction processes, two novel genes, GABRA1 and LAMA2, as methylation             targets in colorectal cancer. For clinical validation pyrosequencing was used             to assess methylation in 134 matched tissue samples from CRC patients. Aberrant             methylation at target CpG sites in GABRA1 and LAMA2 was observed with high frequency             in tumor tissues (92.5% and 80.6%, respectively), while less frequently in matched             tumor-adjacent normal tissues (33.6% for GABRA1 and 13.4% for LAMA2). Methylation             levels in primary tumors were not significantly correlated with clinico-pathological             features including age, sex, survival and TNM stage. Additionally, we found that             ectopic overexpression of GABRA1 in colon cancer cell lines resulted in strong             inhibition of cell growth. These results suggest that two novel hypermethylated             genes in colorectal cancer, GABRA1 and LAMA2, may have roles in colorectal tumorigenesis             and could be potential biomarkers for the screening and the detection of colorectal             cancer in clinical practice.
Genomictree Inc., Daejeon, Republic of Korea.
Sunwoo
S
Lee
Taejeong
T
Oh
Hyuncheol
H
Chung
Sunyoung
S
Rha
Changjin
C
Kim
Youngho
Y
Moon
Benjamin D
BD
Hoehn
Dongjun
D
Jeong
Seunghoon
S
Lee
Namkyu
N
Kim
Chanhee
C
Park
Miae
M
Yoo
Sungwhan
S
An
D014408:Biomarkers, Tumor / Q000235:genetics*; D018938:Caco-2 Cells; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000473:pathology; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology; D018899:CpG Islands; D019175:DNA Methylation; D015536:Down-Regulation; D057890:Epigenomics / Q000379:methods; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D045325:HCT116 Cells; D006801:Humans; D007797:Laminin / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D011963:Receptors, GABA-A / Q000235:genetics*
D014408:Biomarkers, Tumor; C546240:GABRA1 protein, human; D007797:Laminin; D011963:Receptors, GABA-A; C102645:laminin alpha 2