Identification and analysis of an early diagnostic marker for malignant melanoma: ZAR1 intra-genic differential methylation.
BACKGROUND
Epigenetic changes such as aberrant DNA methylation and histone modification have been shown to play an important role in the tumorigenesis of malignant melanoma.


OBJECTIVE
To identify novel tumor-specific differentially methylated regions (DMRs) in human malignant melanoma.


METHODS
The aberrant methylation at 14 candidate human genomic regions identified through a mouse model study with quantitative DNA methylation analysis using the Sequenom MassARRAY system was performed.


RESULTS
The CpG island Exon 1 region of the Zygote arrest 1 (ZAR1) gene, which is responsible for oocyte-to-embryo transition, showed frequent aberrant methylation of 28 out of 30 (93%) melanoma surgical specimens, 16 of 17 (94%) melanoma cell lines, 0% of 4 normal human epidermal melanocyte (NHEM) cell lines, 0% of 10 melanocytic nevi and 100% of 51 various cancer cell lines. According to the real-time RT-PCR, the ZAR1 gene was overexpressed in part of the hypermethylated cell lines, while its low expression with bivalent histone methylation status was seen in unmethylated cell lines.


CONCLUSIONS
Our findings suggest that the ZAR1 intra-genic differentially methylated region would be a useful tumor marker for malignant melanoma and may be other type of cancers. The involvement of ZAR1 in the carcinogenesis of melanoma, still remains unclear, although we have examined tumorigenic capacities by exogenous full-length ZAR1 over-expression and siRNA knock-down experiments.
Shinojima
Yui
Y
Division of Cutaneous Science, Department of Dermatology, Nihon University Graduate School of Medicine, Tokyo 173-8610, Japan.
Terui
Tadashi
T
Hara
Hiroyuki
H
Kimura
Makoto
M
Igarashi
Jun
J
Wang
Xiaofei
X
Kawashima
Hiroyuki
H
Kobayashi
Yujin
Y
Muroi
Satomi
S
Hayakawa
Satoshi
S
Esumi
Mariko
M
Fujiwara
Kyoko
K
Ghosh
Srimoyee
S
Yamamoto
Tatsuo
T
Held
William
W
Nagase
Hiroki
H
D015127:9,10-Dimethyl-1,2-benzanthracene / Q000009:adverse effects; D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism*; D002460:Cell Line; D045744:Cell Line, Tumor; D019175:DNA Methylation; D003937:Diagnosis, Differential; D004527:Egg Proteins / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D006801:Humans; D008544:Melanocytes / Q000378:metabolism / Q000473:pathology; D008545:Melanoma / Q000175:diagnosis / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009506:Nevus / Q000175:diagnosis / Q000378:metabolism / Q000473:pathology; D012878:Skin Neoplasms / Q000175:diagnosis / Q000378:metabolism* / Q000473:pathology
D014408:Biomarkers, Tumor; D004527:Egg Proteins; D006657:Histones; C471631:Zar1 protein, human; D015127:9,10-Dimethyl-1,2-benzanthracene