CpG island methylator phenotype predicts progression of malignant melanoma.
OBJECTIVE
The CpG island methylator phenotype (CIMP) may be associated with development of malignancy through coordinated inactivation of tumor suppressor and tumor-related genes (TRG) and methylation of multiple noncoding, methylated-in-tumor (MINT) loci. These epigenetic changes create a distinct CIMP pattern that has been linked to recurrence and survival in gastrointestinal cancers. Because epigenetic inactivation of TRGs also has been shown in malignant melanoma, we hypothesized the existence of a clinically significant CIMP in cutaneous melanoma progression.


METHODS
The methylation status of the CpG island promoter region of TRGs related to melanoma pathophysiology (WIF1, TFPI2, RASSF1A, RARbeta2, SOCS1, and GATA4) and a panel of MINT loci (MINT1, MINT2, MINT3, MINT12, MINT17, MINT25, and MINT31) in primary and metastatic tumors of different clinical stages (n=122) was assessed.


RESULTS
Here, we show an increase in hypermethylation of the TRGs WIF1, TFPI2, RASSF1A, and SOCS1 with advancing clinical tumor stage. Furthermore, we find a significant positive association between the methylation status of MINT17, MINT31, and TRGs. The methylation status of MINT31 is associated with disease outcome in stage III melanoma.


CONCLUSIONS
These findings show the significance of a CIMP pattern that is associated with advancing clinical stage of malignant melanoma. Future prospective large-scale studies may determine if CIMP-positive primary melanomas are at high risk of metastasis or recurrence.
Tanemura
Atsushi
A
Department of Molecular Oncology, John Wayne Cancer Institute, Saint John's Health Center, Santa Monica, California 90404, USA.
Terando
Alicia M
AM
Sim
Myung-Shin
MS
van Hoesel
Anneke Q
AQ
de Maat
Michiel F G
MF
Morton
Donald L
DL
Hoon
Dave S B
DS
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics*; D002478:Cells, Cultured; D002648:Child; D018899:CpG Islands / Q000235:genetics*; D019175:DNA Methylation; D020405:Dermis / Q000166:cytology / Q000378:metabolism; D018450:Disease Progression; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D016147:Genes, Tumor Suppressor; D006801:Humans; D008207:Lymphatic Metastasis; D008297:Male; D008544:Melanocytes / Q000378:metabolism / Q000473:pathology; D008545:Melanoma / Q000235:genetics* / Q000473:pathology; D008875:Middle Aged; D009367:Neoplasm Staging; D010641:Phenotype; D011379:Prognosis; D011401:Promoter Regions, Genetic; D012878:Skin Neoplasms / Q000235:genetics* / Q000556:secondary; D015996:Survival Rate; D055815:Young Adult
D014408:Biomarkers, Tumor