title: CpG island methylator phenotype predicts progression of malignant melanoma.
abstract: 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.
authors.affiliation: Department of Molecular Oncology, John Wayne Cancer Institute, Saint John's Health Center, Santa Monica, California 90404, USA.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Tanemura
authors.forename: Alicia M
authors.initials: AM
authors.lastname: Terando
authors.forename: Myung-Shin
authors.initials: MS
authors.lastname: Sim
authors.forename: Anneke Q
authors.initials: AQ
authors.lastname: van Hoesel
authors.forename: Michiel F G
authors.initials: MF
authors.lastname: de Maat
authors.forename: Donald L
authors.initials: DL
authors.lastname: Morton
authors.forename: Dave S B
authors.initials: DS
authors.lastname: Hoon
mesh_terms: 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
chemical_list: D014408:Biomarkers, Tumor