title: AIM1 and LINE-1 epigenetic aberrations in tumor and serum relate to melanoma progression and disease outcome.
abstract: Aberrations in the methylation status of noncoding genomic repeat DNA sequences and specific gene promoter region are important epigenetic events in melanoma progression. Promoter methylation status in long interspersed nucleotide element-1 (LINE-1) and absent in melanoma-1 (AIM1; 6q21) associated with melanoma progression and disease outcome was assessed. LINE-1 and AIM1 methylation status was assessed in paraffin-embedded archival tissue (PEAT; n = 133) and in melanoma patients' serum (n = 56). LINE-1 U-Index (hypomethylation) and AIM1 were analyzed in microdissected melanoma PEAT sections. The LINE-1 U-Index of melanoma (n = 100) was significantly higher than that of normal skin (n = 14) and nevi (n = 12; P = 0.0004). LINE-1 U-Index level was elevated with increasing American Joint Committee on Cancer (AJCC) stage (P<0.0001). AIM1 promoter hypermethylation was found in higher frequency (P = 0.005) in metastatic melanoma (65%) than in primary melanomas (38%). When analyzed, high LINE-1 U-Index and/or AIM1 methylation in melanomas were associated with disease-free survival (DFS) and overall survival (OS) in stage I/II patients (P = 0.017 and 0.027, respectively). In multivariate analysis, melanoma AIM1 methylation status was a significant prognostic factor of OS (P = 0.032). Furthermore, serum unmethylated LINE-1 was at higher levels in both stage III (n = 20) and stage IV (n = 36) patients compared with healthy donors (n = 14; P = 0.022). Circulating methylated AIM1 was detected in patients' serum and was predictive of OS in stage IV patients (P = 0.009). LINE-1 hypomethylation and AIM1 hypermethylation have prognostic utility in both melanoma patients' tumors and serum.
authors.affiliation: Department of Molecular Oncology, John Wayne Cancer Institute at Saint John's Health Center, Santa Monica, California 90404, USA.
authors.forename: Sojun
authors.initials: S
authors.lastname: Hoshimoto
authors.forename: Christine T
authors.initials: CT
authors.lastname: Kuo
authors.forename: Kelly K
authors.initials: KK
authors.lastname: Chong
authors.forename: Teh-Ling
authors.initials: TL
authors.lastname: Takeshima
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Takei
authors.forename: Michelle W
authors.initials: MW
authors.lastname: Li
authors.forename: Sharon K
authors.initials: SK
authors.lastname: Huang
authors.forename: Myung-Shin
authors.initials: MS
authors.lastname: Sim
authors.forename: Donald L
authors.initials: DL
authors.lastname: Morton
authors.forename: Dave S B
authors.initials: DS
authors.lastname: Hoon
mesh_terms: D014408:Biomarkers, Tumor / Q000097:blood / Q000235:genetics; D045744:Cell Line, Tumor; D003459:Crystallins / Q000097:blood / Q000235:genetics*; D019175:DNA Methylation / Q000235:genetics; D018450:Disease Progression; D044127:Epigenesis, Genetic / Q000235:genetics*; D006801:Humans; D053208:Kaplan-Meier Estimate; D020084:Long Interspersed Nucleotide Elements / Q000235:genetics*; D008545:Melanoma / Q000235:genetics* / Q000401:mortality / Q000556:secondary; D008565:Membrane Proteins / Q000097:blood / Q000235:genetics*; D016612:Paraffin Embedding; D011379:Prognosis; D012307:Risk Factors; D012878:Skin Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology
chemical_list: D014408:Biomarkers, Tumor; C105445:CRYBG1 protein, human; D003459:Crystallins; D008565:Membrane Proteins