title: Association of circulating tumor cells with serum tumor-related methylated DNA in peripheral blood of melanoma patients.
abstract: Although previous studies have separately shown the utility of circulating tumor cells (CTC) or cell-free tumor-related DNA in blood of cancer patients, there has been no investigation of their association and/or the prognostic value of combining these assessments. To date, the true source of tumor-related DNA in serum remains unknown. We hypothesized that CTC is a possible origin of serum tumor-related methylated DNA and their combination can predict disease outcome. To test this hypothesis, we obtained matched pairs of peripheral blood lymphocytes and serum specimens simultaneously from 50 American Joint Committee on Cancer stage IV melanoma patients before administration of biochemotherapy. Peripheral blood leukocytes were analyzed for three mRNA markers of CTC: MART-1, GalNAc-T, and MAGE-A3. Sera were analyzed for two methylated DNA markers: RASSF1A and RAR-beta2. CTC were detected in 13 of 15 (86%) patients with serum tumor-related methylated DNA and only in 13 of 35 (37%) patients without methylated DNA (P = 0.001). The number of CTC markers detected significantly correlated with methylated DNA (P = 0.008). CTC and methylated DNA were significantly correlated with biochemotherapy-treated patients' outcome. Patients with both CTC and methylated DNA showed significantly poorer response to biochemotherapy (P = 0.02) and worse time to progression and overall survival (P = 0.009 and 0.02, respectively). The correlation between CTC and serum tumor-related methylated DNA and the significant effect of this correlation on disease outcome indicate that a composite molecular assessment in blood may be a useful determinant of disease status and efficacy of systemic therapy for melanoma.
authors.affiliation: Department of Molecular Oncology, John Wayne Cancer Institute at Saint John's Health Center, CA 90404, USA.
authors.forename: Kazuo
authors.initials: K
authors.lastname: Koyanagi
authors.forename: Takuji
authors.initials: T
authors.lastname: Mori
authors.forename: Steven J
authors.initials: SJ
authors.lastname: O'Day
authors.forename: Steve R
authors.initials: SR
authors.lastname: Martinez
authors.forename: He-Jing
authors.initials: HJ
authors.lastname: Wang
authors.forename: Dave S B
authors.initials: DS
authors.lastname: Hoon
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000951:Antigens, Neoplasm / Q000097:blood / Q000235:genetics; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000097:blood*; D005260:Female; D006801:Humans; D058965:MART-1 Antigen; D008297:Male; D008545:Melanoma / Q000097:blood* / Q000235:genetics / Q000473:pathology; D008875:Middle Aged; D017350:N-Acetylgalactosaminyltransferases / Q000235:genetics; D009363:Neoplasm Proteins / Q000097:blood / Q000235:genetics; D009367:Neoplasm Staging; D009360:Neoplastic Cells, Circulating; D012333:RNA, Messenger / Q000097:blood / Q000235:genetics
chemical_list: D000951:Antigens, Neoplasm; D004273:DNA, Neoplasm; C072013:MAGEA3 protein, human; D058965:MART-1 Antigen; C548667:MLANA protein, human; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D017350:N-Acetylgalactosaminyltransferases; C023220:(N-acetylneuraminyl)-galactosylglucosylceramide N-acetylgalactosaminyltransferase