Τίτλος:
A multi-factorial genetic model for prognostic assessment of high risk melanoma patients receiving adjuvant interferon
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
Purpose: IFNa was the first cytokine to demonstrate anti-tumor activity in advanced melanoma. Despite the ability of high-dose IFNa reducing relapse and mortality by up to 33%, large majority of patients experience side effects and toxicity which outweigh the benefits. The current study attempts to identify genetic markers likely to be associated with benefit from IFN-a2b treatment and predictive for survival. Experimental design: We tested the association of variants in FOXP3 microsatellites, CTLA4 SNPs and HLA genotype in 284 melanoma patients and their association with prognosis and survival of melanoma patients who received IFNa adjuvant therapy. Results: Univariate survival analysis suggested that patients bearing either the DRB1*15 or HLA-Cw7 allele suffered worse OS while patients bearing either HLA-Cw6 or HLA-B44 enjoyed better OS. DRB1*15 positive patients suffered also worse RFS and conversely HLA-Cw6 positive patients had better RFS. Multivariate analysis revealed that a five-marker genotyping signature was prognostic of OS independent of disease stage. In the multivariate Cox regression model, HLA-B38 (p = 0.021), HLA-C15 (p = 0.025), HLA-C3 (p = 0.014), DRB1*15 (p = 0.005) and CT60*G/G (0.081) were significantly associated with OS with risk ratio of 0.097 (95% CI, 0.013-0.709), 0.387 (95% CI, 0.169-0.889), 0.449 (95% CI, 0.237-0.851), 1.948 (95% CI, 1.221-3.109) and 1.484 (95% IC, 0.953-2.312) respectively. Conclusion: These results suggest that gene polymorphisms relevant to a biological occurrence are more likely to be informative when studied in concert to address potential redundant or conflicting functions that may limit each gene individual contribution. The five markers identified here exemplify this concept though prospective validation in independent cohorts is needed.
Συγγραφείς:
Wang, E.
Zhao, Y.
Monaco, A.
Uccellini, L.
Kirkwood, J.M.
Spyropoulou-Vlachou, M.
Panelli, M.C.
Marincola, F.M.
Gogas, H.
Λέξεις-κλειδιά:
alpha2b interferon; cytotoxic T lymphocyte antigen 4; HLA B38 antigen; HLA B44 antigen; HLA DRB1 antigen; transcription factor FOXP3, article; cancer adjuvant therapy; cancer prognosis; cancer staging; CT60 gene; CTLA4 gene; cutaneous melanoma; distant metastasis free survival; FOXP3 gene; gene; genetic association; genetic marker; genetic polymorphism; genotype; HLA B38 gene; HLA B44 gene; HLA C15 gene; HLA C3 gene; HLA Cw6 gene; HLA Cw7 gene; HLA DRB1 gene; HLA gene; human; major clinical study; microsatellite marker; multicenter study (topic); overall survival; phase 3 clinical trial (topic); randomized controlled trial (topic); recurrence free survival; single nucleotide polymorphism, Antineoplastic Agents; Chemotherapy, Adjuvant; CTLA-4 Antigen; Forkhead Transcription Factors; Genetic Variation; Genotype; HLA Antigens; Humans; Interferon-alpha; Melanoma; Models, Statistical; Neoplasm Staging; Polymorphism, Single Nucleotide; Prognosis
DOI:
10.1371/journal.pone.0040805
