A multi-factorial genetic model for prognostic assessment of high risk melanoma patients receiving adjuvant interferon

Ena Wang, Yingdong Zhao, Alessandro Monaco, Lorenzo Uccellini, John M. Kirkwood, Maria Spyropoulou-Vlachou, Monica C. Panelli, Francesco M. Marincola, Helen Gogas

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish
Article numbere40805
JournalPLoS One
Volume7
Issue number7
DOIs
Publication statusPublished - 24 Jul 2012
Externally publishedYes

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Bearings (structural)
Genetic Models
interferons
melanoma
HLA-B38 Antigen
Interferons
adjuvants
HLA-B44 Antigen
Melanoma
Genes
Polymorphism
Microsatellite Repeats
Design of experiments
Toxicity
Tumors
Cytokines
Survival
relapse
relative risk
Survival Analysis

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Wang, E., Zhao, Y., Monaco, A., Uccellini, L., Kirkwood, J. M., Spyropoulou-Vlachou, M., ... Gogas, H. (2012). A multi-factorial genetic model for prognostic assessment of high risk melanoma patients receiving adjuvant interferon. PLoS One, 7(7), [e40805]. https://doi.org/10.1371/journal.pone.0040805

A multi-factorial genetic model for prognostic assessment of high risk melanoma patients receiving adjuvant interferon. / Wang, Ena; Zhao, Yingdong; Monaco, Alessandro; Uccellini, Lorenzo; Kirkwood, John M.; Spyropoulou-Vlachou, Maria; Panelli, Monica C.; Marincola, Francesco M.; Gogas, Helen.

In: PLoS One, Vol. 7, No. 7, e40805, 24.07.2012.

Research output: Contribution to journalArticle

Wang, E, Zhao, Y, Monaco, A, Uccellini, L, Kirkwood, JM, Spyropoulou-Vlachou, M, Panelli, MC, Marincola, FM & Gogas, H 2012, 'A multi-factorial genetic model for prognostic assessment of high risk melanoma patients receiving adjuvant interferon', PLoS One, vol. 7, no. 7, e40805. https://doi.org/10.1371/journal.pone.0040805
Wang, Ena ; Zhao, Yingdong ; Monaco, Alessandro ; Uccellini, Lorenzo ; Kirkwood, John M. ; Spyropoulou-Vlachou, Maria ; Panelli, Monica C. ; Marincola, Francesco M. ; Gogas, Helen. / A multi-factorial genetic model for prognostic assessment of high risk melanoma patients receiving adjuvant interferon. In: PLoS One. 2012 ; Vol. 7, No. 7.
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