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

Wang E, Zhao Y, Monaco A, Uccellini L, Kirkwood JM, Spyropoulou-Vlachou M, Panelli MC, Marincola FM, Gogas H - PLoS ONE (2012)

Bottom Line: 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.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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Transfusion Medicine, Clinical Center and Trans-NIH Center for Human Immunology, National Institutes of Health, Bethesda, Maryland, United States of America.

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.

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Related in: MedlinePlus

LOOCV Kaplan-Meier and Time-dependent ROC curves.A prognostic index for a patient with a specific genotyping profile were calculated as the weighted average (weighted as regression coefficient) of the five-marker genotypes. LOOCV Kaplan-Meier curve (Figure 2 A) identified 90 patients (22 deaths) in the low risk group (green line) and 194 (78 deaths) in the high risk group (red line). Time-dependent ROC curves showed that the AUCs at 5 and 7 year were 0.645 and 0.720, respectively (Figure 2B, 7 year survival ROC curve).
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pone-0040805-g002: LOOCV Kaplan-Meier and Time-dependent ROC curves.A prognostic index for a patient with a specific genotyping profile were calculated as the weighted average (weighted as regression coefficient) of the five-marker genotypes. LOOCV Kaplan-Meier curve (Figure 2 A) identified 90 patients (22 deaths) in the low risk group (green line) and 194 (78 deaths) in the high risk group (red line). Time-dependent ROC curves showed that the AUCs at 5 and 7 year were 0.645 and 0.720, respectively (Figure 2B, 7 year survival ROC curve).

Mentions: LOOCV Kaplan-Meier curve (Figure 2 A) identified 90 patients (22 deaths) in the low risk group and 194 (78 deaths) in the high risk group. The median OS of the low risk group has not yet been reached, while it was 68.2 months in the high risk group (log rank test p = 0.0026). The permutation p-value was 0.04 (500 permutations) indicating that the association of genotyping with OS was statistically significant. Time-dependent ROC curves showed that the AUCs at 5 and 7 year were 0.645 and 0.72, respectively (Figure 2B, 7 year survival ROC curve).


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

Wang E, Zhao Y, Monaco A, Uccellini L, Kirkwood JM, Spyropoulou-Vlachou M, Panelli MC, Marincola FM, Gogas H - PLoS ONE (2012)

LOOCV Kaplan-Meier and Time-dependent ROC curves.A prognostic index for a patient with a specific genotyping profile were calculated as the weighted average (weighted as regression coefficient) of the five-marker genotypes. LOOCV Kaplan-Meier curve (Figure 2 A) identified 90 patients (22 deaths) in the low risk group (green line) and 194 (78 deaths) in the high risk group (red line). Time-dependent ROC curves showed that the AUCs at 5 and 7 year were 0.645 and 0.720, respectively (Figure 2B, 7 year survival ROC curve).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3404079&req=5

pone-0040805-g002: LOOCV Kaplan-Meier and Time-dependent ROC curves.A prognostic index for a patient with a specific genotyping profile were calculated as the weighted average (weighted as regression coefficient) of the five-marker genotypes. LOOCV Kaplan-Meier curve (Figure 2 A) identified 90 patients (22 deaths) in the low risk group (green line) and 194 (78 deaths) in the high risk group (red line). Time-dependent ROC curves showed that the AUCs at 5 and 7 year were 0.645 and 0.720, respectively (Figure 2B, 7 year survival ROC curve).
Mentions: LOOCV Kaplan-Meier curve (Figure 2 A) identified 90 patients (22 deaths) in the low risk group and 194 (78 deaths) in the high risk group. The median OS of the low risk group has not yet been reached, while it was 68.2 months in the high risk group (log rank test p = 0.0026). The permutation p-value was 0.04 (500 permutations) indicating that the association of genotyping with OS was statistically significant. Time-dependent ROC curves showed that the AUCs at 5 and 7 year were 0.645 and 0.72, respectively (Figure 2B, 7 year survival ROC curve).

Bottom Line: 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.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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Transfusion Medicine, Clinical Center and Trans-NIH Center for Human Immunology, National Institutes of Health, Bethesda, Maryland, United States of America.

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.

Show MeSH
Related in: MedlinePlus