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


METHODS
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.


CONCLUSIONS
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.
Department of Transfusion Medicine, Clinical Center and Trans-NIH Center for Human Immunology, National Institutes of Health, Bethesda, Maryland, United States of America.
Ena
E
Wang
Yingdong
Y
Zhao
Alessandro
A
Monaco
Lorenzo
L
Uccellini
John M
JM
Kirkwood
Maria
M
Spyropoulou-Vlachou
Monica C
MC
Panelli
Francesco M
FM
Marincola
Helen
H
Gogas
D000970:Antineoplastic Agents / Q000627:therapeutic use; D060908:CTLA-4 Antigen / Q000235:genetics; D017024:Chemotherapy, Adjuvant; D051858:Forkhead Transcription Factors / Q000235:genetics; D014644:Genetic Variation; D005838:Genotype; D006680:HLA Antigens / Q000235:genetics; D006801:Humans; D016898:Interferon-alpha / Q000627:therapeutic use; D008545:Melanoma / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality* / Q000473:pathology; D015233:Models, Statistical; D009367:Neoplasm Staging; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis
D000970:Antineoplastic Agents; D060908:CTLA-4 Antigen; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D006680:HLA Antigens; D016898:Interferon-alpha