IRF5 gene polymorphisms in melanoma.
BACKGROUND
Interferon regulatory factor (IRF)-5 is a transcription factor involved in type I interferon signaling whose germ line variants have been associated with autoimmune pathogenesis. Since relationships have been observed between development of autoimmunity and responsiveness of melanoma to several types of immunotherapy, we tested whether polymorphisms of IRF5 are associated with responsiveness of melanoma to adoptive therapy with tumor infiltrating lymphocytes (TILs).


METHODS
140 TILs were genotyped for four single nucleotide polymorphisms (rs10954213, rs11770589, rs6953165, rs2004640) and one insertion-deletion in the IRF5 gene by sequencing. Gene-expression profile of the TILs, 112 parental melanoma metastases (MM) and 9 cell lines derived from some metastases were assessed by Affymetrix Human Gene ST 1.0 array.


RESULTS
Lack of A allele in rs10954213 (G > A) was associated with non-response (p < 0.005). Other polymorphisms in strong linkage disequilibrium with rs10954213 demonstrated similar trends. Genes differentially expressed in vitro between cell lines carrying or not the A allele could be applied to the transcriptional profile of 112 melanoma metastases to predict their responsiveness to therapy, suggesting that IRF5 genotype may influence immune responsiveness by affecting the intrinsic biology of melanoma.


CONCLUSIONS
This study is the first to analyze associations between melanoma immune responsiveness and IRF5 polymorphism. The results support a common genetic basis which may underline the development of autoimmunity and melanoma immune responsiveness.
Infectious Disease and Immunogenetics Section, Department of Transfusion Medicine, Clinical Center and trans-NIH Center for Human Immunology, National Institutes of Health, Bethesda, MD 20892, USA. uccellinilorenzo@gmail.com
Lorenzo
L
Uccellini
Valeria
V
De Giorgi
Yingdong
Y
Zhao
Barbara
B
Tumaini
Narnygerel
N
Erdenebileg
Mark E
ME
Dudley
Sara
S
Tomei
Davide
D
Bedognetti
Maria Libera
ML
Ascierto
Qiuzhen
Q
Liu
Richard
R
Simon
Leah
L
Kottyan
Kenneth M
KM
Kaufman
John B
JB
Harley
Ena
E
Wang
Steven A
SA
Rosenberg
Francesco M
FM
Marincola
D001483:Base Sequence; D017931:DNA Primers; D020869:Gene Expression Profiling; D006801:Humans; D050835:Interferon Regulatory Factors / Q000235:genetics*; D008545:Melanoma / Q000235:genetics* / Q000473:pathology; D009362:Neoplasm Metastasis; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide
D017931:DNA Primers; C431713:IRF5 protein, human; D050835:Interferon Regulatory Factors