Abstract
Adjuvant therapy of stage IIB/III melanoma with interferon reduces relapse and mortality by up to 33% but is accompanied by toxicity-related complications. Polymorphisms of the CTLA-4 gene associated with autoimmune diseases could help in identifying interferon treatment benefits. We previously genotyped 286 melanoma patients and 288 healthy (unrelated) individuals for six CTLA-4 polymorphisms (SNP). Previous analyses found no significant differences between the distributions of CTLA-4 polymorphisms in the melanoma population vs. controls, no significant difference in relapse free and overall survivals among patients and no correlation between autoimmunity and specific alleles. We report new analysis of these CTLA-4 genetic profiles, using Network Phenotyping Strategy (NPS). It is graph-theory based method, analyzing the SNP patterns. Application of NPS on CTLA-4 polymorphism captures allele relationship pattern for every patient into 6-partite mathematical graph P. Graphs P are combined into weighted 6-partite graph S, which subsequently decomposed into reference relationship profiles (RRP). Finally, every individual CTLA-4 genotype pattern is characterized by the graph distances of P from eight identified RRP's. RRP's are subgraphs of S, collecting equally frequent binary allele co-occurrences in all studied loci. If S topology represents the genetic “dominant model”, the RRP's and their characteristic frequencies are identical to expectation-maximization derived haplotypes and maximal likelihood estimates of their frequencies. The graph-representation allows showing that patient CTLA-4 haplotypes are uniquely different from the controls by absence of specific SNP combinations. New function-related insight is derived when the 6-partite graph reflects allelic state of CTLA-4. We found that we can use differences between individual P and specific RRPs to identify patient subpopulations with clearly different polymorphic patterns relatively to controls as well as to identify patients with significantly different survival.
Highlights
Adjuvant therapy of patients with stage IIB/III melanoma with interferon was approved by FDA (United States Food and Drug administration) and subsequently by regulatory authorities worldwide [1]
CT 318 is located within the promoter region of the CTLA-4 gene, A/G49 is located at exon 1, while the rest of the SNPs tested are located at the 39 untranslated region of CTLA-4
A unique feature of this approach in comparison to the analysis of differences in haplotype frequencies that were tested in our previous paper is that we can quantitatively characterize the difference of the individual genotype profile from ‘‘averaged’’ CTLA-4 haplotype profiles
Summary
Adjuvant therapy of patients with stage IIB/III melanoma (high-risk) with interferon was approved by FDA (United States Food and Drug administration) and subsequently by regulatory authorities worldwide [1]. Attempts to identify the subset of patients destined to benefit from adjuvant treatment with IFNa-2b have failed to discover clinical or demographic features of the patient population that are capable of predicting the benefit from high dose interferon (HDI) therapy. Correlative studies have been undertaken over the years, demonstrating a variety of immunological responses subsequent to therapy [5,6]. We recently published a paper in which six CTLA-4 polymorphisms were evaluated in a cohort of patients treated with adjuvant interferon [7]. The human CTLA-4 gene is located on chromosome 2q33, in a region that is associated with susceptibility for autoimmune disease [8] and multiple polymorphisms of the CTLA-4 gene have been found to be associated with susceptibility to autoimmune diseases (e.g. the GG allele of the +49 AG polymorphism is associated with decreased expression of CTLA-4 upon T-cell activation and a higher proliferation of T-cells) [9,10,11,12]
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