Abstract 4723: Common low penetrance allelic variants for chronic lymphocytic leukemia identified in a genome-wide association study also predict outcome

Abstract

Abstract B-cell chronic lymphocytic leukemia (CLL) is the most common lymphoid malignancy in the western world. Although strong evidence for an inherited susceptibility is provided by first-degree relatives of CLL patients having >5-fold increased risk of themselves developing CLL, the genetic basis of CLL predisposition is principally unknown. Low penetrance risk alleles for CLL have been identified at 11q24.1 (rs735665, GRAMD1B), 15q23 (rs7176508), 2q37.1 (rs13397985, SP140), 2q37.3 (rs757978, FARP2), 2q13 (rs17483466, ACOXL) and 6p25.3 (rs872071, IRF4). The strongest evidence for association was for a single nucleotide polymorphism (rs872071) in the 3′ UTR of the gene encoding the interferon regulatory factor-4 (IRF4) transcription factor. Given a role in determining risk of disease it is plausible that these allelic variants also play a role in disease progression and overall survival. To test this hypothesis, polymorphic status was determined in a large case series of 403 patients diagnosed with CLL recruited via 5 UK clinical centers, and correlated with established prognostic markers and clinical outcome. Variant IRF4 (defined by rs872071) predicts for a more aggressive disease course; carriers of the disease-associated allele at the IRF4 locus (G/G and G/A genotypes) had a significantly shorter treatment-free survival (TFS) compared to non-carriers (A/A genotype). The risk allele was also significantly associated with increased frequency of CD38-positive CLL. We have also examined IRF4 SNPs in linkage disequilbrium with rs872071 and these remain prognostically informative. IRF4 is expressed in germinal centre and post-germinal centre B-cells committed to plasma cell differentiation, and has a complex role in regulating B-cell maturation and homeostasis. Function of the rs870271 polymorphic variant remains undetermined, although given its location in the 3′UTR we speculate that it may affect gene expression, RNA stability or translation efficiency. The 3′ UTR of IRF4 includes several established and putative miRNA binding sites; at least two of these are bound by miRNAs giving rise to a reduction in IRF4 protein expression in germinal centre B-cells. In summary, this study identifies a common variant in IRF4, previously associated with increased risk of developing CLL, as a predictor of a more aggressive disease course and reduced time to first treatment. The strong association with CD38 expression and the identification of a putative IRF4 binding site in the CD38 gene immediately upstream of the transcriptional start site suggests a plausible mechanism by which IRF4 status could affect prognosis. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4723.