Chronic Lymphocytic Leukemia - Biology and Pathophysiology, Excluding Therapy Poster I
A Common Genetic Variant in the 3'UTR of IRF4/MUM1 Associates with Risk of Disease and Poor Prognosis in Chronic Lymphocytic Leukaemia.
James M Allan1,
Robert John Harris, PhD5,*,
Guy Pratt11 and
David J Allsup, MRCP., MRCPath., PhD.12,*
1 Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, United Kingdom, 2 Newcastle University, Newcastle upon Tyne, United Kingdom, 3 Royal Victoria Infirmary, Newcastle upon Tyne, United Kingdom, 4 Queen Elizabeth Hospital, Gateshead, United Kingdom, 5 Haematology, University of Liverpool, Liverpool, United Kingdom, 6 University of Liverpool, Liverpool, United Kingdom, 7 Institute of Cancer Research, Sutton, United Kingdom, 8 University of Hull, Hull, United Kingdom, 9 Cardiff University, Cardiff, United Kingdom, 10 Cardiff and Vale NHS Trust, Cardiff, United Kingdom, 11 Birmingham Heartlands Hospital, Birmingham, United Kingdom, 12 Department of Haematology, Hull Royal Infirmary, Hull, United Kingdom
High frequency low penetrance risk alleles for chronic lymphocyticleukaemia (CLL) have been identified at 6p25.3 (rs872071, IRF4/MUM1),11q24.1 (rs735665, GRAMD1B), 15q23 (rs7176508), 2q37.1 (rs13397985,SP140), 2q13 (rs17483466, ACOXL) and 19q13.32 (rs11083846, PRKD2).Given a role in determining risk of disease it is plausiblethat these allelic variants also play a role in disease progressionand overall survival. In order to test this hypothesis, polymorphicstatus was determined in a case series of 403 patients diagnosedwith CLL recruited via 5 clinical centres in the United Kingdom.Mean follow-up time was 4447 days and 169 patients were deceasedat the time of last follow-up. Kaplan-Meier survival analysisand the log-rank test were used to investigate the prognosticsignificance of constitutional genetic markers. Polymorphicvariation at rs735665, rs7176508, rs13397985, rs17483466 andrs11083846 was not significantly association with time fromdiagnosis to first treatment (p>0.05, log-rank test). However,a genetic variant in the 3'UTR of the interferon regulatoryfactor 4 (IRF4)/multiple myeloma oncogene 1 (MUM1) gene wassignificantly associated with poor prognosis. Specifically,carriers of the disease-associated variant at rs872071 had asignificantly shorter mean time from diagnosis to first treatment(3983 days), compared to non-carriers (7340 days)(p=0.001),although there was no significant difference in overall survival(p=0.29). The association with time to first treatment remainedsignificant in multivariate Cox regression analysis that includedage, gender, immunoglobulin heavy chain variable region mutationalstatus and stage of disease at diagnosis in the model (p=0.021).IRF4 is expressed in germinal centre (GC) and post-GC B-cells,and is important for B-cell maturation and homeostasis. Takentogether with the aetiological evidence, these data suggestthat common allelic variation in IRF4 not only affects riskof CLL, but also predicts poor prognosis.
Disclosures: No relevant conflicts of interest to declare.