Molecular Prognostic Factors in Splenic Marginal Zone Lymphoma (SMZL): Correlation of Clinical Behavior with Immunoglobulin Heavy Chain (IgH) Somatic Mutation Status, Array Comparative Genomic Hybridization (aCGH) and Gene Expression Profiling (GEP)
DS Bosler, ED Remstein, E Braggio, WJ Chng, G Huang, SP Menon, RF McClure, R Fonseca, DX Sun, MJ Maurer, A Dogan. Mayo Clinic, Rochester, MN; National University Hospital, Singapore, Singapore
Background: Unmutated IgH status has been correlated with adverse outcome in SMZL. The aim of this study was to examine IgH variable (V) region usage, somatic mutation, GEP and aCGH in SMZL to analyze the relationships with clinical outcome.
Design: We studied 35 splenectomy confirmed SMZL cases. IgHV analysis was performed from RNA by reverse transcription, PCR and sequencing. Mutation status was scored for productive rearranged sequences (cutoff=98% homology) using the Immunogenetics (IMGT/V-QUEST) database. The Human Agilent 244A platform was used for aCGH analysis. GEP was performed using Affymetrix Human Genome U133 plus 2.0. Progression free survival (PFS) and overall survival (OS) were determined from review of medical records.
Results: IgH status: Of 31 cases with productive sequences, IgHV1-2*04 was utilized in 11, IgHV3-23*01 in 3, and 3-7*01, 1-69*01 and 4-34*01 each twice. Mean sequence homology was 96% (89.1-100%). There were 10 unmutated and 21 mutated. There was no association between IgHV usage and mutation status. GEP: Del7q correlated with hexokinase 2 expression and negatively correlated with UBE1L expression in unsupervised clustering analysis. aCGH: 91% of cases showed genetic imbalance, with a median total imbalance of 54.0 (0-782.4) Mb and a median of 4 (0-55) gains/losses. Nine of 35 had del7q. Clinical data/follow-up: Median age=67 years (42-85), 11 males : 24 females. Median follow-up for living patients was 56 months (11-152). 83% were alive at last follow-up, and 28% had progressed or recurred. Increased total genetic imbalance was associated with shorter PFS (per unit HR=1.006, 95% CI=1.002-1.01, p=.004) and OS (per unit HR=1.005, 95% CI=1.001-1.009, p=.02). Mutated IgHV status was associated with decreased total imbalance (p=.03), though association with PFS and OS was not significant (p=.35 and p=.24). There were no differences in PFS or OS by IgHV region or del7q status.
Conclusions: Frequency of IgHV1-2*04 (35%) and del7q (26%) are similar to previous studies. As increased total genetic imbalance showed the only significant association with shorter PFS and OS, quantification of genetic imbalances by aCGH may be a better marker of adverse outcome than IgHV region usage, mutation status, or del7q.
Tuesday, March 10, 2009 9:30 AM
Poster Session III # 136, Tuesday Morning