Array Comparative Genomic Hybridization (aCGH) Identifies Genetic Changes Exclusive to Chemotherapy-Refractory or Chemotherapy-Responsive Diffuse Large B-Cell Lymphomas
F Kreisel, S Kulkarni, R Kerns, H Deshmukh, R Nagarajan, A Hassan, J Frater, A Cashen. Washington University, Saint Louis, MO
Background: Despite recent attempts at sub-categorization, DLBCL remain biologically heterogenous tumors with no clear prognostic biomarkers to guide therapy. Gene expression profiling of untreated, de novo DLBCL into two main, prognostically different groups of “germinal center B-cell-type” and “activated B-cell-type”, has improved our understanding of their biology. However, even within these two prognostically different groups, clinical outcome is inconsistent. Our study utilizes array comparative genomic hybridization (aCGH) in assessing differences in gene expression profiles between chemotherapy-refractory and chemotherapy-responsive DLBCL.
Design: Whole genome aCGH was performed on 4 cases of chemoresistant DLBCL (chemorefractory or relapse within one year of treatment) and 4 cases of chemoresponsive DLBCL (no progression at least one year after treatment). Resulting DNA copy numbers were compared to a reference genome of a normal donor pool. All cases were then screened for genes of gained or lost DNA segments significant in 3 or 4 of the chemoresistant DLBCL samples, but not significant in the chemoresponsive DLBCL samples and vice versa. Genes were not filtered to remove genes that overlap published copy number variant regions.
Results: In the chemoresistant group loss of DNA segments encoding for the tumor suppressor genes CDKN2A and CDKN2B was observed as well as gain of segments encoding for the drug resistance gene ABCA3 and the 3p21.3 tumor-suppressor gene cluster (TUSC4, RASSF1, TUSC2, and ZMYND10). In the chemoresponsive group, gene amplifications were noted for the tumor suppressor gene RUNX3 and the MTHFR gene. MTHFR gene polymorphisms have been implicated in different response rates to 5-FU-based chemotherapy.
Conclusions: Whole genome aCGH analysis of chemoresistant and chemoresponsive DLBCL has provided gene amplifications and deletions exclusive to one or the other group that may represent consistent clonal changes predictive for prognosis and outcome of chemotherapy. Verification of these genomic alterations is being performed using independent techniques such as FISH or SNP assays. In summary, our findings represent a discovery set and longitudinal studies with more specimens are underway.
Wednesday, March 24, 2010 9:30 AM
Poster Session V # 172, Wednesday Morning