Follicular Lymphomas with and without Translocation t(14;18) Differ in Gene Expression Profiles and Genetic Alterations.

Abstract

Follicular lymphoma (FL) is a B-cell non-Hodgkin lymphoma that is characterized in approximately 85% of cases by the chromosomal translocation t(14;18) involving BCL2. While FL3b generally lack the t(14;18), this translocation is also absent in 15% of FL grades 1, 2 and 3a. The current study was designed to identify the frequency of t(14;18)-negative FL in a series of 166 cases of FL1, 2 and 3a in which global gene expression profiles had been established previously (Dave et al., NEJM 351:2159–69, 2004). Furthermore, we sought to compare genetic alterations and gene expression profiles between FL with and without the t(14;18). Combined polymerase chain reaction (PCR) and tissue microarray-based fluorescence in situ hybridization (FISH) identified 17 t(14;18)-negative FL cases in this series (9%). Virtually all FL cases carrying the t(14;18) showed BCL2 expression by immunohistochemistry (Dako, clone 124), whereas 11 of the FL cases without a t(14;18) were BCL2-negative at the protein level. Clinically, there was no difference between the t(14;18)-negative and -positive FL subgroups regarding age and gender distribution as well as in median survival times. Comparative genomic hybridization (CGH) in the 166 FL cases revealed a characteristic pattern of chromosomal gains and losses, as previously described. However, significant differences were observed between the t(14;18)-negative and -positive FL subgroups. Specifically, the t(14;18)-positive FL subgroup showed gains of chromosomes 18q (18%), 8q (12%) and X (13%), as well as losses of 13q (16%) and 10q (16%), whereas none of these aberrations were observed in the t(14;18)-negative FL cases. To compare gene expression between the two groups, we used gene set enrichment analysis (GSEA), BRB array tools and a two-sided t-test. Cell cycle-associated genes were found to be enriched in the t(14;18)-negative FL subset. These differences were even more pronounced in FL cases that lacked both the t(14;18) and BCL2 expression at the protein level. Importantly, genes expressed in non-malignant bystander cells appeared also differentially enriched and a cytotoxic gene expression signature was found to be more prominent in t(14;18)-negative FL. These findings point to a different composition of the non-neoplastic cells in t(14;18)-positive and -negative FL and could indicate subtle differences in the immunological microenvironment of t(14;18)-negative FL.