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., NEJM351:2159–69, 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.

Follicular lymphoma in Taiwan: a low frequency of t(14;18), with grade 3A tumours more closely related to grade 3B than to low‐grade tumours

“…These findings indicate that there are genuine genetic and clinicopathological differences between these two groups of morphologically similar tumours. 36,37 This is in line with the finding that the microRNA profile of IGH-BCL2 translocation-negative FL was distinct from that of translocation-positive cases, and supported a late germinal centre B-cell phenotype. 38 Studies with more cases, including a substantial number of translocation-negative ones, are needed to confirm whether there are phenotypic and survival differences between these two groups of LG FL.…”

CD5‐positive follicular lymphoma characterized by CD25, MUM1, low frequency of t(14;18) and poor prognosis

“…They suggested that FL without t(14;18)(q32;q21) and with MUM1 expression was composed of neoplastic B-cells in a late germinal center B-cell (GCB) stage of differentiation. 15,19 In the present study, six cases had MUM1 expression in ten cases lacked t(14;18)(q32;q21) among the 19 cases with CD5-positive FL for which, assessments of both t(14;18)(q32;q21) and MUM1 expression could be performed. On the other hand, only two cases had MUM1 expression in 14 cases lacking t(14;18)(q32;q21) among 58 control cases with both assessments.…”

Another look at follicular lymphoma: immunophenotypic and molecular analyses identify distinct follicular lymphoma subgroups

“…6,[35][36][37] In our series, the CD10-negative cases differed in their molecular and pathological characteristics ( Table 2) from those published by others. 32,33,35 FL lacking expression of both bcl-2 and CD10 is uncommon, the exception being primary cutaneous follicle centre cell lymphoma. 39 In the present study, the 12 identified bcl-2-negative and CD10-negative FLs (all with nodal localization and typical morphological characteristics) showed molecular similarities to the category of true bcl-2negative FL (i.e.…”