Follicular lymphomas with and without translocation t(14;18) differ in gene expression profiles and genetic alterations

Abstract

Follicular lymphoma (FL) is genetically characterized by the presence of the t(14;18)(q32;q21) chromosomal translocation in approximately 90% of cases. In contrast to FL carrying the t(14;18), their t(14;18)-negative counterparts are less well studied about their immunohistochemical, genetic, molecular, and clinical features. Within a previously published series of 184 FLs grades 1 to 3A with available gene expression data, we identified 17 FLs lacking the t(14;18). Comparative genomic hybridization and high-resolution single nucleotide polymorphism (SNP) array profiling showed that gains/amplifications of the BCL2 gene locus in 18q were restricted to the t(14;18)-positive FL subgroup. A comparison of gene expression profiles showed an enrichment of germinal center B cell-associated signatures in t(14;18)-positive FL, whereas activated B cell-like, NFkappaB, proliferation, and bystander cell signatures were enriched in t(14;18)-negative FL. These findings were confirmed by immunohistochemistry in an independent validation series of 84 FLs, in which 32% of t(14;18)-negative FLs showed weak or absent CD10 expression and 91% an increased Ki67 proliferation rate. Although overall survival did not differ between FL with and without t(14;18), our findings suggest distinct molecular features of t(14;18)-negative FL.

Figure 1

Comparative genomic hybridization in follicular lymphoma. (A) Chromosomal gains and losses in 127 FL cases showing altered karyotypes by comparative genomic hybridization (CGH). Gains are displayed in green bars and losses are displayed in red bars. (B) Selected genes that show up-regulation in follicular lymphoma (FL) with chromosomal gains in respective regions (1q, 2p, 7q, 8q, 12q and 18q) or down-regulation in FL with chromosomal losses in respective regions (6q, 10q).

Figure 2

Definition of FL subgroups with and without translocation t(14;18). 147 FLs showed evidence of the t(14;18) by PCR or FISH techniques, whereas 17 FLs were t(14;18)-negative. Within the t(14;18)-negative subgroup, 11 FLs were negative for BCL2 on the protein level, and 6 were positive, as determined by IHC.

Figure 3

Chromosomal gains and losses in FLs with and without translocation t(14;18) detected by CGH. (A) Gains (green bars) and losses (red bars) in t(14;18)-positive FL. (B) Gains and losses in t(14;18)-negative FL.

Figure 4

High-density SNP array profiling in t(14;18)-negative FL. Copy number gains (green bars) and losses (red bars) in 11 t(14;18)-negative FLs determined by high-resolution 250K SNP array analysis.

Figure 5

Immunohistochemistry in FLs with and without t(14;18). Representative stainings for CD10, IRF4/MUM1, Ki67, and Granzyme B (GRZMB) in FL grade 1/2 cases with t(14;18) (A, C, E, G) and without t(14;18) (B, D, F, H). (A-B) Images were captured at magnification ×200, and (C-H) at magnification ×400 with the use of an Olympus, Color View, BX50 microscope, the Color View digital camera, and the analysis work soft imaging system (all Olympus).