These findings suggest that the der(3)t(3;18)(q27;q21) involving BCL2 and BCL6 had a crucial role in the pathogenesis of FL with t(3;14;18)(q27;q32;q21).
Three cases corresponded to FL with the minor breakpoint in the bcl-2 gene and these patients had a favorable clinical evolution, whereas the 4 patients with p53 mutations and the major breakpoint had a bad clinical outcome with morphologic transformation to high-grade lymphoma in three cases.
Rearrangement of the bcl-2 gene at the MBR (major breakpoint region) locus with the immunoglobulin heavy-chain joining region has been reported in a high proportion of follicular lymphomas.
Follicular lymphomas that lack a t(14;18) were segregated into two subgroups with distinct cytogenetic, phenotypic and possibly clinical features: one with BCL2 protein overexpression not related to an IGH/BCL2 rearrangement and a second without BCL2 overexpression.
Conventional cytogenetic or fluorescence in situ hybridization studies performed in 3 cases showed t(14;18)(q32;q21) or IGH-BCL2, supporting the diagnosis of FL.
The MCL1 gene, recently identified in a myeloid leukemia cell line, has sequence similarity to BCL2, the gene at the t(14;18) translocation in follicular lymphoma.
We therefore suggest that the relatively low incidence of FL in Asian populations is caused not by a lower frequency of bcl-2 rearrangements in healthy populations but by distinct molecular pathways developing in different geographic regions that nonetheless culminate in FL, which is morphologically similar but molecularly distinct.
The bcl-2 gene, encoding a mitochondrial membrane protein suggested to play an important role in cell survival, is translocated into the Ig loci in about 80% of human follicular lymphomas, which results in a high level of expression.
The nine patients with 5'BCL2 rearrangement included two with follicular lymphoma, four with diffuse large cell lymphoma and immunoblastic variant, two with leukemic phase of follicular lymphoma, and one with CLL.
The hallmark t(14;18)(q32;q21) in follicular lymphoma (FL) results in constitutive overexpression of the BCL2 protein, allowing B cells to abrogate the default germinal center apoptotic program.
We analyzed the presence of the t(14;18)(q32;q21) as a surrogate marker of the malignant clone in cells of the FL microenvironment using combined fluorescence immunophenotyping and interphase cytogenetics targeting the BCL2 gene locus.
Bcl-2 protooncogene, originally discovered at the chromosomal breakpoint of the t(14;18) in follicular lymphoma, is known to regulate the process of programmed cell death or apoptosis.
BCL6 gene amplification/3q27 gain is associated with unique clinicopathological characteristics among follicular lymphoma without BCL2 gene translocation.
The immunoglobulin heavy chain gene and bcl-2 gene rearrangement analysis confirmed the clonal origin of both the original FL, as well as the lymphoma, with a marginal zone pattern in the spleen.
Analysis of the BCL2 mutation pattern in clonally related FL/FL and FL/tFL samples revealed two distinct scenarios of genomic evolution: (i) direct evolution from the antecedent FL clone, with few novel clonal mutations acquired by the tFL major clone, and (ii) evolution from a common mutated long-lived progenitor cell, which subsequently acquired distinct mutations in the FL and in the relapsed or transformed counterpart.
We observed significant association of EZH2 mutation with low morphologic grade follicular lymphomas (grade 1-2, 23.6% vs. grade 3, 7.7%, χ(2) test, P = 0.02).
The study of BCL2 rearrangement will yield deeper insights into the pathogenesis of follicular lymphomas and into clinical applications of molecular diagnosis for Asian follicular lymphoma patients.
A total of 116 patients (male:female ratio 64:52; median age: 52 years) with indolent FL and BCL-2 rearrangement (at MBR or mcr breakpoints) assessable in peripheral blood (pb) by PCR prior to treatment, and with two or more PCR determinations during the first year, were selected for the present study.
The genetic hallmark of adult follicular lymphoma, t(14;18)(q32;q21), was not detectable in any of the pediatric cases, although BCL2 protein was expressed in 55% of the latter cases.
In a multivariate analysis, BCL2 mutations and high FL international prognostic index were independent risk factors for transformation and death due to lymphoma.
Two single case reports documenting IDCS harboring t(14;18) translocation involving immunoglobulin heavy chain (IGH) and BCL2 have been reported recently; however, one of the 2 IDCS has a synchronous follicular lymphoma, the absence or presence of a follicular lymphoma in the remaining case is not mentioned.