Follicular Lymphoma

The t(14;18)(q32;q21) translocation, detected in about 80% of follicular lymphomas (FLs) at the time of initial diagnosis, is the cytogenetic hallmark of FL and juxtaposes the BCL2 oncogene on 18q21with a JH segment of IGH on

14q32. Overexpression of a normal BCL2 protein results from this translocation and protects the cells from apop-tosis. Molecular analysis for the IGH/BCL2 translocation using FISH17 (illustrated in Figure 32-2f) or PCR18 is occasionally needed for confirmation of the initial diagnosis of FL in cases with equivocal histologic and immunologic findings. However, the vast majority of molecular testing in FL patients today is performed to evaluate the course of disease and the impact of therapy19,20 (see section on IGH/BCL2 MRD detection, below). Most BCL2 breakpoints occur in the 3' untranslated region, 60% in a 150 base pair (bp) span termed the major breakpoint cluster region (M-bcr) and 20% in the minor breakpoint cluster region (m-bcr). In the remaining cases, the breakpoint occurs outside of these areas, either in the variable cluster region (vcr) or the intermediate cluster region (icr). The insertion of variable numbers of random extra nucleotides at the breakpoint junction during crossover and the variability of the breakpoints in the BCL2 fusion gene and the six JH fragments result in considerable variation in the length of PCR products when testing is performed for this translocation. PCR fragment length usually ranges from 120 to 270 bp for the M-bcr, but occasional breakpoints as much as 800 bp downstream of the M-bcr region have been detected with standard M-bcr primers, resulting in PCR products of more than 1000bp. The clustering of breakpoints on chromosome 18 and the high degree of sequence homology among the 3' portions of the JH segments make the IGH/BCL2 translocation very amenable to PCR detection and a good PCR target for MRD detection.

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