Chromosomal translocations

As shown in Table 6.2, a number of chromosomal translocations and gene rearrangements associated with NHL have been identified; the breakpoints have been sequenced and are applicable for PCR amplification.

t(14;18) translocation

One of the most widely studied non-random chromosomal translocations in NHL is the t(14;18), occurring in 85% of patients with follicular lymphoma and 30% of patients with diffuse large cell lymphoma. In the t(14;18) the BCL-2 proto-oncogene on chromosome 18 is juxtaposed with the IgH locus on chromosome 14 (Figure 6.9). The breakpoints have been cloned and sequenced, and have been shown to cluster at two main regions 3' to the BCL-2 coding region: the major breakpoint region (MBR) within the 3' untranslated region of the BCL-2 gene, and the minor breakpoint cluster region (m-BCR) located 20 kb downstream. Juxtaposition of the transcriptionally active IgH with the BCL-2 gene results in upregulation of the BCL-2 gene product and subsequent resistance to programmed cell death by apoptosis.

The clustering of the breakpoints at these two main regions at the BCL-2 gene and the availability of consensus regions of the IgH joining (J) regions make this an ideal candidate for PCR amplification to detect lymphoma cells containing the t(14;18) translocation. A major advantage in the detection of lymphoma cells bearing the BCL-2/IgH translocation is that DNA rather than RNA can be used to detect the translocation. In addition, since there is variation at the site of the breakpoint at the BCL-2 gene, the PCR products for individual patients differ in size and have unique sequences. The size of the PCR product can be assessed by gel electrophoresis and used as confirmation that the expected size fragment is amplified from a specific patient.

18q21

14q32

3' exon

3' untranslated Intron

bcl-2

MBR ~15 kb mcr

bcl-2 18

Fig. 6.9 t(14;18) translocation

In the t(14;18) the BCL-2 locus on chromosome 18 is juxtaposed to the IgH locus on chromosome 14. The breakpoints on chromosome 18 cluster at two main regions: the major breakpoint region (MBR) in the 5' untranslated region of the BCL-2 gene, and the minor cluster region (mcr) downstream in the intron. The chimeric gene product provides a unique tumor marker that can be PCR-amplified using primers upstream of the MBR or mcr region with consensus primers within the J region of the IgH gene.

Other translocations in non-Hodgkin's lymphoma

The t(11;14)(q13;q32) is associated with a number of B-cell malignancies, particularly mantle cell lymphomas (MCL). In this translocation the proto-oncogene BCL-1 (also called PRAD-1) on chromosome 11 is juxtaposed to the IgH chain locus on chromosome 14.

One-third of anaplastic lymphomas express the chromosomal translocation t(2;5)(p23;q35), which involves a novel protein tyrosine kinase and nucleophosmin, resulting in a p80 fusion protein. This translocation is detected by RT-PCR where the mRNA sequence is converted into cDNA before PCR amplification.

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