Direct sequence analysis of 14q+ and 18q- chromosome junctions at the MBR and MCR revealing clustering within the MBR in follicular lymphoma

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Abstract
The t(14; 18) translocation is a highly consistent feature of follicular lymphoma although the under-lying mechanism generating this fusion remains uncertain. The breakpoints on chromosome 18 are at one of two sites, designated mbr and mcr, in the bcl-2 gene. A polymerase chain reaction strategy has been developed for amplification and direct sequencing of the resultant 14q+ and 18q− reciprocal junctions. Sequence analysis of the amplified 14q+ junction established that 21 tumours contained a bcl-2 (mbr) sequence to an immunoglobulin JH region, the majority being J5 or J6. A nonrandom pattern of breakpoints within the mbr region was found. Cluster-ing of the breakpoint occurred with over 60% of the translocations clustering within 10 bases. There was a second cluster within the mbr 50 bases 3′ of the first cluster. One of these junctions had an unusual configuration with the bcl-2 and JH sequences separated by a recognisable DH region. This suggests that at least some of the junctional sequences, previously thought of as N insertions, may be fragments of unrecognised DH regions. In one of these tumours it was possible to sequence the reciprocal 18q− junction, showing it to consist of a DH/bcl-2 (mbr) fusion. Analysis of both reciprocal junctions for a translocation in the mcr region of bcl-2, showed that this 18q− junction also consisted of DH fused to a bcl-2 sequence. In contrast to previous analyses, which demonstrated either loss or duplication of bcl-2 sequences at the breakpoints, the bcl-2 sequence was conserved during the mbr and mcr translocations in this study. Although the precise mechanism of the t(14; 18) translocation remains unclear, these data demonstrate that breakpoints are nonrandomly distributed within the mbr.

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