Mechanism of the t(14;18) chromosomal translocation: structural analysis of both derivative 14 and 18 reciprocal partners

To elucidate the mechanism of the t(14;18)(q32;q21) chromosomal translocation found in follicular lymphoma, the authors examined the structure of both derivative (der) chromosomal breakpoints as well as their germ-line predecessors. They noted that chromosome segment 18q21 was juxtaposed with immunoglobulin heavy (H) chain gene diversity (D/sub H/) regions on all five der(18) chromosomes they examined, and they confirmed the juncture with immunoglobulin H-chain gene joining (J/sub H/) regions on the der(14) chromosome. However, the t(14;18) was not fully reciprocal in that chromosome 14 DNA between the D/sub H/ and J/sub H/ regions was deleted. Furthermore, extra nucleotides, reminiscent of N segments, were present at the der(14) and possibly der(18) junctions. This indicates that despite the mature B-cell phenotype of follicular lymphoma, the t(14;18) occurs during attempted D/sub H/-J/sub H/ joining, the earliest event in immunoglobulin rearrangement in a pre-B-cell. The detailed analysis of the germ-line 18q21 region indicated that most breakpoints clustered within a 150-base-pair major breakpoint region. A direct repeat duplication of chromosome 18 sequences was discovered at both chromosomal junctures, typical of the repair of a naturally occurring staggered double-stranded DNA break. These results prompt a translocation model with illegitimate pairing of a staggered double-stranded DNA break at 18q21 and an immunoglobulin endonuclease-mediated break at 14q32 and with N-segment addition, repair, and ligation to generate der(14) and der(18) chromosomes