A submicroscopic interstitial deletion of chromosome 14 frequently occurs adjacent to the t(14;18) translocation breakpoint in human follicular lymphoma.
The t(14;18) chromosomal translocation characteristic of follicular lymphoma (FL) juxtaposes the immunoglobulin heavy chain locus (IGH) and the BCL2 proto-oncogene. The translocation can be readily detected as a non-germline Notl fragment resolved by pulsed-field gel electrophoresis. A benefit of this approach is that it enables examination of the structure of a large region (+/- 300 kb) surrounding the chromosomal breakpoint. In 40/46 cases the observed translocated Notl fragment was smaller than the 680-690 kb expected from published restriction maps of the involved loci suggesting a deletion in the region of the breakpoint. Analysis of the der(14) allele by molecular hybridization demonstrated that in 35/46 cases the mu constant region (C mu) was deleted. Further molecular dissection of the IGH locus demonstrated that this resulted from an interstitial deletion of the der(14) chromosome within the region defined by the mu switch region (S mu) on the 5' side and the epsilon constant region (C epsilon) on the 3' end. Thus, the deletion resembled a class switch (CS) recombination event. Surprisingly, the CS deletion was as common in FL which was sIGM positive (24/33, 72.7%) as in cases where the productive allele had already undergone CS deletion (11/13, 84.6%) suggesting that the observed non-physiologic CS deletion resulted from a cis effect of the chromosomal translocation. Similar interstitial deletions of the non-productive IGH allele were not seen in B cell lymphocytic lymphomas which do not have the t(14;18) translocation. Mapping of the 3' extent of the deletion by an isotype PCR assay demonstrated frequent involvement (11/12 cases) of the gamma 1 constant region (C gamma 1). Analysis of cases in which the deletion was not evident by Southern blotting but detectable by PCR suggested that the CS deletion had occurred in a small subpopulation of FL cells subsequent to the t(14;18) translocation. The biological role of frequent interstitial deletions of the der(14) chromosome in t(14;18)-carrying lymphomas remains to be elucidated.
Zelenetz
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AD
Division of Hematologic Oncology/Lymphoma Service, Memorial Sloan-Kettering Cancer Center, New York, New York 10021.
Cleary
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ML
Levy
R
R
D000483:Alleles; D001483:Base Sequence; D002883:Chromosomes, Human, Pair 14 / Q000648:ultrastructure*; D002887:Chromosomes, Human, Pair 18 / Q000648:ultrastructure*; D016521:Electrophoresis, Gel, Pulsed-Field; D005803:Genes, Immunoglobulin; D006801:Humans; D007127:Immunoglobulin Constant Regions; D007148:Immunoglobulin mu-Chains / Q000235:genetics*; D008224:Lymphoma, Follicular / Q000235:genetics*; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000235:genetics; D016133:Polymerase Chain Reaction; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D019253:Proto-Oncogene Proteins c-bcl-2; D011993:Recombinant Fusion Proteins / Q000235:genetics; D017384:Sequence Deletion; D014178:Translocation, Genetic
D007127:Immunoglobulin Constant Regions; D007148:Immunoglobulin mu-Chains; C000715470:MAS1 protein, human; D009363:Neoplasm Proteins; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011993:Recombinant Fusion Proteins