Chromosome 11 translocation breakpoints at the PRAD1/cyclin D1 gene locus in centrocytic lymphoma.

Centrocytic lymphoma is a CD5-positive B-cell neoplasm. Rearrangements at the chromosome 11q13 bcl-1 breakpoint loci are present in the majority of these lymphomas, as a result of reciprocal translocation with the 14q32 immunoglobulin heavy chain joining genes. Recently, a gene lying approximately 110 kb telomeric of the bcl-1 major translocation cluster breakpoint locus, designated PRAD1, was proposed as a candidate bcl-1 oncogene. Accumulated evidence now indicates that this gene is the postulated bcl-1 oncogene. It encodes a protein with homology to cyclin family proteins designated cyclin D1 (CCND1). In order to determine whether 11q13 translocation breakpoints were present near the PRAD1 coding region in addition to the previously defined bcl-1 sites, we analyzed 27 centrocytic lymphomas by Southern blot using genomic and cDNA probes flanking the first exon of PRAD1. Five samples showed rearrangement at PRAD1 sites. In four of these, the breakpoints could be mapped from approximately one to 25 kb upstream of the first PRAD1 exon; each showed comigration of rearranged PRAD1 and immunoglobulin heavy-chain joining gene bands consistent with the t(11;14)(q13;q32). The fifth case was rearranged with PRAD1 probes only on BamHI-digested DNA, indicating either a point mutation or a polymorphism at this site. This sample also had rearrangement on multiple enzyme digests with the bcl-1 p94PS probe. None of 80 non-centrocytic B-cell neoplasms showed PRAD1 rearrangement. Thus, rearrangement at both bcl-1 and PRAD1 loci is strongly associated with centrocytic lymphoma, and provides a useful molecular marker for classifying this subtype of lymphoma. Furthermore, translocation-induced aberrant expression of the PRAD1 cyclin may lead to deregulated cell cycle control and play an important role in the pathogenesis of centrocytic lymphoma.