The characterization of the common fragile site FRA16D and its involvementin multiple myeloma translocations

Fragile sites appear as breaks, gaps, or decondensations on metaphase chrom osomes when cells are grown under specific culture conditions. The breaks a re nonrandom, appearing in defined, conserved locations throughout the mamm alian genome. Common fragile sites, as their name implies, are present in v irtually all individuals. With three common fragile sites cloned, their mec hanism of expression and the role, if any, they play in human disease are s till unclear. We have assembled a BAC contig of >1 Mb across the second mos t active common fragile site, FRA16D (16q23.2), We fluorescently labeled th ese BACs and used them as probes on metaphases from aphidicolin-induced lym phocytes and demonstrated that FRA16D decondensation/breakage occurs over a region of at least 1 Rib. Thus, this is the largest common fragile site cl oned to date. Microsatellite markers that map within FRA16D show a very hig h loss in prostate, breast, and ovarian tumors, indicating that loss within this fragile site may be important in the development or progression of th ese tumors. In addition, a common t(14q32; 16q23) translocation is observed in up to 25% of all multiple myelomas (MM). We localized four of four such cloned t(14;16) MM breakpoints within the FRA16D region. This work further demonstrates that the common fragile sites may play an important role in c ancer development. (C) 2000 Academic Press.