Distribution of breakpoints on chromosome 18 in breast, colorectal, and pancreatic carcinoma cell lines

Chromosome 18 is frequently rearranged in carcinomas. We explored the distribution of breakpoints affecting chromosome 18 by mapping 56 breakpoints in 26 carcinoma cell lines by fluorescence in situ hybridization (FISH) using bacterial artificial chromosomes (BACs) and band paints. The distribution of breaks among 18 intervals of chromosome 18 was significantly nonrandom. The interval spanning the centromere contained the greatest number of breaks and had the highest average copy number of any interval. There was a high density of breaks close to the centromere as well as actually within the centromere. A cluster of breaks encompassing SMAD4 was associated with the minimum average copy number, consistent with SMAD4 being a tumor suppressor gene. There may be another cluster of breaks around 18q12. We offer two interpretations of the concentration of breaks near the centromere. It may reflect selection for an oncogene near the centromere, or there may be an underlying bias of breakage toward the centromere. We show that the latter is predicted by a simple model that invokes random breakage following anchorage of some random point on the chromosome, or selection of breaks proximal to one of several tumor suppressor genes.