Mechanisms underlying losses of heterozygosity in human colorectal cancers

Losses of heterozygosity are the most common molecular genetic alteration o bserved in human cancers. However, there have been few systematic studies t o understand the mechanism(s) responsible for losses of heterozygosity in s uch tumors. Here we report a detailed investigation of the five chromosomes lost most frequently in human colorectal cancers. A total of 10,216 determ inations were made with 88 microsatellite markers, revealing 245 chromosoma l loss events. The mechanisms of loss were remarkably chromosome-specific. Some chromosomes displayed complete loss such as that predicted to result f rom mitotic nondisjunction. However, more than half of the losses were asso ciated with losses of only part of a chromosome rather than a whole chromos ome. Surprisingly, these losses were due largely to structural alterations rather than to mitotic recombination, break-induced replication, or gene co nversion, suggesting novel mechanisms for the generation of much of the ane uploidy in this common tumor type.