Chromosomal fragile sites and cancer-specific rearrangements.

I T IS NOW WELL established that human tumors, particularly leukemias and lymphomas, are characterized by nonrandom chromosomal abnormalities. During the past 2 years, a number of proto-oncogenes and transforming genes have been mapped to the chromosomal breakpoints involved in the specific structural rearrangements. Experimental evidence obtained recently suggests that the genes located at these breakpoints play an integral role in tumorigenesis. Another factor that has added to the interest in cancerspecific chromosomal abnormalities is the recent recognition that the breakpoints noted in the recurring structural rearrangements in human tumors have a remarkable concordance with the location of both heritable and common fragile sites. Moreover, several individuals with malignant diseases characterized by specific abnormalities have been identified as carriers of a fragile site at the point where a chromosome break occurred. Thus, the potential importance of fragile sites relative to genetic predisposition to the development of human tumors is substantial. For this reason, hematologists and oncologists should be aware of research efforts to clarify the role of fragile sites in the pathogenesis of human tumors. Scientific interest in this association is very high, although there are many unresolved issues. In this review, I will examine the nature and characteristics of the chromosomal fragile sites with an emphasis on those sites that are heritable, the current theories regarding the mechanism(s) of fragile site formation, the correlation of fragile site location with the chromosomal breakpoints in the nonrandom abnormalities noted in human tumors, and the gaps in our current understanding of the role of fragile sites in the pathogenesis of human tumors.