Patterns of chromosome breakage in nonHodgkin lymphoma: significance to gene alteration in tumorigenesis.

In a comprehensive cytogenetic analysis of nonHodgkin lymphoma (NHL) that was based on a database derived from karyotypic descriptions of 264 tumors, we previously established correlations between specific chromosome changes and histologic subtypes of lymphoma. In the present paper we analyze the total chromosome breakage encountered in this group of tumors. This analysis permitted distinction between sites of nonrandom breakage that are specific for lymphoid tumors (and hence of probable primary or etiologic significance) and sites of nonrandom breakage that are common to lymphoid as well as nonlymphoid tumors (and hence of probable secondary or evolutionary significance). We also observed that breakage affected all of the immunoglobulin and T cell receptor gene sites and most of the known cellular oncogene and fragile sites; however, only a limited number of these sites exhibited statistically significant breakage. Of special interest was the fact that the fragile sites that exhibited significant breakage were mostly those that also were sites of cellular oncogenes. Our data suggest that breakage at sites of immunoglobulin genes and a limited number of cellular oncogenes alone is of importance in B-cell lymphomagenesis. While the timing or causes of genomic destabilization in tumorigenesis are unknown, recent molecular analysis of junction regions of chromosome rearrangements designated here as primary translocations has suggested that more than one mechanism may be involved in their generation. This study identifies chromosomal sites of nonrandom perturbation that may be targeted for detailed molecular analysis aimed at understanding the origin, evolution, and spread of B-cell NHL.