Patterns of Chromosomal Breakpoint Locations in Burkitt's Lymphoma: Relevance to Geography and Epstein-Barr Virus Association

Abstract

AbstractWe have examined, by Southern blotting, the patterns of chromosomal breakpoint locations in 55 cases of Burkitt's lymphoma (BL) with respect to geography and Epstein-Barr virus (EBV) association. We have confirmed the association between chromosome 8 breakpoint and geography: 74% of endemic (eBL) but only 9% of sporadic BL (sBL) had breakpoints outside the Hin dIII fragment encompassing the c-myc gene (P2 < .00001). Conversely, not only did 91% of sBL manifest a rearranged M'odili fragment, but at least 56% of these cases, in contrast to 17% of eBL cases, had a breakpoint within the first exon or intron of c-myc (P2 < .004). Breakpoints outside the switch μ (Sp.) region (ie, the Hin dIII fragment encompassing S μ) on chromosome 14 were twice as common overall (73%) as those within Sμ. (27%), but in the 15 tumors with Sμ breakpoints, 13 (87%) had a rearranged c-myc gene. Breakpoints outside the Hin dlII fragment encompassing c-myc on chromosome 8 were predominantly associated with non-Sμ breakpoints on chromosome 14 (85%) and this was the combination most frequently associated with eBL (65%; 6% of sBL, P2 < .00001). In sBL, the most frequent breakpoint combination was a rearranged c-myc gene with a non-Sμ breakpoint (63%; 13% of eBL). Twenty-eight percent of sBL and 13% of eBL had breakpoints both within c-myc and within Sμ. EBV DNA was present in 19 of 20 tumors with breakpoints outside c-myc, in none of 7 with a breakpoint in the immediate 5’ region of c-myc, in 4 of 5 tumors with breakpoints in the first exon, and in 7 of 12 tumors with breakpoints in the first intron. These data suggest that the pathogeneses of eBL and sBL differ with regard to the mechanism of c-myc deregulation, and probably also with regard to the state of differentiation of the target cell for malignant transformation. We have formulated a testable hypothesis regarding the potential role of EBV in pathogenesis: that it is required to contribute to the deregulation of c-myc in the presence of some, but not all, types of c-myc damage arising from the chromosomal translocations.