Patterns of chromosomal breakpoint locations in Burkitt's lymphoma: relevance to geography and Epstein-Barr virus association.
We 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 HindIII fragment encompassing the c-myc gene (P2 less than .00001). Conversely, not only did 91% of sBL manifest a rearranged HindIII 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 less than .004). Breakpoints outside the switch mu (S mu) region (ie, the HindIII fragment encompassing S mu) on chromosome 14 were twice as common overall (73%) as those within S mu (27%), but in the 15 tumors with S mu breakpoints, 13 (87%) had a rearranged c-myc gene. Breakpoints outside the HindIII fragment encompassing c-myc on chromosome 8 were predominantly associated with non-S mu breakpoints on chromosome 14 (85%) and this was the combination most frequently associated with eBL (65%; 6% of sBL, P2 less than .00001). In sBL, the most frequent breakpoint combination was a rearranged c-myc gene with a non-S mu breakpoint (63%; 13% of eBL). Twenty-eight percent of sBL and 13% of eBL had breakpoints both within c-myc and within S mu. 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.
Shiramizu
B
B
Pediatric Branch, National Cancer Institute, Bethesda, MD 20892.
Barriga
F
F
Neequaye
J
J
Jafri
A
A
Dalla-Favera
R
R
Neri
A
A
Guttierez
M
M
Levine
P
P
Magrath
I
I
D015139:Blotting, Southern; D002051:Burkitt Lymphoma / Q000453:epidemiology / Q000235:genetics* / Q000382:microbiology; D002460:Cell Line; D002869:Chromosome Aberrations; D002874:Chromosome Mapping; D002883:Chromosomes, Human, Pair 14; D002898:Chromosomes, Human, Pair 8; D015342:DNA Probes; D004273:DNA, Neoplasm / Q000235:genetics / Q000302:isolation & purification; D015321:Gene Rearrangement; D016259:Genes, myc; D005869:Ghana; D004854:Herpesvirus 4, Human / Q000302:isolation & purification*; D006801:Humans; D015183:Restriction Mapping; D014481:United States
D015342:DNA Probes; D004273:DNA, Neoplasm