Significance of Chromosome 8 Breakpoint Location in Burkitt's. Lymphoma: Correlation with Geographical Origin and. Association with Epstein-Barr Virus.
Significance of Chromosome 8 Breakpoint Location in Burkitt's Lymphoma: Correlation with Geographical Origin and Association with Epstein-Barr Virus F.
BARRIGA, J. KIWANUKA, M. ALVAREZ-MoN, B. SHIRAMIZU,
B. HUBER, P. LEVINE,
and I. MAGRATH INTRODUCTION Burkitt's lymphoma (BL) is a B cell neoplasm, which occurs throughout the world, predominantly in children and young adults [Magrath 19831. Its relatively high incidence in equatorial AfrIca has led to the African form of the disease being designated as "endemic" (eBL), while cases outside equatorial Africa are referred to as "sporadic" (sBL) Burkitt's lymphoma. A number of differences between eBL and sBL have been descr ibed [Magrath 19861 and are summar ized in table 1. The Epstein-Barr virus (EBV), which was discovered in a BL cell line derived from an African patient [Epstein 19641, is present in a latent phase in about 95% of eBLs and some 10% to 15% of sBLs. These observations make it highly unlikely that EBV can have a role in the pathogenesis of all cases of Burkitt's lymphoma, and have served to shed doubt on a causal role for EBV even in EBV positive cases. The discovery of non-random, reciprocal chromosomal translocations in all cases of BL [Zech 19761 has focused attention on a genetic event as the critical pathogenetic step, and the potential role of EBV has remained entirely speculative. The translocations invariably include chromosome 8 as one partner and one of the immunoglobulin chain loci on chromosomes 14 (heavy chain), 2 (kappa chain) or 22 (lambda) as the other. The 8;14 translocation is the most frequent, occurring in some 80% or more of tumors, regardless of geographic origin. At a molecular level, the translocations result in the juxtaposition of the c-myc oncogene to one of the immunoglobulin loci, an event that has suggested involvement of cis-acting transcriptional enhancing elements present in the immunoglobulin loci in the deregulation of c-myc associated with the translocations. Recently, a difference between sBL and eBL with regard to the location of the breakpoints in chromosome 8 has been described [Pellici 19861. In sBL the breakpoint lies within c-myc or in the immediate 5' flanking sequences in the majority of tumors, while in eBL, the breakpoint is usually far upstream of c-myc, although most, if not all tumors with a far 5' breakpoint have mutations in the first exon of cmyc. This observation implies that the pathogenetic events and the mechanism of deregulation of c-myc differ in sBL from eBL, a finding
Pediatric and Epidemiology Branches, National Cancer Institute, Bethesda, Maryland, and Burroughs Wellcome, Research Triangle, North Carolina.
Current Topics in Microbiology and Immunology. Vol. 141 © Springer-Verlag Berlin· Heidelberg 1988
129
Table 1.
DIFFERENC~S
BETWEEN ENDEMIC AND SPORADIC BURKITT'S LYMPHOMA eBL
sBL
Average annual incidence children < 15 yrs.)
10 per 100,000
Occurrence
Climatically determined
Not climatically determined
Association with EBV
95%
15%
Chromosome 8 breakpoints
Upstream of c-myc
Within c-myc
Immunological features
CALLA T 1 +, B2 +
CALLA + T 1 -, B2 -
Common sites of tumor
Jaw Abdomen Orbit Paraspinal
Abdomen Bone marrow Nasopharynx Lymph nodes
Good
Poor
Response of recurrent tumor (including CNS)
0.2 per 100,000
which is consistent with the clinical and biological differences referred to. Moreover, genetic differences between sBL and eBL leave open the possibility that EBV has a causal role in the majority of cases of eBL. Indeed, a correlation between EBV association and specific structural changes in c-myc would strongly support this possibility. To examine this issue further, we have determined the breakpoint locations on chromosome 8 in 56 cases of BL and related them to the presence of the EBV genome in the tumor cell DNA. SAMPLES, ORIGIN AND DIAGNOSTIC CRITERIA. Table 2. shows the type and origin of the 56 BLs analyzed. Samples of eBL, obtained at the time of tumor biopsy or resection and kept frozen, were obtained from the Burkitt's Lymphoma Project in Ghana. Samples of sBL were obtained from patients treated at NCI (10) and other institutions in the U.S. (10). Most of the sBL cell lines were derived from patients seen at NCI; most of them and all 6 eBL have been extensively studied. All cell lines had a t(8;14) karyotype and so did all the fresh tumors in which cytogenetic data was available (10 sBL, 0 eBL). Histological diagnosis was made at the referring institution, immunophenotyping being done in a few patients. All the tumors included in the analysis had rearrangements of the immunoglobulin heavy chain locus detected by Southern blot utilizing JH and C probes.
130
Table 2.0RIGIN AND TYPE OF 56 BLs STUDIED Endemic Fresh tumors Cell lines Total
Total
SEoradic
19
21'1
39
6
11
17
25
31
56
SOUTHERN BLOT STRATEGY
1
