Genome-Wide Analysis of 30 Burkitt Lymphomas Using High-Density SNP Arrays Reveals Frequent Cryptic Alterations Including Amplification of the microRNA 17-92 Locus.

Burkitt lymphomas/leukemias (BL) are highly aggressive mature B-cell malignancies characterized by a constant MYC rearrangement. MYC deregulation is an oncogenic event known to be necessary but not sufficient in BL pathogenesis. Additional (epi)genetic alterations should cooperate, such as inactivation of the p14arf-MDM2-TP53 pathway which is frequently detected. We recently demonstrated the independent negative prognostic impact of specific chromosomal alterations, del(13q) and +7q, in childhood BL. We also showed by Multi-FISH that 13q abnormalities are more heterogeneous than expected and that13q gains are underestimated by conventional cytogenetics (CC). DNA from 30 BL (15 adults/15 children) was analyzed with 50K Xba single nucleotide polymorphisms (SNP) arrays (Affymetrix), in order to characterize additional allelic imbalances and losses of heterozygosity. 47 gains and 30 losses were found in 22 BL; 57 chromosomal imbalances were cryptic (not detected by CC). A recurring 13q amplification was detected in 6 BL. The minimal amplified region (MAR) of 4.35 Mb includes 3 candidate genes: C13orf25, GPC5 and GPC6. One C13orf25 transcripts contains a miRNA 17–92 cluster. The amplicon was unmasked with BAC probes in 2/8 other screened BL with 13q abnormalities. This amplification was associated with a terminal deletion (minimal size: 5Mb) in half cases. A recurring 11q abnormality was also assessed by FISH with a MAR of 3.2 Mb containing candidate genes such as CBL, BLR1. Acquired partial uniparental disomies (pUPD) are characterized by loss of heterozygosity without chromosomal deletion. 73 pUPD (>5 Mb) were found in 15 BL; 14 were telomeric and probably resulted from one mitotic recombination. The pathogenic role of pUPD remains unclear. Some of them may be polymorphisms also detected in healthy population. Other may reflect genomic instability but in our series, no higher incidence of pUPD was detected in BL with a complex karyotype. Thirdly, non random pUPD may render the neoplastic cell homozygous for a preexisting mutation leading to the activation of an oncogene or inactivation of a tumor suppressor gene (TSG). Four telomeric pUPD on 1p, 9p, 17p and 17q were found in at least 2 BL. We confirmed homozygous mutations of 2 TSG (TP53 and CDKN2A) located on 17p and 9p pUPD, respectively. These pUPD may be another way of p14arf-MDM2-TP53 inactivation. Moreover, these results suggest an involvement of the miR 17–92 cluster known to interact with the MYC oncogene in BL pathogenesis. The expression pattern of the different mature miR 17–92 in BL with and without 13q amplification will be presented at the meeting.