Cryptic MYC insertions in Burkitt lymphoma: New data and a review of the literature

Abstract

The occurrence of MYC-negative Burkitt lymphoma (BL) has been discussed for many years. The real frequency of the MYC insertion in MYC-negative BL is still unknown. Fine-needle aspiration biopsies of 108 consecutive patients with clinicopathologically suspected BL (suspBL) were evaluated by flow cytometry, classical cytogenetics, and fluorescence in situ hybridization (FISH). We found 12 cases (11%) without the MYC rearrangement by FISH with a MYC breakapart probe: two patients (1.9%) with cryptic MYC/IGH fusion (finally diagnosed as BL) and 10 patients (9.3%) with 11q gain/loss (finally diagnosed as Burkitt-like lymphoma with 11q aberration). The exact breakpoints of the cryptic MYC/IGH were investigated by next-generation sequencing. The MYC insertions’ breakpoints were identified in PVT1 in the first case, and 42 kb upstream of 5′MYC in the second case. To date, a molecular characterization of the MYC insertion in BL has only been reported in one case. Detailed descriptions of our MYC insertions in a routinely and consecutively diagnosed suspBL cohort will contribute to resolving the issue of MYC negativity in BL. In our opinion, the presence of the MYC insertions in BL and other lymphomas might be underestimated, because routine genetic diagnostics are usually based on FISH only, without karyotyping.

Cytological Diagnosis of Aggressive Small-Cell Lymphomas

“…In MCL, concurrent TP53 and CDKN2A gene aberrations correlate with chemoresistance [50]. In BL, we already assessed the prognostic role of MYC insertions or concomitant BCL2 and BCL6 mutations [46, 51]. In B-ALL/LBL and HGBL with MYC and BCL2 and/or BCL6 rearrangements, NGS sequencing has shown recurrent variants of genes coding for transcription factors (MYC, FOXO1), epigenetic modulators (KMT2D, EZH2, and CREBBP), and antiapoptotic proteins (BCL2) [51, 52].…”

“…Molecular testing for LN-FNAC was traditionally limited to IGH/TCR receptor assessment for clonality testing [44,45]. Nonetheless, different studies have assessed that LN-FNAC samples are suitable for extensive and accurate analysis [13,39,40,[46][47][48][49].…”

An artificial intelligence system applied to recurrent cytogenetic aberrations and genetic progression scores predicts MYC rearrangements in large B‐cell lymphoma

“…Therefore, establishing a MYC status in these patients is essential for prognostic purposes. Due to cryptic rearrangements and variation in MYC breakpoints, both chromosome and fluorescence in situ hybridization (FISH) analysis may fail to detect these translocations in some cases [ 15 , 16 , 17 ]. In case of FISH analysis, up to 10% of the cases may be incorrectly identified [ 18 , 19 , 20 , 21 ].…”

“…In a separate study, 8q24 breakpoints were mapped greater than 350-645 kb 3′-downstream from MYC inside a cluster region [22]. Consequently, current commercially available FISH probes such as the dual color dual fusion probe set and the MYC break-apart probe may both fail to detect MYC R. Furthermore, other genetic alterations such as mutations, cryptic insertion of MYC into IGH, cryptic insertion of IG regulatory regions into MYC, deregulation of micro RNA-34B, or single nucleotide polymorphisms at 8q24 that may convey a shared underlying biology to MYC R have been implicated [15]. In fact, Hilton et al [23] showed that the expression signature of MYC high grade DLBCL in which MYC had either cryptic alterations or rearrangements with non-IG partners is similar to the MYC double-hit DLBCL.…”

TCF3-HLF-Positive Acute Lymphoblastic Leukemia Resembling Burkitt Leukemia: Cell Morphologic and Immunophenotypic Findings

“… 3 Therefore, patients with leukemia with BL morphology and no MYC rearrangement may be diagnosed as BL-like ALL, BL without MYC rearrangement, or BL with cryptic MYC rearrangement, on the basis of next-generation sequencing. 4 However, distinctions should be made because of differences in management and prognosis.…”