Unbalanced MYC break-apart FISH patterns indicate the presence of a MYC rearrangement in HGBCL-DH-BCL2

• Published in: Blood 2024-10, Vol.144 (15), p.1611-1616
• Main Authors: Collinge, Brett, Ben-Neriah, Susana, Hilton, Laura K., Alduaij, Waleed, Tucker, Tracy, Slack, Graham W., Farinha, Pedro, Craig, Jeffrey W., Boyle, Merrill, Meissner, Barbara, Villa, Diego, Gerrie, Alina S., Sehn, Laurie H., Savage, Kerry J., Morin, Ryan D., Mungall, Andrew J., Steidl, Christian, Scott, David W.
• Format: Article
• Language: English
• Subjects: Female; Gene Rearrangement; Genes, myc; Humans; In Situ Hybridization, Fluorescence; Lymphoma, B-Cell - genetics; Lymphoma, B-Cell - pathology; Male; Proto-Oncogene Proteins c-bcl-2 - genetics; Proto-Oncogene Proteins c-myc - genetics
• ISSN: 0006-4971; 1528-0020; 1528-0020
• DOI: 10.1182/blood.2024025603

•Unbalanced MYC break-apart FISH patterns, in which red or green signal is lost, are observed in ∼13% of HGBCL-DH-BCL2 tumors.•Balanced and unbalanced MYC rearrangements have the same biological consequences and should be reported as positive for rearrangement. [Display omitted] Fluorescence in situ hybridization (FISH) using break-apart probes is recommended for identifying high-grade B-cell lymphoma with MYC and BCL2 rearrangements (HGBCL-DH-BCL2). Unbalanced MYC break-apart patterns, in which the red or green signal is lost, are commonly reported as an equivocal result by clinical laboratories. In a cohort of 297 HGBCL-DH-BCL2, 13% of tumors had unbalanced MYC break-apart patterns with loss of red (LR; 2%) or loss of green (LG; 11%) signal. To determine the significance of these patterns, MYC rearrangements were characterized by sequencing in 130 HGBCL-DH-BCL2, including 3 LR and 14 LG tumors. A MYC rearrangement was identified for 71% of tumors with LR or LG patterns, with the majority involving immunoglobulin loci or other recurrent MYC rearrangement partners. The architecture of these rearrangements consistently preserved the rearranged MYC allele, with the MYC gene predicted to be on the derivative chromosome containing the signal that is still present in nearly all cases. MYC protein expression, MYC messenger RNA expression, and the proportion of tumors expressing the dark-zone signature was not significantly different between balanced and unbalanced groups. These results support a recommendation that unbalanced MYC break-apart FISH patterns be reported as positive for MYC rearrangement in the context of diagnosing HGBCL-DH-BCL2. Fluorescence in situ hybridization (FISH) is the method for identifying high-grade B-cell lymphoma with MYC and BCL2 rearrangements (double-hit lymphoma [DHL]). Unbalanced MYC patterns, where a signal is lost, are usually identified as equivocal, raising the issue as to whether the gene is deleted or rearranged. Collinge and colleagues studied a cohort of 297 DHL tumors, 13% of which had unbalanced break-apart signals. MYC rearrangement was identified in 71% of these tumors with MYC gene overexpression, suggesting that these tumors should be reported as DHL.