Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2024 Oct 10;144(15):1611-1616.
doi: 10.1182/blood.2024025603.

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

Brett Collinge  1   2 , Susana Ben-Neriah  1 , Laura K Hilton  1   3 , Waleed Alduaij  1 , Tracy Tucker  4 , Graham W Slack  1   2 , Pedro Farinha  1   2 , Jeffrey W Craig  5 , Merrill Boyle  1 , Barbara Meissner  1 , Diego Villa  1 , Alina S Gerrie  1   6 , Laurie H Sehn  1 , Kerry J Savage  1   6 , Ryan D Morin  1   3 , Andrew J Mungall  7 , Christian Steidl  1   2 , David W Scott  1   6
Affiliations

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

Brett Collinge et al. Blood. .

Abstract

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.

PubMed Disclaimer

Conflict of interest statement

Conflict-of-interest disclosure: T.T. has received honoraria from AstraZeneca and Merck and research funding from Pfizer. J.W.C. has provided consultancy/expert testimony for Bayer and received honoraria from BeiGene. D.V. reports consulting/honoraria from AbbVie, AstraZeneca, BeiGene, Bristol Myers Squibb (BMS)/Celgene, Gilead/Kite, Incyte, Janssen, Merck, Roche, and ZetaGene and research funding (to the institution) from AstraZeneca and Roche. A.S.G. reports consultancy/honoraria from AbbVie, AstraZeneca, BeiGene, and Janssen and research funding (to the institution) from AbbVie, AstraZeneca, Janssen, and Roche. L.H.S. reports consulting/honoraria from AbbVie, Amgen, AstraZeneca, BeiGene, BMS/Celgene, Genmab, Kite/Gilead, Incyte, Janssen, Merck, Seagen, and Roche/Genentech and research funding from Roche/Genentech and Teva. K.J.S. reports honoraria/consulting fees from BMS, Merck, Seagen, and AbbVie; research funding from BMS; and has served on the drug safety monitoring committee for Regeneron. C.S. has performed consultancy for Bayer and Eisai and has received research funding from Epizyme and Trillium Therapeutics. D.W.S. has received honoraria from AbbVie, AstraZeneca, Genmab, Roche, and Veracyte; research funding from Roche/Genentech; and is an inventor on patents describing the use of gene expression to subtype aggressive B-cell lymphomas, one of which is licensed to NanoString Technologies. The remaining authors declare no competing financial interests.

Figures

None
Graphical abstract
Figure 1.
Figure 1.
Patterns of MYC break-apart FISH probe signals and their proportions in HGBCL-DH-BCL2. (A) Representative MYC break-apart FISH patterns. When the MYC locus is undisturbed, the red (centromeric) and green (telomeric) signals are in close proximity and produce a fused signal. An example of a rearrangement producing a balanced break-apart pattern is depicted using MYC and IGH as example loci. (B) Frequency of break-apart FISH patterns observed in 297 HGBCL-DH-BCL2 tumors. Balanced represents equal number of break-apart probe signals, whereas unbalanced gain indicates that both red and green break-apart signals are present but not equal in numbers.
Figure 2.
Figure 2.
MYC partner gene and rearrangement architecture in HGBCL-DH-BCL2 according to MYC break-apart FISH pattern. (A) Frequency of MYC rearrangement partners and break points relative to the MYC gene determined in whole-genome and/or capture sequencing. Rearrangement partners are grouped as IG (IGH, IGK, or IGL), recurrent non-IG (BCL6 or PAX5), other non-IG (all other partners), intrachromosomal, or not found. Intrachromosomal rearrangements were defined as structural events involving the MYC locus and another region of chromosome 8 >20kb away. Intragenic breaks occurring in intron 1 of MYC are included in the centromeric group. (B) MYC breakpoint location in tumors with LR and LG patterns, showing that the MYC gene is predicted to be on the derivative chromosome with the signal that is still present in almost all tumors.
Figure 3.
Figure 3.
Impact of MYC break-apart FISH patterns on MYC and DZsig expression. (A) Proportion of tumors positive for MYC protein expression by IHC. P values are from Fisher exact tests. (B) MYC mRNA expression, as determined by digital gene expression profiling. P values are from t tests. Dotted lines indicate the mean MYC mRNA expression for the balanced (gray) and GCB DLBCL (orange) groups. (C) Proportion of tumors positive for DZsig, as determined by the DLBCL90 assay. P values are from χ2 tests. ∗P < .05; ∗∗P < .01; ∗∗∗P < .001; ∗∗∗∗P < .0001. ns, not significant; ref, reference group.
See this image and copyright information in PMC

Comment in

References

    1. Campo E, Jaffe ES, Cook JR, et al. The International Consensus Classification of mature lymphoid neoplasms: a report from the Clinical Advisory Committee. Blood. 2022;140(11):1229–1253. - PMC - PubMed
    1. Alaggio R, Amador C, Anagnostopoulos I, et al. The 5th edition of the World Health Organization classification of haematolymphoid tumours: lymphoid neoplasms. Leukemia. 2022;36(7):1720–1748. - PMC - PubMed
    1. Scott DW, King RL, Staiger AM, et al. High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements with diffuse large B-cell lymphoma morphology. Blood. 2018;131(18):2060–2064. - PMC - PubMed
    1. Ennishi D, Jiang A, Boyle M, et al. Double-hit gene expression signature defines a distinct subgroup of germinal center B-cell-like diffuse large B-cell lymphoma. J Clin Oncol. 2019;37(3):190–201. - PMC - PubMed
    1. Alduaij W, Collinge B, Ben-Neriah S, et al. Molecular determinants of clinical outcomes in a real-world diffuse large B-cell lymphoma population. Blood. 2023;141(20):2493–2507. - PubMed

Publication types

Substances