CRYPTIC <i>MYC</i> AND <i>BCL2</i> REARRANGEMENTS ARE AMONG A RANGE OF GENETIC MECHANISMS UNDERLYING THE DOUBLE HIT SIGNATURE IN NON‐DOUBLE HIT DIFFUSE LARGE B‐CELL LYMPHOMA
Bibliographic record
Abstract
Introduction: High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements (HGBL-DH/TH) has poor outcome after standard therapy. We recently described a gene expression signature (DHITsig) that was characteristic for HGBL-DH/TH with BCL2 rearrangement (Ennishi et al. J Clin Oncol 2019). Interestingly, while this signature identified 27% of GCB diffuse large B-cell lymphoma (DLBCL) as DHITsig positive, only half of these tumors harbored both MYC and BCL2 rearrangements detected by FISH. Here, through whole genome sequencing (WGS), we sought to identify potential mechanisms for expression of DHITsig, including aberrant MYC and BCL2 expression, in non-HGBL-DH/TH-BCL2 tumors. Methods: We performed WGS on 20 DHITsig-pos tumors from Ennishi et al that lack rearrangements of MYC, BCL2, or both. Of these, 18 cases lack a matched normal and were analyzed for somatic SNVs and indels using a combination of Strelka2 and Mutect2, using the GnomAD database to filter germline variants based on population allele fraction. Structural variants and copy number alterations were identified using Manta and Control-FREEC, respectively. Results: Our analysis identified MYC or BCL2 rearrangements that were cryptic to breakapart FISH assays, revealing that 40% of these apparently non-HGBL-DH/TH-BCL2 tumors had, in fact, a “genetic double hit” (Figure 1). These MYC rearrangements involved recurrent non-IG partner loci ZCCHC7, RFTN1, or CD96. Although the breakpoints for two of these translocations were outside of the locus interrogated by FISH, the remainder involved small insertions of either the MYC gene or enhancer regions. Three tumors had focal copy number gains of MYC, including one with a double minute, and six tumors harbored gains of MIR-17-HG, a regulator of MYC expression. Similarly, rearrangements involving BCL2 that were cryptic to breakapart FISH were identified in three tumors, including the insertion of an IGK enhancer element into the BCL2 locus. In the only case lacking both BCL2 and MYC translocations, the 11q alteration associated with MYC-negative high-grade lymphomas was found. Finally, several focal deletions were found affecting the promoter region around TSS1 of the lncRNA PVT1 gene, telomeric of MYC. This locus has recently been found to contain a boundary element that insulates MYC from the actions of downstream enhancers. Keywords: diffuse large B-cell lymphoma (DLBCL); gene expression profile (GEP); high-grade B-cell lymphoma with or without rearrangement of MYC and BCL2 and/or BCL6. Disclosures: Scott, D: Research Funding: Receives research funds from NanoString Technologies; Other Remuneration: Named inventor on a patent for identifying novel sub-types of DLBCL. Morin, R: Other Remuneration: Named inventor on a patent for identifying novel sub-types of DLBCL.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".