SESSION 10: LYMPHOMA BIOLOGY 2
THE TOPOLOGY OF MYC REARRANGEMENTS IN DOUBLE-HIT LYMPHOMA IS CONSTRAINED BY THE PRECEDING IGH-BCL2 REARRANGEMENT – AN LLMPP PROJECT abstract
L. K. Hilton, B. Collinge, S. Ben-Neriah, B. M. Grande, et al.
The study authors conclude that their study demonstrates that the pattern of MYC rearrangements in HGBL-DH/TH-BCL2 is constrained by the presence of IGH-BCL2. MYC is infrequently rearranged to the IG variable regions, supporting that MYC translocation is a class switch-related event that occurs later in lymphomagenesis. The observed MYC rearrangements preserve both an intact IGH allele and the relationship between BCL2 and the IGH Eµ enhancer. This lends the authors to the hypothesis that, at the time of acquiring the MYC rearrangement, tumor survival is contingent on both intact B-cell receptor expression and the anti-apoptotic activity of BCL2.
THE MUTATIONAL LANDSCAPE OF DOUBLE/TRIPLE-HIT HIGH-GRADE B-CELL LYMPHOMA WITH BCL2 REARRANGEMENT (DH/TH-BCL2) – AN LLMPP PROJECT abstract
B. J. Collinge, L. K. Hilton, J. Wong, S. Ben-Neriah, et al.
The study authors conclude that the similarity to FL is suggestive of an evolutionary trajectory through an FL/FL-like common progenitor, where DH/TH-BCL2 diverges from this trajectory by adopting a DZ-like identity. This is supported by near-universal DHITsig positivity of both DH/TH-BCL2 and BL. According to the authors, suggesting this signature more accurately identifies a DZ biology that may be at least partly promoted by MYC rearrangement and mutations in FOXO1 and CCND3. Infrequent mutations promoting immune escape in DH/TH-BCL2 and BL are consistent with a decreased selective pressure due to the “immune cold” nature of the DZ.
DO CELL-OF-ORIGIN, DOUBLE EXPRESSER, AND DOUBLE HIT STATUS AFFECT OUTCOMES IN RELAPSED/REFRACTORY DIFFUSE LARGE B CELL LYMPHOMA (R/R DLBCL)? A PROSPECTIVE OBSERVATIONAL STUDY. abstract
S. H. Desai, R. Mwangi, M. Maurer, R. King, et al.
The study authors conclude that COO at diagnosis by IHC or GEP does not impact outcome of R/R DLBCL while DHL and DEL status was associated with worse outcomes in R/R setting. Hence, evolving molecular signatures of DLBCL beyond COO and interaction with tumor microenvironment may be more important drivers of the pathophysiology of R/R DLBCL. Finally: the results of this study will be helpful in the design and interpretation of clinical trials evaluating novel therapeutics in R/R DLBCL, while patterns of relapse, resistance to chemotherapy, and efficacy of transplant need to be explored to better characterize poor outcomes of R/R DHL and DEL.
COPY NUMBER VARIATION ANALYSIS IDENTIFIES DISTINCT GENOMIC FEATURES IN ADULT BURKITT LYMPHOMA abstract
K. Dreval, N. Thomas, D. S. Gerhard, L. K. Hilton, et al.
The study authors show that aBL has a distinct CNV profile compared to pBL, suggesting either distinct mutational processes or selective pressures in this malignancy. They conclude that these differences are not explained when samples are stratified on EBV status or sex. aBL-specific CNVs affect genes that regulate or cooperate with MYC-mediated transactivation. In addition, they show that chromosomal abnormalities affecting 1q, 6q, and 13q predominantly occur in EBV-negative BL.
KEY GENETIC AND MOLECULAR ABERRATIONS IDENTIFIED IN BOTH ADULT AND EBV-POSITIVE BURKITT LYMPHOMA PATIENTS abstract
J. Orem, M.-R. Martin, S. M. Mbulaiteye, C. G. Mullighan, et al.
The study authors conclude that their work highlights key mechanisms underlying BL pathogenesis and key genetic differences based on age and EBV status. They show the first evidence of mutations in TET2, HNRNPU, BRAF, and EZH2 being associated with BL, with TET2 mutations specifically associated with aBL. Among the SMGs, TP53 mutations were associated with inferior PFS in aBL, presenting a subset of patients to be considered for novel treatment approaches. These findings further elucidate differences between adult and pediatric BL and highlight model systems for the further development of novel therapeutics exploiting these differences.
TRIPLE POSITIVE (CD10+BCL6+MUM1+) DIFFUSE LARGE B-CELL LYMPHOMAS IN ADULTS ARE A HETEROGENEOUS GROUP ENRICHED IN LARGE B-CELL LYMPHOMAS WITH IRF4 REARRANGEMENT abstract
L. Frauenfeld, N. Castrejon-de-Anta, J. E. Ramis-Zaldivar, F. Otto, et al.
The study authors conclude that:
- Triple positive DLBCL is a heterogeneous group that should not be classified with the HA.
- Triple positive DLBCL in adults are enriched in LBCL-IRF4 (20%) and show frequent IRF4 mutations, which are absent in other groups.
- LBCL-IRF4 in adults is more often ABC-type and shows higher genetic complexity when compared with the pediatric counterpart.