Molecular Features of Diffuse Large B‐Cell Lymphoma Associated With Primary Treatment Resistance
Diffuse large B-cell lymphoma (DLBCL) patients that fail to achieve a complete metabolic response with frontline immunochemotherapy have a poor prognosis. Genomic profiling has led to a broader understanding of the molecular drivers in DLBCL, but it is unknown how well current classifiers identify patients that will experience primary treatment resistance (PTR). Using whole exome and RNA sequencing data from newly diagnosed DLBCL patients, we evaluated the genomic landscape of PTR and compared it to that of non-PTR DLBCL. We found a significant increase in the frequency of TP53 (34% vs. 15%, p = 0.005) and ARID1A mutations (21% vs. 7%, p = 0.007) in PTR cases, with pathway analysis further demonstrating a downregulation of TP53 and an increase in chromatin modifying pathways. These results suggest that TP53 and ARID1A may be key mediators of PTR and important pathways contributing to the poor outcomes. We found that the current molecular classifiers were unable to identify PTR cases at diagnosis. However, our newly identified high-risk signature identified 46% of PTR cases at diagnosis. Overall, these results contribute to our understanding of the genomic landscape of patients with primary treatment resistance.
Authors
- Kerstin Wenzl (ORCID: https://orcid.org/0000-0002-3363-1795)
- Thomas E. Witzig (ORCID: https://orcid.org/0000-0002-4215-6500)
- Jordan E. Krull (ORCID: https://orcid.org/0000-0001-6507-8085)
- Joseph P. Novak (ORCID: https://orcid.org/0000-0001-5676-6118)
- Thomas Matthew Habermann (ORCID: https://orcid.org/0000-0003-3532-9132)
- Anne J. Novak (ORCID: https://orcid.org/0000-0002-7904-1651)
- Vivek Sarangi
- Matthew E. Stokes (ORCID: https://orcid.org/0000-0002-1953-1616)
- Allison Marie Bock (ORCID: https://orcid.org/0000-0002-3174-8877)
- Anita K. Gandhi (ORCID: https://orcid.org/0000-0001-5512-1625)
- Chuican Huang (ORCID: https://orcid.org/0000-0003-0220-9978)
- Abigail R. Dropik (ORCID: https://orcid.org/0000-0002-7543-5768)
- Matthew J. Maurer (ORCID: https://orcid.org/0000-0002-1867-0526)
- Grzegorz S. Nowakowski (ORCID: https://orcid.org/0000-0002-6955-9393)
- Nicholas Stong (ORCID: https://orcid.org/0000-0002-0678-637X)
- Melissa A. Hopper (ORCID: https://orcid.org/0000-0003-0675-8253)
- James R. Cerhan (ORCID: https://orcid.org/0000-0002-7482-178X)
- Maria Ortiz
- Umar Farooq (ORCID: https://orcid.org/0000-0001-7891-9891)
- Yucai Wang (ORCID: https://orcid.org/0000-0002-1576-8341)
- Rebecca L. King
- Stephen M. Ansell
Institutions
- University of Iowa (US)
- Mayo Clinic (US)
- University of Utah (US)
- Huntsman Cancer Institute (US)
- Bristol-Myers Squibb (United States) (US)
- Mayo Clinic in Florida (US)
- Predictive Science (United States) (US)
Publication Details
- Journal
- Hematological Oncology
- Published
- 2024-11-29
- DOI
- https://doi.org/10.1002/hon.70006
- Citations
- 1
- Primary Topic
- Lymphoma Diagnosis and Treatment
- Type
- article
- Field-Weighted Citation Impact
- 0.42
Funders
- Eli Lilly and Company
- Pfizer
- Gilead Sciences
- Celgene
- F. Hoffmann-La Roche
- Karyopharm Therapeutics
- Regeneron Pharmaceuticals
- TG Therapeutics
- MEI Pharma
- Adaptive Biotechnologies
- BeiGene
- Incyte
- Tanoto Foundation
- Seagen
- MorphoSys
- National Institutes of Health
- Genentech
- Kite Pharma
- Loxo Oncology