Integrated DNA/RNA targeted genomic profiling of diffuse large B-cell lymphoma using a clinical assay.

Abstract

We sought to define the genomic landscape of diffuse large B-cell lymphoma (DLBCL) by using formalin-fixed paraffin-embedded (FFPE) biopsy specimens. We used targeted sequencing of genes altered in hematologic malignancies, including DNA coding sequence for 405 genes, noncoding sequence for 31 genes, and RNA coding sequence for 265 genes (FoundationOne-Heme). Short variants, rearrangements, and copy number alterations were determined. We studied 198 samples (114 de novo, 58 previously treated, and 26 large-cell transformation from follicular lymphoma). Median number of GAs per case was 6, with 97% of patients harboring at least one alteration. Recurrent GAs were detected in genes with established roles in DLBCL pathogenesis (e.g. MYD88, CREBBP, CD79B, EZH2), as well as notable differences compared to prior studies such as inactivating mutations in TET2 (5%). Less common GAs identified potential targets for approved or investigational therapies, including BRAF, CD274 (PD-L1), IDH2, and JAK1/2. TP53 mutations were more frequently observed in relapsed/refractory DLBCL, and predicted for lack of response to first-line chemotherapy, identifying a subset of patients that could be prioritized for novel therapies. Overall, 90% (n = 169) of the patients harbored a GA which could be explored for therapeutic intervention, with 54% (n = 107) harboring more than one putative target.

• Authors: Andrew M Intlekofer, Erel Joffe, Connie L Batlevi, Patrick Hilden, Jie He, Venkatraman E Seshan, Andrew D Zelenetz, M Lia Palomba, Craig H Moskowitz, Carol Portlock, David J Straus, Ariela Noy, Steven M Horwitz, John F Gerecitano, Alison Moskowitz, Paul Hamlin, Matthew J Matasar, Anita Kumar, Marcel R van den Brink, Kristina M Knapp, Janine D Pichardo, Michelle K Nahas, Sally E Trabucco, Tariq Mughal, Amanda R Copeland, Elli Papaemmanuil, Mathai Moarii, Ross L Levine, Ahmet Dogan, Vincent A Miller, Anas Younes
• Journal: Blood cancer journal (Blood Cancer J) Vol. 8 Issue 6 Pg. 60 (06 12 2018) ISSN: 2044-5385 [Electronic] United States
• PMID: 29895903 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Biomarkers, Tumor

Topics

• Aged
• Aged, 80 and over
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Biomarkers, Tumor
• Biopsy
• Computational Biology (methods)
• DNA Copy Number Variations
• Female
• Gene Expression Profiling (methods)
• Genomics (methods)
• High-Throughput Nucleotide Sequencing
• Humans
• Lymphoma, Large B-Cell, Diffuse (diagnosis, genetics, mortality, therapy)
• Male
• Middle Aged
• Molecular Sequence Annotation
• Neoplasm Grading
• Neoplasm Staging
• Prognosis
• Transcriptome
• Treatment Outcome