Session: 621. Lymphomas: Translational – Molecular and Genetic: Poster II
Hematology Disease Topics & Pathways:
Lymphomas, T Cell lymphoma, Diseases, Lymphoid Malignancies
Methods: Expert consensus pathology review was conducted in the Lymphoma/Leukemia Molecular Profiling Project (LLMPP). RNAseq was performed and fusions were identified using FusionCatcher. Here, we focused on recurrent in-frame coding fusions. Previously unreported fusions were validated by RT-PCR. Type I/II was assigned using a previously validated gene expression-based model. Genes with adjusted (adj) P<0.05 were considered differentially expressed. Overall survival (OS) was assessed for systemic ALCL, when available.
Results: We evaluated 379 ALCLs (229M/150F; mean age, 56 y). Of 199 candidate fusions (excluding reciprocal events), 28 were recurrent and passed quality metrics. At least 1 of these 28 fusions was present in 150 cases (40%).
ALK fusions were present in 106 ALK+ ALCLs (all Type I; P<0.0001). Of these, NPM1::ALK was seen in 68/106 (64%). Alternate partners (X::ALK) included ATIC (N=24) and CTLC, COL1A2, MSN, MYH9, RNF213, SATB1, TFH, TPM3, and TRAF1 (1-3 cases each). X::ALK was associated with older age (mean, 52 y) than NPM1::ALK (32 y; P<0.0001) and showed relative overexpression of 49 genes, including multiple activators of small GTPases such as CGNL1 (FC, 5.6; Padj=2.4×10‑6), SRGAP1, ALS2, DOCK1, and NCKAP1. ALK expression was similar in cases with NPM1::ALK and X::ALK and there was no significant difference in OS.
Non-ALK TK fusions were seen in 17/273 ALK− cases (6%), including TYK2 (N=9); JAK2 (N=6); and ROS1 (N=2). All were Type I ALCLs (P<0.0001). ALK− cases with non-ALK TK fusions overexpressed 38 genes compared to ALK− cases without TK fusions, including cytokines involved in the IL17 signaling pathway such as CXCL6 (FC, 12.5; Padj=4.2×10-3), CXCL1, and CSF3.
We then assessed the relationship between ALK− cases with non-ALK TK fusions and ALK+ cases by separately comparing each subset to ALK− cases without TK fusions. FC values for ALK− cases with non-ALK TK fusions were significantly correlated with FC values for ALK+ ALCLs over the set of expressed genes (R=0.54; P<0.0001). At a median follow-up of 32 months, 0/4 systemic ALCL patients with non-ALK TK fusions had died, while 30% of those with ALK− ALCL without TK fusions had died, but this was not statistically significant (P=0.26). The other 13 ALK− cases with non-ALK TK fusions were either localized ALCLs or did not have outcome data available.
Of 20 TP63 fusions, 17 (85%) were TBL1XR1::TP63 and 3 were X::TP63. As previously reported, TP63 fusions were associated with poor OS (median OS, 10 months; not reached for other ALK− ALCLs; P=0.007).
Four ALCLs had a novel NCL::UBTF fusion involving genes encoding the nucleolar proteins nucleolin and nucleolar (upstream binding) transcription factor-1. Four cases each had PARG::BMS1 and TNK1::GPS2 (the latter seen only in Type I ALCLs).
Conclusions: This large consortium-based analysis of coding fusions further elucidates the molecular distinction between Type I and Type II ALCLs. Both ALK and non-ALK TK fusions were seen exclusively in Type I ALCLs, which we have shown previously are enriched for JAK-STAT3 pathway genes and correlate strongly with pSTAT3Y705 positivity by immunohistochemistry. These fusions were not identified in Type II ALCLs, which previous data suggest are associated with epigenetic alterations. ALK+ ALCLs with NPM1::ALK and X::ALK showed differences in gene expression, suggesting biological differences. Furthermore, ALCLs with non-ALK TK fusions shared gene expression features with ALK+ ALCL. Clinical fusion detection could enhance molecular classification of Type I and Type II ALCLs and may guide precision therapy.
Disclosures: Feldman: Zeno Pharmaceuticals: Patents & Royalties; Seattle Genetics: Research Funding. Dasari: The Binding Site: Patents & Royalties: Intellectual Property Rights licensed to Binding Site with potential royalties. Scott: Roche: Consultancy, Honoraria; Genmab: Consultancy, Honoraria; AstraZenenca: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Veracyte: Consultancy, Honoraria; Roche/Genentech: Research Funding; Nanostring: Patents & Royalties: use of gene expresssion to subtype aggressive lymphoma. Inghirami: Daiichi Sankyo: Consultancy. Rosenwald: MorphoSys: Other: institutional research contract; Incyte: Other: Institutional research contract . Savage: Bristol Myers Squibb: Consultancy, Research Funding; Regeneron: Other: DSMC; AbbVie: Consultancy; Seagen: Consultancy, Honoraria, Research Funding. Ansell: Takeda: Research Funding; SeaGen: Research Funding; AstraZeneca: Research Funding; Bristol Myers Squibb: Research Funding; ADC Therapeutics: Research Funding; Pfizer: Research Funding; Regeneron Pharmaceuticals, Inc.: Research Funding; Affimed: Membership on an entity's Board of Directors or advisory committees, Research Funding. Cerhan: BMS: Research Funding; GenMab: Research Funding; Protagonist Therapeutics: Other: SMC; Genentech: Research Funding. Gru: Innate-Pharma: Consultancy. Kahl: AstraZeneca: Consultancy, Research Funding; ADCT: Consultancy; Bristol Myers Squibb: Consultancy, Honoraria; BeiGene: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Genentech: Consultancy; AbbVie: Consultancy; Lilly: Consultancy, Honoraria.
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