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Background

Background and Significance

Sézary syndrome (SS) is a leukemic variant of cutaneous T-cell lymphoma (CTCL) and represents an ideal model for study of T-cell transformation. We describe whole-exome and single-nucleotide polymorphism array–based copy number analyses of CD4+ tumor cells from untreated patients at diagnosis and targeted resequencing of 101 SS cases. A total of 824 somatic nonsynonymous gene variants were identified including indels, stop–gain/loss, splice variants, and recurrent gene variants indicative of considerable molecular heterogeneity. Driver genes identified using MutSigCV include POT1, which has not been previously reported in CTCL; and TP53 and DNMT3A, which were also identified consistent with previous reports. Mutations in PLCG1 were detected in 11% of tumors including novel variants not previously described in SS. This study is also the first to show BRCA2 defects in a significant proportion (14%) of SS tumors. Aberrations in PRKCQ were found to occur in 20% of tumors highlighting selection for activation of T-cell receptor/NF-κB signaling. A complex but consistent pattern of copy number variants (CNVs) was detected and many CNVs involved genes identified as putative drivers. Frequent defects involving the POT1 and ATM genes responsible for telomere maintenance were detected and may contribute to genomic instability in SS. Genomic aberrations identified were enriched for genes implicated in cell survival and fate, specifically PDGFR, ERK, JAK STAT, MAPK, and TCR/NF-κB signaling; epigenetic regulation (DNMT3A, ASLX3, TET1-3); and homologous recombination (RAD51C, BRCA2, POLD1). This study now provides the basis for a detailed functional analysis of malignant transformation of mature T cells and improved patient stratification and treatment.

Sézary syndrome (SS) is a leukemic variant of cutaneous T-cell lymphoma (CTCL) and represents an ideal model for study of T-cell transformation. We describe whole-exome and single-nucleotide polymorphism array–based copy number analyses of CD4+tumor cells from untreated patients at diagnosis and targeted resequencing of 101 SS cases. A total of 824 somatic nonsynonymous gene variants were identified including indels, stop–gain/loss, splice variants, and recurrent gene variants indicative of considerable molecular heterogeneity. Driver genes identified using MutSigCV include POT1,which has not been previously reported in CTCL; and TP53and DNMT3A, which were also identified consistent with previous reports. Mutations in PLCG1were detected in 11% of tumors including novel variants not previously described in SS. This study is also the first to show BRCA2defects in a significant proportion (14%) of SS tumors. Aberrations in PRKCQwere found to occur in 20% of tumors highlighting selection for activation of T-cell receptor/NF-κB signaling. A complex but consistent pattern of copy number variants (CNVs) was detected and many CNVs involved genes identified as putative drivers. Frequent defects involving the POT1and ATMgenes responsible for telomere maintenance were detected and may contribute to genomic instability in SS. Genomic aberrations identified were enriched for genes implicated in cell survival and fate, specifically PDGFR, ERK, JAK STAT, MAPK, and TCR/NF-κB signaling; epigenetic regulation (DNMT3A, ASLX3, TET1-3); and homologous recombination (RAD51C, BRCA2, POLD1). This study now provides the basis for a detailed functional analysis of malignant transformation of mature T cells and improved patient stratification and treatment.

Background

Zonder: Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Research Funding; Alnylam: Consultancy; Janssen: Consultancy; Amgen: Consultancy; Caelum Biosciences: Consultancy; Intellia: Consultancy; Regeneron: Consultancy. Richter: BMS, Karyopharm, Antengene: Membership on an entity's Board of Directors or advisory committees; Adaptive biotechnologies: Speakers Bureau; Janssen, Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Tisch Cancer Institute: Icahn School of Medicine at Mount Sinai: Current Employment. Bumma: Amgen, Sanofi: Speakers Bureau; Janssen, Oncopeptides, Sanofi: Consultancy. Hoffman: BMS, Celgene: Honoraria. Bensinger: BMS, Janssen, Poseida, Regeneron, Trillium: Research Funding; Amgen, BMS, Janssen, Sanofi: Speakers Bureau. Xu: Regeneron Pharmaceuticals, Inc: Current Employment; Regeneron Pharmaceuticals, Inc: Current holder of stock options in a privately-held company. Chokshi: Regeneron Pharmaceuticals, Inc: Current holder of stock options in a privately-held company; Regeneron Pharmaceuticals, Inc: Current Employment. Boyapati: Regeneron Pharmaceuticals, Inc: Current Employment; Regeneron Pharmaceuticals, Inc: Current holder of stock options in a privately-held company. Sharma: Regeneron Pharmaceuticals, Inc.: Patents & Royalties: US17/112,564: Methods of Treating Multiple Myeloma with Bispecific anti-BCMA X anti-CD3 Antibodies (Status: Pending). Rodriguez Lorenc: Regeneron Pharmaceuticals, Inc: Current Employment; Regeneron Pharmaceuticals, Inc, Novartis Pharmaceuticals: Current holder of stock options in a privately-held company. Kroog: Regeneron Pharmaceuticals, Inc: Current Employment; Regeneron Pharmaceuticals, Inc: Current holder of stock options in a privately-held company. Lentzsch: Magenta Therapeutics: Current equity holder in publicly-traded company; Ossium Health: Consultancy; Caelum Biosciences: Consultancy, Current holder of individual stocks in a privately-held company; Oncopeptides: Consultancy; Sanofi: Consultancy, Research Funding; Karyopharm: Consultancy, Research Funding; Takeda: Consultancy; GSK: Consultancy; AbbVie: Consultancy; Celularity: Consultancy; Janssen: Consultancy; Kadmon: Current equity holder in publicly-traded company. Jagannath: Janssen Pharmaceuticals: Consultancy; Takeda: Consultancy; Legend Biotech: Consultancy; Karyopharm Therapeutics: Consultancy; Bristol Myers Squibb: Consultancy; Sanofi: Consultancy.The data described in the abstract will report on use of REGN5458 in a Phase 1 clinical trial of patients with relapsed/refractory multiple myeloma