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Sézary Syndrome: Translating Genetic Diversity into Personalized Medicine

2016; Elsevier BV; Volume: 136; Issue: 7 Linguagem: Inglês

10.1016/j.jid.2016.04.027

1523-1747

Edith Chevret, Jean‐Philippe Merlio,

Fungal Infections and Studies

Sézary syndrome is probably the most studied cutaneous T-cell lymphoma subtype. Beyond the consensus criteria for Sézary syndrome diagnosis, Sézary cells display heterogeneous phenotypes and differentiation profiles. In the face of SS diversity, the great hope is to develop targeted therapies based on next-generation sequencing to define the genetic landscape of Sézary syndrome.Prasad et al. report on the use of exome sequencing and RNA sequencing to study selected CD4+ blood cells from 15 patients with erythroderma Sézary syndrome, 14 of whom fulfilled the conventional criteria for diagnosis. The most common genetic abnormality, TP53 gene deletion on chromosome arm 17p and/or mutation, was observed in 58% of patients. However, mutations affecting PLCG1, STAT5B, GLI3, and CARD11 each were detected in only one individual. Nevertheless, Prasad et al. report single point mutations or copy number alterations in several new genes and in new fusion genes, with predicted biological relevance. This information underscores the diversity of genetic alterations and of the mechanisms of alterations of single genes. At the individual level, Sézary cells may combine alterations of genes involved in T-cell signaling, NF-kB and JAK-signal transducer and activator of transcription pathways, apoptosis control, chromatin remodeling, and DNA damage response. The therapeutic relevance of these potential targets needs to be evaluated with tests of function. Sézary syndrome is probably the most studied cutaneous T-cell lymphoma subtype. Beyond the consensus criteria for Sézary syndrome diagnosis, Sézary cells display heterogeneous phenotypes and differentiation profiles. In the face of SS diversity, the great hope is to develop targeted therapies based on next-generation sequencing to define the genetic landscape of Sézary syndrome. Prasad et al. report on the use of exome sequencing and RNA sequencing to study selected CD4+ blood cells from 15 patients with erythroderma Sézary syndrome, 14 of whom fulfilled the conventional criteria for diagnosis. The most common genetic abnormality, TP53 gene deletion on chromosome arm 17p and/or mutation, was observed in 58% of patients. However, mutations affecting PLCG1, STAT5B, GLI3, and CARD11 each were detected in only one individual. Nevertheless, Prasad et al. report single point mutations or copy number alterations in several new genes and in new fusion genes, with predicted biological relevance. This information underscores the diversity of genetic alterations and of the mechanisms of alterations of single genes. At the individual level, Sézary cells may combine alterations of genes involved in T-cell signaling, NF-kB and JAK-signal transducer and activator of transcription pathways, apoptosis control, chromatin remodeling, and DNA damage response. The therapeutic relevance of these potential targets needs to be evaluated with tests of function. Clinical Implications•Prasad et al., 2016Prasad A. Rabionet R. Espinet B. Zapata L. Puiggros A. Melero C. et al.Identification of gene mutations and fusion genes in patients with Sézary syndrome.J Invest Dermatol. 2016; 136: 1490-1499Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar confirm TP53 gene deletions and/or mutations at chromosome arm 17p in 58% of patients with SS, but they observed PLCG1, STAT5B, GLI3, and CARD11 mutations only in single individuals.•They report single point mutations or copy number alterations in newly recognized genes and in new fusion genes, with varying combinations of these alterations in each patient.•This work underscores the diversity of genetic mutations, with predicted impact, in T-cell signaling, NF-kB and JAK-STAT pathways, apoptosis control, chromatin remodeling, and DNA damage responses.Sézary syndrome (SS), a rare leukemic variant of cutaneous T-cell lymphoma (CTCL), is probably the most studied CTCL subtype because of the severity of the disease and the ability of investigators to obtain circulating malignant T cells for further phenotypic and genetic studies. •Prasad et al., 2016Prasad A. Rabionet R. Espinet B. Zapata L. Puiggros A. Melero C. et al.Identification of gene mutations and fusion genes in patients with Sézary syndrome.J Invest Dermatol. 2016; 136: 1490-1499Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar confirm TP53 gene deletions and/or mutations at chromosome arm 17p in 58% of patients with SS, but they observed PLCG1, STAT5B, GLI3, and CARD11 mutations only in single individuals.•They report single point mutations or copy number alterations in newly recognized genes and in new fusion genes, with varying combinations of these alterations in each patient.•This work underscores the diversity of genetic mutations, with predicted impact, in T-cell signaling, NF-kB and JAK-STAT pathways, apoptosis control, chromatin remodeling, and DNA damage responses. Although consensus criteria for SS diagnosis and staging have been established (Olsen et al., 2007Olsen E. Vonderheid E. Pimpinelli N. Willemze R. Kim Y. Knobler R. et al.Revisions to the staging and classification of mycosis fungoides and Sezary syndrome: a proposal of the International Society for Cutaneous Lymphomas (ISCL) and the cutaneous lymphoma task force of the European Organization of Research and Treatment of Cancer (EORTC).Blood. 2007; 110: 1713-1722Crossref PubMed Scopus (1084) Google Scholar), the phenotype of Sézary cells is heterogeneous, because they may develop from naïve T cells, effector memory T cells, or central memory T cells, with differentiation plasticity mainly into T helper 2 (Th2) cells (Nicolay et al., 2016Nicolay J.P. Felcht M. Schledzewski K. Goerdt S. Geraud C. Sezary syndrome: old enigmas, new targets.J Dtsch Dermatol Ges. 2016; 14: 256-264PubMed Google Scholar). The altered expressions of several biomarkers, including CD26 and/or CD7, in CD4+ cells was confirmed as specific for SS diagnosis in a multicenter study (Boonk et al., 2016Boonk S.E. Zoutman W.H. Marie-Cardine A. van der Fits L. Out-Luiting J.J. Mitchell T.J. et al.Evaluation of immunophenotypic and molecular biomarkers for Sézary syndrome using standard operating procedures: a multicenter study of 59 patients.J Invest Dermatol. 2016; 136: 1364-1372Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar). A great hope in the face of SS diversity has been to develop targeted therapies that rely on next-generation sequencing (NGS) techniques to define the genetic alterations found in patients with SS. Recently, advances have been made in documenting alterations in genes that play roles in T-cell activation, NF-κB and JAK-signal transducer and activator of transcription (STAT) pathways, apoptosis control, chromatin remodeling, and DNA damage response (Choi et al., 2015Choi J. Goh G. Walradt T. Hong B.S. Bunick C.G. Chen K. et al.Genomic landscape of cutaneous T cell lymphoma.Nat Genet. 2015; 47: 1011-1019Crossref PubMed Scopus (287) Google Scholar, da Silva Almeida et al., 2015da Silva Almeida A.C. Abate F. Khiabanian H. Martinez-Escala E. Guitart J. Tensen C.P. et al.The mutational landscape of cutaneous T cell lymphoma and Sezary syndrome.Nat Genet. 2015; 47: 1465-1470Crossref PubMed Scopus (272) Google Scholar, Kiel et al., 2015Kiel M.J. Sahasrabuddhe A.A. Rolland D.C. Velusamy T. Chung F. Schaller M. et al.Genomic analyses reveal recurrent mutations in epigenetic modifiers and the JAK-STAT pathway in Sezary syndrome.Nat Commun. 2015; 6: 8470Crossref PubMed Scopus (150) Google Scholar, Ungewickell et al., 2015Ungewickell A. Bhaduri A. Rios E. Reuter J. Lee C.S. Mah A. et al.Genomic analysis of mycosis fungoides and Sezary syndrome identifies recurrent alterations in TNFR2.Nat Genet. 2015; 47: 1056-1060Crossref PubMed Scopus (209) Google Scholar, Vaque et al., 2014Vaque J.P. Gomez-Lopez G. Monsalvez V. Varela I. Martinez N. Perez C. et al.PLCG1 mutations in cutaneous T-cell lymphomas.Blood. 2014; 123: 2034-2043Crossref PubMed Scopus (159) Google Scholar, Wang et al., 2015Wang L. Ni X. Covington K.R. Yang B.Y. Shiu J. Zhang X. et al.Genomic profiling of Sezary syndrome identifies alterations of key T cell signaling and differentiation genes.Nat Genet. 2015; 47: 1426-1434Crossref PubMed Scopus (232) Google Scholar). Some of these studies included patients with one of the two major epidermotropic CTCL subtypes, mycosis fungoides and SS (Choi et al., 2015Choi J. Goh G. Walradt T. Hong B.S. Bunick C.G. Chen K. et al.Genomic landscape of cutaneous T cell lymphoma.Nat Genet. 2015; 47: 1011-1019Crossref PubMed Scopus (287) Google Scholar, da Silva Almeida et al., 2015da Silva Almeida A.C. Abate F. Khiabanian H. Martinez-Escala E. Guitart J. Tensen C.P. et al.The mutational landscape of cutaneous T cell lymphoma and Sezary syndrome.Nat Genet. 2015; 47: 1465-1470Crossref PubMed Scopus (272) Google Scholar, Vaque et al., 2014Vaque J.P. Gomez-Lopez G. Monsalvez V. Varela I. Martinez N. Perez C. et al.PLCG1 mutations in cutaneous T-cell lymphomas.Blood. 2014; 123: 2034-2043Crossref PubMed Scopus (159) Google Scholar, Wang et al., 2015Wang L. Ni X. Covington K.R. Yang B.Y. Shiu J. Zhang X. et al.Genomic profiling of Sezary syndrome identifies alterations of key T cell signaling and differentiation genes.Nat Genet. 2015; 47: 1426-1434Crossref PubMed Scopus (232) Google Scholar). Prasad et al., 2016Prasad A. Rabionet R. Espinet B. Zapata L. Puiggros A. Melero C. et al.Identification of gene mutations and fusion genes in patients with Sézary syndrome.J Invest Dermatol. 2016; 136: 1490-1499Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar used exome sequencing and RNA sequencing to study selected CD4+ peripheral blood cells from 15 patients with erythroderma, 14 of whom fulfilled requirements for a diagnosis of SS. A median of 54 somatic point mutations per patient was observed, but very few of the mutations (TP53, ITPR1, DSC1, and PRH) were detected in more than one patient (Table 1). The most frequent genetic abnormality involved the TP53 gene, with deletion at chromosome arm 17p and/or mutation observed in 58% of patients, which corresponds with other NGS study results and a pilot study (Lamprecht et al., 2012Lamprecht B. Kreher S. Mobs M. Sterry W. Dorken B. Janz M. et al.The tumour suppressor p53 is frequently nonfunctional in Sezary syndrome.Br J Dermatol. 2012; 167: 240-246Crossref PubMed Scopus (25) Google Scholar) (Table 1). TP53 deletion at chromosome arm 17p was reported by several groups to be the most common deletion observed in SS (Izykowska and Przybylski, 2011Izykowska K. Przybylski G.K. Genetic alterations in Sezary syndrome.Leukemia Lymphoma. 2011; 52: 745-753Crossref PubMed Scopus (19) Google Scholar). A double knockout TP53 clone was observed in two patients who were diagnosed at an early age, suggesting that TP53 loss may represent a clinical subtype of SS (Prasad et al., 2016Prasad A. Rabionet R. Espinet B. Zapata L. Puiggros A. Melero C. et al.Identification of gene mutations and fusion genes in patients with Sézary syndrome.J Invest Dermatol. 2016; 136: 1490-1499Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar).Table 1Potential relevant genes in Sézary syndromeCategoryGene NameChromosome LocationProtein FunctionAnomaly and Frequency from Prasad et al., 2016Prasad A. Rabionet R. Espinet B. Zapata L. Puiggros A. Melero C. et al.Identification of gene mutations and fusion genes in patients with Sézary syndrome.J Invest Dermatol. 2016; 136: 1490-1499Abstract Full Text Full Text PDF PubMed Scopus (60) Google ScholarAnomaly and Frequency from Other AuthorsOncogeneCBLB3q13.11T-cell activationDeletion, 6.67% (1/15)Kiel et al., 2015Kiel M.J. Sahasrabuddhe A.A. Rolland D.C. Velusamy T. Chung F. Schaller M. et al.Genomic analyses reveal recurrent mutations in epigenetic modifiers and the JAK-STAT pathway in Sezary syndrome.Nat Commun. 2015; 6: 8470Crossref PubMed Scopus (150) Google Scholar: mutation, 1.4%da Silva Almeida et al., 2015da Silva Almeida A.C. Abate F. Khiabanian H. Martinez-Escala E. Guitart J. Tensen C.P. et al.The mutational landscape of cutaneous T cell lymphoma and Sezary syndrome.Nat Genet. 2015; 47: 1465-1470Crossref PubMed Scopus (272) Google Scholar: mutation, 4%CD282q33.2T-cell activationNot reportedKiel et al., 2015Kiel M.J. Sahasrabuddhe A.A. Rolland D.C. Velusamy T. Chung F. Schaller M. et al.Genomic analyses reveal recurrent mutations in epigenetic modifiers and the JAK-STAT pathway in Sezary syndrome.Nat Commun. 2015; 6: 8470Crossref PubMed Scopus (150) Google Scholar: mutation, 7%Choi et al., 2015Choi J. Goh G. Walradt T. Hong B.S. Bunick C.G. Chen K. et al.Genomic landscape of cutaneous T cell lymphoma.Nat Genet. 2015; 47: 1011-1019Crossref PubMed Scopus (287) Google Scholar: mutation, 4%CDKN2A9p21.3Cell cycleNot reportedChoi et al., 2015Choi J. Goh G. Walradt T. Hong B.S. Bunick C.G. Chen K. et al.Genomic landscape of cutaneous T cell lymphoma.Nat Genet. 2015; 47: 1011-1019Crossref PubMed Scopus (287) Google Scholar: mutation, 17%/deletion, 40%Kiel et al., 2015Kiel M.J. Sahasrabuddhe A.A. Rolland D.C. Velusamy T. Chung F. Schaller M. et al.Genomic analyses reveal recurrent mutations in epigenetic modifiers and the JAK-STAT pathway in Sezary syndrome.Nat Commun. 2015; 6: 8470Crossref PubMed Scopus (150) Google Scholar: mutation, 4%Wang et al., 2015Wang L. Ni X. Covington K.R. Yang B.Y. Shiu J. Zhang X. et al.Genomic profiling of Sezary syndrome identifies alterations of key T cell signaling and differentiation genes.Nat Genet. 2015; 47: 1426-1434Crossref PubMed Scopus (232) Google Scholar: deletion, 58%NAV312q21.2May be involved in IL-2 production by T-cell/neuron regenerationMutation, 6.67% (1/15)Kiel et al., 2015Kiel M.J. Sahasrabuddhe A.A. Rolland D.C. Velusamy T. Chung F. Schaller M. et al.Genomic analyses reveal recurrent mutations in epigenetic modifiers and the JAK-STAT pathway in Sezary syndrome.Nat Commun. 2015; 6: 8470Crossref PubMed Scopus (150) Google Scholar: mutation, 5.6%RASA23q22–q23Cellular proliferation and differentiationDeletion, 6.67% (1/15)Kiel et al., 2015Kiel M.J. Sahasrabuddhe A.A. Rolland D.C. Velusamy T. Chung F. Schaller M. et al.Genomic analyses reveal recurrent mutations in epigenetic modifiers and the JAK-STAT pathway in Sezary syndrome.Nat Commun. 2015; 6: 8470Crossref PubMed Scopus (150) Google Scholar: mutation, 4%Tumor suppressor geneBCL7C16p11.2Wnt-signaling pathway/apoptotic pathwayDuplication, 6.67% (1/15)Kiel et al., 2015Kiel M.J. Sahasrabuddhe A.A. Rolland D.C. Velusamy T. Chung F. Schaller M. et al.Genomic analyses reveal recurrent mutations in epigenetic modifiers and the JAK-STAT pathway in Sezary syndrome.Nat Commun. 2015; 6: 8470Crossref PubMed Scopus (150) Google Scholar: mutation, 1.4%PTEN10q23.3AKT/PKB signaling pathwayNot reportedda Silva Almeida et al., 2015da Silva Almeida A.C. Abate F. Khiabanian H. Martinez-Escala E. Guitart J. Tensen C.P. et al.The mutational landscape of cutaneous T cell lymphoma and Sezary syndrome.Nat Genet. 2015; 47: 1465-1470Crossref PubMed Scopus (272) Google Scholar: deletion, 20%Kiel et al., 2015Kiel M.J. Sahasrabuddhe A.A. Rolland D.C. Velusamy T. Chung F. Schaller M. et al.Genomic analyses reveal recurrent mutations in epigenetic modifiers and the JAK-STAT pathway in Sezary syndrome.Nat Commun. 2015; 6: 8470Crossref PubMed Scopus (150) Google Scholar: mutation, 4%TP5317p13.1Cell cycle arrest in G1/apoptosis/senescenceMutation or deletion, 58% (7/12)Choi et al., 2015Choi J. Goh G. Walradt T. Hong B.S. Bunick C.G. Chen K. et al.Genomic landscape of cutaneous T cell lymphoma.Nat Genet. 2015; 47: 1011-1019Crossref PubMed Scopus (287) Google Scholar: mutation, 43%da Silva Almeida et al., 2015da Silva Almeida A.C. Abate F. Khiabanian H. Martinez-Escala E. Guitart J. Tensen C.P. et al.The mutational landscape of cutaneous T cell lymphoma and Sezary syndrome.Nat Genet. 2015; 47: 1465-1470Crossref PubMed Scopus (272) Google Scholar: mutation, 16%Kiel et al., 2015Kiel M.J. Sahasrabuddhe A.A. Rolland D.C. Velusamy T. Chung F. Schaller M. et al.Genomic analyses reveal recurrent mutations in epigenetic modifiers and the JAK-STAT pathway in Sezary syndrome.Nat Commun. 2015; 6: 8470Crossref PubMed Scopus (150) Google Scholar: mutation, 17%Ungewickell et al., 2015Ungewickell A. Bhaduri A. Rios E. Reuter J. Lee C.S. Mah A. et al.Genomic analysis of mycosis fungoides and Sezary syndrome identifies recurrent alterations in TNFR2.Nat Genet. 2015; 47: 1056-1060Crossref PubMed Scopus (209) Google Scholar: mutation, 19%Wang et al., 2015Wang L. Ni X. Covington K.R. Yang B.Y. Shiu J. Zhang X. et al.Genomic profiling of Sezary syndrome identifies alterations of key T cell signaling and differentiation genes.Nat Genet. 2015; 47: 1426-1434Crossref PubMed Scopus (232) Google Scholar: mutation, 30%T-cell signalingCARD117p22T-cell receptor signaling/activates NF-κB and induces BCL10 phosphorylationMutation, 6.67% (1/15)Kiel et al., 2015Kiel M.J. Sahasrabuddhe A.A. Rolland D.C. Velusamy T. Chung F. Schaller M. et al.Genomic analyses reveal recurrent mutations in epigenetic modifiers and the JAK-STAT pathway in Sezary syndrome.Nat Commun. 2015; 6: 8470Crossref PubMed Scopus (150) Google Scholar: mutation, 7%da Silva Almeida et al., 2015da Silva Almeida A.C. Abate F. Khiabanian H. Martinez-Escala E. Guitart J. Tensen C.P. et al.The mutational landscape of cutaneous T cell lymphoma and Sezary syndrome.Nat Genet. 2015; 47: 1465-1470Crossref PubMed Scopus (272) Google Scholar: mutation, 8%Wang et al., 2015Wang L. Ni X. Covington K.R. Yang B.Y. Shiu J. Zhang X. et al.Genomic profiling of Sezary syndrome identifies alterations of key T cell signaling and differentiation genes.Nat Genet. 2015; 47: 1426-1434Crossref PubMed Scopus (232) Google Scholar: mutation, 22%CCR43p24T-cell migration into skin/leukocyte cell traffic/angiogenesisNot reportedWang et al., 2015Wang L. Ni X. Covington K.R. Yang B.Y. Shiu J. Zhang X. et al.Genomic profiling of Sezary syndrome identifies alterations of key T cell signaling and differentiation genes.Nat Genet. 2015; 47: 1426-1434Crossref PubMed Scopus (232) Google Scholar: mutation, 14%PKHD1L18q23Receptor with inducible T-lymphocyte expressionMutation, 13.33% (2/15)Kiel et al., 2015Kiel M.J. Sahasrabuddhe A.A. Rolland D.C. Velusamy T. Chung F. Schaller M. et al.Genomic analyses reveal recurrent mutations in epigenetic modifiers and the JAK-STAT pathway in Sezary syndrome.Nat Commun. 2015; 6: 8470Crossref PubMed Scopus (150) Google Scholar: mutation, 19%PLCG120q12–q13.1Intracellular transduction of receptor-mediated tyrosine kinase activatorsMutation, 6.67% (1/15)Choi et al., 2015Choi J. Goh G. Walradt T. Hong B.S. Bunick C.G. Chen K. et al.Genomic landscape of cutaneous T cell lymphoma.Nat Genet. 2015; 47: 1011-1019Crossref PubMed Scopus (287) Google Scholar: mutation, 4%da Silva Almeida et al., 2015da Silva Almeida A.C. Abate F. Khiabanian H. Martinez-Escala E. Guitart J. Tensen C.P. et al.The mutational landscape of cutaneous T cell lymphoma and Sezary syndrome.Nat Genet. 2015; 47: 1465-1470Crossref PubMed Scopus (272) Google Scholar: mutation, 12%Kiel et al., 2015Kiel M.J. Sahasrabuddhe A.A. Rolland D.C. Velusamy T. Chung F. Schaller M. et al.Genomic analyses reveal recurrent mutations in epigenetic modifiers and the JAK-STAT pathway in Sezary syndrome.Nat Commun. 2015; 6: 8470Crossref PubMed Scopus (150) Google Scholar: mutation, 10%Ungewickell et al., 2015Ungewickell A. Bhaduri A. Rios E. Reuter J. Lee C.S. Mah A. et al.Genomic analysis of mycosis fungoides and Sezary syndrome identifies recurrent alterations in TNFR2.Nat Genet. 2015; 47: 1056-1060Crossref PubMed Scopus (209) Google Scholar: mutation, 0% in SSWang et al., 2015Wang L. Ni X. Covington K.R. Yang B.Y. Shiu J. Zhang X. et al.Genomic profiling of Sezary syndrome identifies alterations of key T cell signaling and differentiation genes.Nat Genet. 2015; 47: 1426-1434Crossref PubMed Scopus (232) Google Scholar: mutation, 14%TNFRSF1B1p36.22Encodes the receptor TNFR2 that regulates key T-cell signaling pathwayNot reportedda Silva Almeida et al., 2015da Silva Almeida A.C. Abate F. Khiabanian H. Martinez-Escala E. Guitart J. Tensen C.P. et al.The mutational landscape of cutaneous T cell lymphoma and Sezary syndrome.Nat Genet. 2015; 47: 1465-1470Crossref PubMed Scopus (272) Google Scholar: mutation, 8%Ungewickell et al., 2015Ungewickell A. Bhaduri A. Rios E. Reuter J. Lee C.S. Mah A. et al.Genomic analysis of mycosis fungoides and Sezary syndrome identifies recurrent alterations in TNFR2.Nat Genet. 2015; 47: 1056-1060Crossref PubMed Scopus (209) Google Scholar: gain, 44%Wang et al., 2015Wang L. Ni X. Covington K.R. Yang B.Y. Shiu J. Zhang X. et al.Genomic profiling of Sezary syndrome identifies alterations of key T cell signaling and differentiation genes.Nat Genet. 2015; 47: 1426-1434Crossref PubMed Scopus (232) Google Scholar: mutation, 8%RAG211p13Initiation of V(D)J recombination during B- and T-cell development/T-cell differentiation in the thymusMutation, 6.67% (1/15)Kiel et al., 2015Kiel M.J. Sahasrabuddhe A.A. Rolland D.C. Velusamy T. Chung F. Schaller M. et al.Genomic analyses reveal recurrent mutations in epigenetic modifiers and the JAK-STAT pathway in Sezary syndrome.Nat Commun. 2015; 6: 8470Crossref PubMed Scopus (150) Google Scholar: mutation, 3%STAT5B17q11.2Transcription factor/transcriptional activator/T-cell receptor signaling/apoptosisMutation, 6.67% (1/15)Kiel et al., 2015Kiel M.J. Sahasrabuddhe A.A. Rolland D.C. Velusamy T. Chung F. Schaller M. et al.Genomic analyses reveal recurrent mutations in epigenetic modifiers and the JAK-STAT pathway in Sezary syndrome.Nat Commun. 2015; 6: 8470Crossref PubMed Scopus (150) Google Scholar: mutation, 2.77%Choi et al., 2015Choi J. Goh G. Walradt T. Hong B.S. Bunick C.G. Chen K. et al.Genomic landscape of cutaneous T cell lymphoma.Nat Genet. 2015; 47: 1011-1019Crossref PubMed Scopus (287) Google Scholar: mutation, 26%da Silva Almeida et al., 2015da Silva Almeida A.C. Abate F. Khiabanian H. Martinez-Escala E. Guitart J. Tensen C.P. et al.The mutational landscape of cutaneous T cell lymphoma and Sezary syndrome.Nat Genet. 2015; 47: 1465-1470Crossref PubMed Scopus (272) Google Scholar: mutation, 4%SignalingALDH1A19q21.13Alcohol metabolismMutation, 6.67% (1/15)—ANKRD2610p12.1Transcription factor binding sitesMutation, 6.67% (1/15)Kiel et al., 2015Kiel M.J. Sahasrabuddhe A.A. Rolland D.C. Velusamy T. Chung F. Schaller M. et al.Genomic analyses reveal recurrent mutations in epigenetic modifiers and the JAK-STAT pathway in Sezary syndrome.Nat Commun. 2015; 6: 8470Crossref PubMed Scopus (150) Google Scholar: mutation, 10%BRAF7q34MAP kinase signaling pathway/transduction of mitogenic signals from the cell membrane to the nucleusNot reportedChoi et al., 2015Choi J. Goh G. Walradt T. Hong B.S. Bunick C.G. Chen K. et al.Genomic landscape of cutaneous T cell lymphoma.Nat Genet. 2015; 47: 1011-1019Crossref PubMed Scopus (287) Google Scholar: mutation, 1%CRIP36p21.1Transcription factor binding sitesDuplication, 6.67% (1/15)—DAD114q11.2ApoptosisDeletion, 13.33% (2/15)—DSC118q12.1Cell adhesion and desmosome formationMutation, 13.33% (2/15)Kiel et al., 2015Kiel M.J. Sahasrabuddhe A.A. Rolland D.C. Velusamy T. Chung F. Schaller M. et al.Genomic analyses reveal recurrent mutations in epigenetic modifiers and the JAK-STAT pathway in Sezary syndrome.Nat Commun. 2015; 6: 8470Crossref PubMed Scopus (150) Google Scholar: mutation, 4%GLI37p13Transcription factor/mediators of Sonic hedgehog signalingMutation, 6.67% (1/15)Kiel et al., 2015Kiel M.J. Sahasrabuddhe A.A. Rolland D.C. Velusamy T. Chung F. Schaller M. et al.Genomic analyses reveal recurrent mutations in epigenetic modifiers and the JAK-STAT pathway in Sezary syndrome.Nat Commun. 2015; 6: 8470Crossref PubMed Scopus (150) Google Scholar: mutation, 11%FAS10q24.1ApoptosisNot reportedChoi et al., 2015Choi J. Goh G. Walradt T. Hong B.S. Bunick C.G. Chen K. et al.Genomic landscape of cutaneous T cell lymphoma.Nat Genet. 2015; 47: 1011-1019Crossref PubMed Scopus (287) Google Scholar: mutation, 19%Kiel et al., 2015Kiel M.J. Sahasrabuddhe A.A. Rolland D.C. Velusamy T. Chung F. Schaller M. et al.Genomic analyses reveal recurrent mutations in epigenetic modifiers and the JAK-STAT pathway in Sezary syndrome.Nat Commun. 2015; 6: 8470Crossref PubMed Scopus (150) Google Scholar: mutation, 3%Wang et al., 2015Wang L. Ni X. Covington K.R. Yang B.Y. Shiu J. Zhang X. et al.Genomic profiling of Sezary syndrome identifies alterations of key T cell signaling and differentiation genes.Nat Genet. 2015; 47: 1426-1434Crossref PubMed Scopus (232) Google Scholar: mutation, 8%IL67p21Inflammation and the maturation of B cellsMutation, 6.67% (1/15)Kiel et al., 2015Kiel M.J. Sahasrabuddhe A.A. Rolland D.C. Velusamy T. Chung F. Schaller M. et al.Genomic analyses reveal recurrent mutations in epigenetic modifiers and the JAK-STAT pathway in Sezary syndrome.Nat Commun. 2015; 6: 8470Crossref PubMed Scopus (150) Google Scholar: mutation, 1.4%ITPR13p26.1Intracellular receptor that mediates calcium release from endoplasmic reticulumMutation, 13.33% (2/15)Kiel et al., 2015Kiel M.J. Sahasrabuddhe A.A. Rolland D.C. Velusamy T. Chung F. Schaller M. et al.Genomic analyses reveal recurrent mutations in epigenetic modifiers and the JAK-STAT pathway in Sezary syndrome.Nat Commun. 2015; 6: 8470Crossref PubMed Scopus (150) Google Scholar: mutation, 4%ITPR212p11Mediates intracellular calcium release necessary for eccrine sweat productionMutation, 6.67% (1/15)Kiel et al., 2015Kiel M.J. Sahasrabuddhe A.A. Rolland D.C. Velusamy T. Chung F. Schaller M. et al.Genomic analyses reveal recurrent mutations in epigenetic modifiers and the JAK-STAT pathway in Sezary syndrome.Nat Commun. 2015; 6: 8470Crossref PubMed Scopus (150) Google Scholar: mutation, 4%PDE4C19p13.11Hydrolyzes the second messenger cAMPDeletion, 6.67% (1/15)Kiel et al., 2015Kiel M.J. Sahasrabuddhe A.A. Rolland D.C. Velusamy T. Chung F. Schaller M. et al.Genomic analyses reveal recurrent mutations in epigenetic modifiers and the JAK-STAT pathway in Sezary syndrome.Nat Commun. 2015; 6: 8470Crossref PubMed Scopus (150) Google Scholar: mutation, 3%PRKG110q11.2Nitric oxide/cGMP signaling pathway/signal transductionNot reportedda Silva Almeida et al., 2015da Silva Almeida A.C. Abate F. Khiabanian H. Martinez-Escala E. Guitart J. Tensen C.P. et al.The mutational landscape of cutaneous T cell lymphoma and Sezary syndrome.Nat Genet. 2015; 47: 1465-1470Crossref PubMed Scopus (272) Google Scholar: mutation, 8%Kiel et al., 2015Kiel M.J. Sahasrabuddhe A.A. Rolland D.C. Velusamy T. Chung F. Schaller M. et al.Genomic analyses reveal recurrent mutations in epigenetic modifiers and the JAK-STAT pathway in Sezary syndrome.Nat Commun. 2015; 6: 8470Crossref PubMed Scopus (150) Google Scholar: mutation, 3%RAMP37p13–p12Calcium ion transport/receptor signaling pathway in heart processDuplication, 6.67% (1/15)Kiel et al., 2015Kiel M.J. Sahasrabuddhe A.A. Rolland D.C. Velusamy T. Chung F. Schaller M. et al.Genomic analyses reveal recurrent mutations in epigenetic modifiers and the JAK-STAT pathway in Sezary syndrome.Nat Commun. 2015; 6: 8470Crossref PubMed Scopus (150) Google Scholar: mutation, 1.38%RHOACell migration/cytoskeleton organization/mitotic spindle assemblyNot reportedChoi et al., 2015Choi J. Goh G. Walradt T. Hong B.S. Bunick C.G. Chen K. et al.Genomic landscape of cutaneous T cell lymphoma.Nat Genet. 2015; 47: 1011-1019Crossref PubMed Scopus (287) Google Scholar: mutation, 3%Kiel et al., 2015Kiel M.J. Sahasrabuddhe A.A. Rolland D.C. Velusamy T. Chung F. Schaller M. et al.Genomic analyses reveal recurrent mutations in epigenetic modifiers and the JAK-STAT pathway in Sezary syndrome.Nat Commun. 2015; 6: 8470Crossref PubMed Scopus (150) Google Scholar: mutation, 1.4%Wang et al., 2015Wang L. Ni X. Covington K.R. Yang B.Y. Shiu J. Zhang X. et al.Genomic profiling of Sezary syndrome identifies alterations of key T cell signaling and differentiation genes.Nat Genet. 2015; 47: 1426-1434Crossref PubMed Scopus (232) Google Scholar: mutation, 5%RIPK28q21Activator of NF-κB/cytokine production/inducer of apoptosis/immune responseMutation, 6.67% (1/15)Kiel et al., 2015Kiel M.J. Sahasrabuddhe A.A. Rolland D.C. Velusamy T. Chung F. Schaller M. et al.Genomic analyses reveal recurrent mutations in epigenetic modifiers and the JAK-STAT pathway in Sezary syndrome.Nat Commun. 2015; 6: 8470Crossref PubMed Scopus (150) Google Scholar: mutation, 1.4%TBRG47p13Transcription factor binding sites/potential role in cell cycle progressionDuplication, 6.67% (1/15)—TNFAIP36q23Immune and inflammatory responses/NF-κB signaling pathwayNot reportedChoi et al., 2015Choi J. Goh G. Walradt T. Hong B.S. Bunick C.G. Chen K. et al.Genomic landscape of cutaneous T cell lymphoma.Nat Genet. 2015; 47: 1011-1019Crossref PubMed Scopus (287) Google Scholar: deletion, 25%Chromatin and DNA modifierARID1A1p35.3Chromatin remodelingNot reportedChoi et al., 2015Choi J. Goh G. Walradt T. Hong B.S. Bunick C.G. Chen K. et al.Genomic landscape of cutaneous T cell lymphoma.Nat Genet. 2015; 47: 1011-1019Crossref PubMed Scopus (287) Google Scholar: mutation, 25%Kiel et al., 2015Kiel M.J. Sahasrabuddhe A.A. Rolland D.C. Velusamy T. Chung F. Schaller M. et al.Genomic analyses reveal recurrent mutations in epigenetic modifiers and the JAK-STAT pathway in Sezary syndrome.Nat Commun. 2015; 6: 8470Crossref PubMed Scopus (150) Google Scholar: mutation, 10% (mutation/deletion 34%)Wang et al., 2015Wang L. Ni X. Covington K.R. Yang B.Y. Shiu J. Zhang X. et al.Genomic profiling of Sezary syndrome identifies alterations of key T cell signaling and differentiation genes.Nat Genet. 2015; 47: 1426-1434Crossref PubMed Scopus (232) Google Scholar: mutation, 8%DMNT3A2p23Epigenetic modifier required for methylationNot reportedChoi et al., 2015Choi J. Goh G. Walradt T. Hong B.S. Bunick C.G. Chen K. et al.Genomic landscape of