HAEM5:Sezary syndrome: Difference between revisions
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Balanced translocations have not been detected in SS<ref name=":0">1. Arber DA, et al., (2017). Sézary syndrome, in World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, Revised 4<sup>th</sup> edition. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Arber DA, Hasserjian RP, Le Beau MM, Orazi A, and Siebert R, Editors. IARC Press: Lyon, France, p390-391. </ref>. | Balanced translocations have not been detected in SS<ref name=":0">1. Arber DA, et al., (2017). Sézary syndrome, in World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, Revised 4<sup>th</sup> edition. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Arber DA, Hasserjian RP, Le Beau MM, Orazi A, and Siebert R, Editors. IARC Press: Lyon, France, p390-391. </ref>. | ||
Gene fusion between CTLA4 and CD28 is highly expressed. Additional fusion events include TYK2-UPF1, COL25A1-NFKB2, FASN-SGMS1, SMS1-ZEB1, SPATA21-RASA2, PITRM1-HK1, and BCR-NDUFAF6<ref name=": | Gene fusion between CTLA4 and CD28 is highly expressed. Additional fusion events include TYK2-UPF1, COL25A1-NFKB2, FASN-SGMS1, SMS1-ZEB1, SPATA21-RASA2, PITRM1-HK1, and BCR-NDUFAF6<ref name=":1">{{Cite journal|last=Prasad|first=Aparna|last2=Rabionet|first2=Raquel|last3=Espinet|first3=Blanca|last4=Zapata|first4=Luis|last5=Puiggros|first5=Anna|last6=Melero|first6=Carme|last7=Puig|first7=Anna|last8=Sarria-Trujillo|first8=Yaris|last9=Ossowski|first9=Stephan|date=2016-07|title=Identification of Gene Mutations and Fusion Genes in Patients with Sézary Syndrome|url=https://pubmed.ncbi.nlm.nih.gov/27039262|journal=The Journal of Investigative Dermatology|volume=136|issue=7|pages=1490–1499|doi=10.1016/j.jid.2016.03.024|issn=1523-1747|pmid=27039262}}</ref>. | ||
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* Gene Mutations (SNV/INDEL)}}</blockquote> | * Gene Mutations (SNV/INDEL)}}</blockquote> | ||
SS is aggressive; however, prognosis is variable and largely depends on stage. A median survival of 32 months and a 5-year survival rate of 10-30% has been reported <ref name=":0" />. Death usually results from opportunistic infections, as SS patients are at an increased risk for infection due to underlying immune dysfunction<ref name=":1" | SS is aggressive; however, prognosis is variable and largely depends on stage. A median survival of 32 months and a 5-year survival rate of 10-30% has been reported <ref name=":0" />. Death usually results from opportunistic infections, as SS patients are at an increased risk for infection due to underlying immune dysfunction<ref name=":1" />. Lymph node and visceral involvement are poor prognostic factors, as is the degree of peripheral blood involvement by Sézary cells. Bone marrow involvement is of unknown prognostic relevance <ref name=":0" />. | ||
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Recurrent gain-of-function mutations in SS include ''PLGC1'', ''CD28'', and ''TNFRSF1B''. Recurrent loss-of-function mutations include ''ARID1A'', which has been observed in 40% of SS cases<ref name=":0" />. | Recurrent gain-of-function mutations in SS include ''PLGC1'', ''CD28'', and ''TNFRSF1B''. Recurrent loss-of-function mutations include ''ARID1A'', which has been observed in 40% of SS cases<ref name=":0" />. | ||
Somatic duplications can be found ranging from duplications of chromosome bands (8p23.3-q24.3, 17p11.2-q23.2) to entire chromosomes (chr 18). Several somatic deletions have also been demonstrated including a 15-25 Mb deletion on 17p12-p13.3<ref name=": | Somatic duplications can be found ranging from duplications of chromosome bands (8p23.3-q24.3, 17p11.2-q23.2) to entire chromosomes (chr 18). Several somatic deletions have also been demonstrated including a 15-25 Mb deletion on 17p12-p13.3<ref name=":1" />. | ||
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Numerical and structural alterations are common in SS. These include loss of 1p, 6q, and 10q with gains of 7 and 8q<ref name=":4">{{Cite journal|displayauthors=1|last=Almeida|first=Ana|date=December 2015|title=The mutational landscape of cutaneous T cell lymphoma and Sezary syndrome|url=|journal=Nature Genetics|volume=47|pages=|via=}}</ref><ref name=": | Numerical and structural alterations are common in SS. These include loss of 1p, 6q, and 10q with gains of 7 and 8q<ref name=":1" /><ref name=":4">{{Cite journal|displayauthors=1|last=Almeida|first=Ana|date=December 2015|title=The mutational landscape of cutaneous T cell lymphoma and Sezary syndrome|url=|journal=Nature Genetics|volume=47|pages=|via=}}</ref><ref name=":2">{{Cite journal|last=da Silva Almeida|first=Ana Carolina|last2=Abate|first2=Francesco|last3=Khiabanian|first3=Hossein|last4=Martinez-Escala|first4=Estela|last5=Guitart|first5=Joan|last6=Tensen|first6=Cornelis P.|last7=Vermeer|first7=Maarten H.|last8=Rabadan|first8=Raul|last9=Ferrando|first9=Adolfo|date=2015-12|title=The mutational landscape of cutaneous T cell lymphoma and Sézary syndrome|url=https://pubmed.ncbi.nlm.nih.gov/26551667|journal=Nature Genetics|volume=47|issue=12|pages=1465–1470|doi=10.1038/ng.3442|issn=1546-1718|pmc=4878831|pmid=26551667}}</ref>. Isochromosome 17q is a recurrent finding in SS<ref name=":0" />. | ||
Deletions are often associated with loss of tumor suppressor genes such as recurrent deletions involving 17p13.1 (TP53), 13q14.2 (RB1), 10q23.3 (PTEN) and 12p13.1 (CDKN1B). Focal chromosome 2p23.3 deletions (DNMT3A) were observed | Deletions are often associated with loss of tumor suppressor genes such as recurrent deletions involving 17p13.1 (TP53), 13q14.2 (RB1), 10q23.3 (PTEN) and 12p13.1 (CDKN1B). Focal chromosome 2p23.3 deletions (DNMT3A) were observed<ref name=":2" />. | ||
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The mutational landscape of Sezary syndrome is complex and over 1000 different gene mutations have been identified. Mutational signature characterized by C>T substitutions at NpCpG trinucleotides and C>A substitutions at CpCpN trinucleotides and C>T substitutions at CpCpN and TpCpN trinulceotides have been identified<ref name=": | The mutational landscape of Sezary syndrome is complex and over 1000 different gene mutations have been identified. Mutational signature characterized by C>T substitutions at NpCpG trinucleotides and C>A substitutions at CpCpN trinucleotides and C>T substitutions at CpCpN and TpCpN trinulceotides have been identified<ref name=":2" />. | ||
''RHOA'' mutations have also been described in SS. Mutations (including single nucleotide mutations and copy number variants) in the JAK/STAT pathway likely result in the constitutive activation of ''STAT3'' in Sézary cells. Inactivating mutations in ''TP53'' and deletions of ''CDKN2A'' (p16INK4a) are frequent. Mutations in ''DNMT3A'' have been reported in SS<ref name=":0" />. | ''RHOA'' mutations have also been described in SS. Mutations (including single nucleotide mutations and copy number variants) in the JAK/STAT pathway likely result in the constitutive activation of ''STAT3'' in Sézary cells. Inactivating mutations in ''TP53'' and deletions of ''CDKN2A'' (p16INK4a) are frequent. Mutations in ''DNMT3A'' have been reported in SS<ref name=":0" />. | ||
Mutations in epigenetic regulator genes including TET2, CREBPP, KMT2C (MLL3) histone H3 lysine 4 (H3K4) methyltransferase, WI/SNF, and NuRD chromatin-remodeling complexes have been demonstrated as well<ref name=": | Mutations in epigenetic regulator genes including TET2, CREBPP, KMT2C (MLL3) histone H3 lysine 4 (H3K4) methyltransferase, WI/SNF, and NuRD chromatin-remodeling complexes have been demonstrated as well<ref name=":2" />. | ||
Recurrent mutations in TP53, ITPR1, DSC1 and PKHD1L1 are found in a cohort study by Prasad et al. The study found damaging mutations to ITPR1 in two Sezary Syndrome patients. ITPR1 mediates calcium release from the endoplasmic reticulum and may be functional partners with BCL2, which is an apoptosis suppressor. | Recurrent mutations in TP53, ITPR1, DSC1 and PKHD1L1 are found in a cohort study by Prasad et al. The study found damaging mutations to ITPR1 in two Sezary Syndrome patients. ITPR1 mediates calcium release from the endoplasmic reticulum and may be functional partners with BCL2, which is an apoptosis suppressor. | ||
Mutations in the p53, p15, p16, JunB, and PTEN genes are generally found in late-stage disease, suggesting that they are secondary genetic events after disease initiation<ref name=":3">{{Cite journal | Mutations in the p53, p15, p16, JunB, and PTEN genes are generally found in late-stage disease, suggesting that they are secondary genetic events after disease initiation<ref name=":3">{{Cite journal|last=Hwang|first=Sam T.|last2=Janik|first2=John E.|last3=Jaffe|first3=Elaine S.|last4=Wilson|first4=Wyndham H.|date=2008-03-15|title=Mycosis fungoides and Sézary syndrome|url=https://pubmed.ncbi.nlm.nih.gov/18342689|journal=Lancet (London, England)|volume=371|issue=9616|pages=945–957|doi=10.1016/S0140-6736(08)60420-1|issn=1474-547X|pmid=18342689}}</ref>. | ||
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Loss of Fas expression, which is involved in T-cell apoptotic pathways, has also been reported. Specifically, changes affecting the Fas ligand is seen in 50-83% of cases. Loss of Fas expression is seen in 14-59% of cases<ref name=":3" />. | Loss of Fas expression, which is involved in T-cell apoptotic pathways, has also been reported. Specifically, changes affecting the Fas ligand is seen in 50-83% of cases. Loss of Fas expression is seen in 14-59% of cases<ref name=":3" />. | ||
Genes involved in NF-kB signaling, chromatin remodeling, and DNA damage response have also been found to be altered. Notably, alterations to signaling pathways including Jak/signal transducer and activator of transcription (STAT) signaling and cell-cycle checkpoint have been shown to be involved in the pathogenesis<ref name=": | Genes involved in NF-kB signaling, chromatin remodeling, and DNA damage response have also been found to be altered. Notably, alterations to signaling pathways including Jak/signal transducer and activator of transcription (STAT) signaling and cell-cycle checkpoint have been shown to be involved in the pathogenesis<ref name=":1" />.<br /> | ||
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==References== | ==References== | ||
<references /> | <references /> | ||