HAEM5:Sezary syndrome: Difference between revisions

 

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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>.  

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" />.  

!Chr #!!Gain, Loss, Amp, LOH!!Minimal Region Cytoband and/or Genomic Coordinates [Genome Build; Size]!!Relevant Gene(s)

!Diagnostic, Prognostic, and Therapeutic Significance - D, P, T

!Established Clinical Significance Per Guidelines - Yes or No (Source)

!Clinical Relevance Details/Other Notes

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" />.  

!Prevalence -  

Common >20%, Recurrent 5-20% or Rare <5% (Disease)

!Diagnostic, Prognostic, and Therapeutic Significance - D, P, T

!Established Clinical Significance Per Guidelines - Yes or No (Source)

!Clinical Relevance Details/Other Notes

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<ref name=":2" />.

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!Gene!!Genetic Alteration!!Tumor Suppressor Gene, Oncogene, Other!!Prevalence -

Common >20%, Recurrent 5-20% or Rare <5% (Disease)

!Diagnostic, Prognostic, and Therapeutic Significance - D, P, T  

!Established Clinical Significance Per Guidelines - Yes or No (Source)

!Clinical Relevance Details/Other Notes

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" />.

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" />.

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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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 />