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| {{DISPLAYTITLE:Myelodysplastic neoplasm with biallelic TP53 inactivation}} | | {{DISPLAYTITLE:Myelodysplastic neoplasm with biallelic TP53 inactivation}} |
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| [[HAEM5:Table_of_Contents|Haematolymphoid Tumours (WHO Classification, 5th ed.)]] | | [[HAEM5:Table_of_Contents|Haematolymphoid Tumours (WHO Classification, 5th ed.)]] |
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| |Myelodysplastic neoplasm with biallelic TP53 inactivation | | |Myelodysplastic neoplasm with biallelic TP53 inactivation |
| |} | | |} |
| | ==Related Terminology== |
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| ==Definition / Description of Disease==
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| Myelodysplastic neoplasm with biallelic ''TP53'' inactivation (MDS-bi''TP53'') is a myeloid neoplasm which is characterized by ineffective hematopoiesis, manifesting clinically and pathologically as cytopenia(s), bone marrow morphologic dysplasia, and propensity to progress to acute myeloid leukemia, and which carries either two ''TP53'' mutations or a single mutation accompanied by either evidence of concurrent ''TP53'' deletion or copy-neutral loss of heterozygosity (LOH); in the appropriate setting, a pathogenic ''TP53'' variant with high variant allele fraction (VAF > 49%) can be considered presumptive evidence of biallelic inactivation status.<ref>{{Cite journal|last=Khoury|first=Joseph D.|last2=Solary|first2=Eric|last3=Abla|first3=Oussama|last4=Akkari|first4=Yassmine|last5=Alaggio|first5=Rita|last6=Apperley|first6=Jane F.|last7=Bejar|first7=Rafael|last8=Berti|first8=Emilio|last9=Busque|first9=Lambert|date=2022-07|title=The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Myeloid and Histiocytic/Dendritic Neoplasms|url=https://pubmed.ncbi.nlm.nih.gov/35732831|journal=Leukemia|volume=36|issue=7|pages=1703–1719|doi=10.1038/s41375-022-01613-1|issn=1476-5551|pmc=9252913|pmid=35732831}}</ref><ref name=":2" />
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| MDS bi-''TP53'' supersedes other genetically and morphologically defined MDS entities. By definition, in addition to the requirement for evidence of biallelic ''TP53'' inactivation, general criteria for diagnosis of MDS must be met and diagnostic criteria for acute myeloid leukemia must not be met. Acute erythroid leukemia, in which ''TP53'' mutations are common, must be specifically excluded by morphologic and/or immunophenotypic assessment.<ref name=":2" />
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| ==Synonyms / Terminology==
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| Myelodysplastic neoplasm with multi-hit ''TP53'' inactivation, MDS-bi''TP53''
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| ==Epidemiology / Prevalence==
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| Inactivating mutations or losses of ''TP53'', whether monoallelic or biallelic, have been reported to occur in approximately 11% of MDS, with a higher frequency in therapy-related MDS (18%) relative to ''de novo'' MDS (6%).<ref name=":0">{{Cite journal|last=Bernard|first=Elsa|last2=Nannya|first2=Yasuhito|last3=Hasserjian|first3=Robert P.|last4=Devlin|first4=Sean M.|last5=Tuechler|first5=Heinz|last6=Medina-Martinez|first6=Juan S.|last7=Yoshizato|first7=Tetsuichi|last8=Shiozawa|first8=Yusuke|last9=Saiki|first9=Ryunosuke|date=2020-10|title=Implications of TP53 allelic state for genome stability, clinical presentation and outcomes in myelodysplastic syndromes|url=https://pubmed.ncbi.nlm.nih.gov/32747829|journal=Nature Medicine|volume=26|issue=10|pages=1549–1556|doi=10.1038/s41591-020-1008-z|issn=1546-170X|pmc=8381722|pmid=32747829}}</ref> These genomic aberrations resulting in loss of ''TP53'' are present in a biallelic or multi-hit state in two-thirds of patients with MDS (with a higher reported frequency of 84% in patients with therapy-related disease).<ref name=":0" /> The incidence of MDS-bi''TP53'' has been estimated to be approximately 0.03 persons per 100,000 per year.<ref name=":2">Germing U., Claudi M., Zerbini N., et al. Myelodysplastic neoplasm with biallelic TP53 inactivation. In: WHO Classification of Tumours Editorial Board. Haematolymphoid tumours [Internet; beta version ahead of print]. Lyon (France): International Agency for Research on Cancer; 2022 [cited YYYY Mmm D]. (WHO classification of tumours series, 5th ed.; vol. 11). Available from: <nowiki>https://tumourclassification.iarc.who.int/chapters/63</nowiki>.</ref>
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| ==Clinical Features==
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| Signs and symptoms are typically nonspecific and related to cytopenias (unified thresholds for cytopenias in WHO5 diagnostic categories are detailed below, though these must be interpreted in the context of laboratory reference ranges, patient sex, and relevant comorbidities). ''TP53'' mutations show a strong association with thrombocytopenia in MDS.<ref name=":0" /><ref name=":1">{{Cite journal|last=Haase|first=Detlef|last2=Stevenson|first2=Kristen E.|last3=Neuberg|first3=Donna|last4=Maciejewski|first4=Jaroslaw P.|last5=Nazha|first5=Aziz|last6=Sekeres|first6=Mikkael A.|last7=Ebert|first7=Benjamin L.|last8=Garcia-Manero|first8=Guillermo|last9=Haferlach|first9=Claudia|date=2019-07|title=TP53 mutation status divides myelodysplastic syndromes with complex karyotypes into distinct prognostic subgroups|url=https://pubmed.ncbi.nlm.nih.gov/30635634|journal=Leukemia|volume=33|issue=7|pages=1747–1758|doi=10.1038/s41375-018-0351-2|issn=1476-5551|pmc=6609480|pmid=30635634}}</ref>
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|
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| *Anemia (hemoglobin < 130 g/L in males, < 120 g/L in females)
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| **Pallor, fatigue
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| *Neutropenia (absolute neutrophil count < 1.8x10<sup>9</sup>/L)
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| **Infection
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| *Thrombocytopenia (platelet count < 150x10<sup>9</sup>/L)
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| **Bruising, petechiae, bleeding
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| MDS-bi''TP53'' is a high-risk disease, with increased risk of leukemic transformation and decreased overall survival; this elevated risk is independent of IPSS-R risk stratification and persists in the context of allogeneic hematopoietic stem cell transplantation. In the absence of comprehensive assessment for copy number losses or copy neutral LOH affecting the ''TP53'' locus, evidence suggests that the presence of a ''TP53'' mutation at high (>40%) VAF, particularly in the context of a complex karyotype, may be associated with a similarly poor prognosis to MDS-bi''TP53''.<ref name=":0" /><ref name=":2" /><ref>{{Cite journal|last=Sallman|first=D. A.|last2=Komrokji|first2=R.|last3=Vaupel|first3=C.|last4=Cluzeau|first4=T.|last5=Geyer|first5=S. M.|last6=McGraw|first6=K. L.|last7=Al Ali|first7=N. H.|last8=Lancet|first8=J.|last9=McGinniss|first9=M. J.|date=2016-03|title=Impact of TP53 mutation variant allele frequency on phenotype and outcomes in myelodysplastic syndromes|url=https://pubmed.ncbi.nlm.nih.gov/26514544|journal=Leukemia|volume=30|issue=3|pages=666–673|doi=10.1038/leu.2015.304|issn=1476-5551|pmc=7864381|pmid=26514544}}</ref><ref>{{Cite journal|last=Grob|first=Tim|last2=Al Hinai|first2=Adil S. A.|last3=Sanders|first3=Mathijs A.|last4=Kavelaars|first4=François G.|last5=Rijken|first5=Melissa|last6=Gradowska|first6=Patrycja L.|last7=Biemond|first7=Bart J.|last8=Breems|first8=Dimitri A.|last9=Maertens|first9=Johan|date=2022-04-14|title=Molecular characterization of mutant TP53 acute myeloid leukemia and high-risk myelodysplastic syndrome|url=https://pubmed.ncbi.nlm.nih.gov/35108372|journal=Blood|volume=139|issue=15|pages=2347–2354|doi=10.1182/blood.2021014472|issn=1528-0020|pmid=35108372}}</ref>
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| {| class="wikitable"
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| |'''Signs and Symptoms'''
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| |Pallor
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|
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| Fatigue
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| Infection
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| Bruising
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| Bleeding
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| Petechiae
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| |-
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| |'''Laboratory Findings'''
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| |Anemia (hemoglobin < 130 g/L in males, < 120 g/L in females)
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| Neutropenia (neutrophils < 1.8x10<sup>9</sup>/L)
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| Thrombocytopenia (platelets < 150x10<sup>9</sup>/L)
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| Circulating blasts (+/-)
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| Elevated lactate dehydrogenase (+/-)
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| |}
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|
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| ==Sites of Involvement==
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| Bone marrow and peripheral blood; rarely, extramedullary proliferations occur.<ref>{{Cite journal|last=Fan|first=N.|last2=Lavu|first2=S.|last3=Hanson|first3=C. A.|last4=Tefferi|first4=A.|date=2018-11-19|title=Extramedullary hematopoiesis in the absence of myeloproliferative neoplasm: Mayo Clinic case series of 309 patients|url=https://pubmed.ncbi.nlm.nih.gov/30455416|journal=Blood Cancer Journal|volume=8|issue=12|pages=119|doi=10.1038/s41408-018-0156-6|issn=2044-5385|pmc=6242913|pmid=30455416}}</ref>
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| ==Morphologic Features==
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| Morphologic dysplasia is the hallmark of MDS, including MDS-bi''TP53''; by definition, at least one lineage . ''TP53'' mutations in MDS have been associated with particularly severe granulocytic dysplasia and with increased frequency of bone marrow blasts.<ref name=":0" /><ref name=":1" /><ref>{{Cite journal|last=Della Porta|first=M. G.|last2=Travaglino|first2=E.|last3=Boveri|first3=E.|last4=Ponzoni|first4=M.|last5=Malcovati|first5=L.|last6=Papaemmanuil|first6=E.|last7=Rigolin|first7=G. M.|last8=Pascutto|first8=C.|last9=Croci|first9=G.|date=2015-01|title=Minimal morphological criteria for defining bone marrow dysplasia: a basis for clinical implementation of WHO classification of myelodysplastic syndromes|url=https://pubmed.ncbi.nlm.nih.gov/24935723|journal=Leukemia|volume=29|issue=1|pages=66–75|doi=10.1038/leu.2014.161|issn=1476-5551|pmid=24935723}}</ref> ''TP53'' mutations are enriched in MDS associated with bone marrow fibrosis.<ref>{{Cite journal|last=Duarte|first=Fernando B.|last2=Barbosa|first2=Maritza C.|last3=Jesus Dos Santos|first3=Talyta E.|last4=Lemes|first4=Romélia P. G.|last5=Vasconcelos|first5=João P.|last6=de Vasconcelos|first6=Paulo R. L.|last7=Rocha|first7=Francisco D.|last8=Zalcberg|first8=Ilana|last9=Coutinho|first9=Diego F.|date=2018-05|title=Bone marrow fibrosis at diagnosis is associated with TP53 overexpression and adverse prognosis in low-risk myelodysplastic syndrome|url=https://pubmed.ncbi.nlm.nih.gov/28318026|journal=British Journal of Haematology|volume=181|issue=4|pages=547–549|doi=10.1111/bjh.14656|issn=1365-2141|pmid=28318026}}</ref><ref>{{Cite journal|last=Loghavi|first=Sanam|last2=Al-Ibraheemi|first2=Alyaa|last3=Zuo|first3=Zhuang|last4=Garcia-Manero|first4=Guillermo|last5=Yabe|first5=Mariko|last6=Wang|first6=Sa A.|last7=Kantarjian|first7=Hagop M.|last8=Yin|first8=Cameron C.|last9=Miranda|first9=Roberto N.|date=2015-10|title=TP53 overexpression is an independent adverse prognostic factor in de novo myelodysplastic syndromes with fibrosis|url=https://pubmed.ncbi.nlm.nih.gov/26123119|journal=British Journal of Haematology|volume=171|issue=1|pages=91–99|doi=10.1111/bjh.13529|issn=1365-2141|pmc=5577911|pmid=26123119}}</ref>
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| {| class="wikitable"
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| !Hematopoietic lineage
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| !Characteristic dysplastic features
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| |-
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| |'''Erythroid'''
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| |Nuclear budding
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| Internuclear bridging
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| Multinuclearity
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| Karyorrhexis
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| Megaloblastosis
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| Cytoplasmic vacuolation
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| Ring sideroblasts
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| Periodic acid Schiff positivity
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| |-
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| |'''Granulocytic'''
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| |Nuclear hyposegmentation (Pelgeroid changes)
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| Nuclear hypersegmentation
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| Cytoplasmic hypogranularity
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| Abnormally small cell size
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| Auer rods
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| Pseudo-Chédiak–Higashi granules
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| |-
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| |'''Megakaryocytic'''
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| |Nuclear hypolobation
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| Widely separated nuclear lobes
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|
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| Micromegakaryocytes
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| |}
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| [[File:Dysplastic_blood_and_bone_marrow_features_in_MDS.tif|alt=|thumb|1300x1300px|Multilineage dysplasia in MDS. Left: ''TP53'' mutation is associated with severe dysgranulopoiesis, including hypogranular and hypolobated neutrophils (black arrows). Center: Dysgranulopoiesis (arrows) and dyserythropoiesis with basophilic stippling and nuclear atypia (arrowheads). Right: Dysmegakaryopoiesis with separated nuclear lobes and small hypolobated cells (white arrows). Image from: Eric McGinnis, Vancouver General Hospital|none]]
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| <br />[[File:Bone marrow morphology in MDS biTP53.tif|thumb|1300x1300px|MDS-bi''TP53'' is associated with high-grade features, including increased blasts and bone marrow fibrosis, at an increased frequency. Left: Bone marrow showing disorganized hematopoiesis and increased numbers of blasts forming small clusters (white arrows). Center: Immunohistochemical staining for CD34 highlighting blasts in increased number and small dense blast clusters (arrowheads). Right: Bone marrow reticulin fibrosis (black arrows). Image from: Eric McGinnis, Vancouver General Hospital|alt=|none]]
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| <br />
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| ==Immunophenotype==
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| Immunophenotyping by flow cytometry using assays designed to detect abnormal numbers, light scatter characteristics, and antigen expression patterns of hematopoietic cells can provide useful data supportive of a diagnosis of MDS (and aid in blast enumeration); however, these findings are not specific to MDS-bi''TP53'' and are not formalized in current diagnostic criteria.<ref name=":2" /><ref>{{Cite journal|last=Kern|first=Wolfgang|last2=Westers|first2=Theresia M.|last3=Bellos|first3=Frauke|last4=Bene|first4=Marie Christine|last5=Bettelheim|first5=Peter|last6=Brodersen|first6=Lisa Eidenschink|last7=Burbury|first7=Kate|last8=Chu|first8=Sung-Chao|last9=Cullen|first9=Matthew|date=2023-01|title=Multicenter prospective evaluation of diagnostic potential of flow cytometric aberrancies in myelodysplastic syndromes by the ELN iMDS flow working group|url=https://pubmed.ncbi.nlm.nih.gov/36416672|journal=Cytometry. Part B, Clinical Cytometry|volume=104|issue=1|pages=51–65|doi=10.1002/cyto.b.22105|issn=1552-4957|pmid=36416672}}</ref>
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| Immunohistochemical evaluation of TP53 protein expression in bone marrow specimens can be used to inform ''TP53'' mutation status. Several studies evaluating TP53 protein expression in bone marrow specimens have consistently demonstrated nuclear overexpression (thought to result from stabilization of TP53 resulting from dominant negative mutations), when present in an increased fraction of cells, to be associated with pathogenic ''TP53'' mutation and to be similarly predictive of poor outcomes.<ref name=":3">{{Cite journal|last=Tashakori|first=Mehrnoosh|last2=Kadia|first2=Tapan|last3=Loghavi|first3=Sanam|last4=Daver|first4=Naval|last5=Kanagal-Shamanna|first5=Rashmi|last6=Pierce|first6=Sherry|last7=Sui|first7=Dawen|last8=Wei|first8=Peng|last9=Khodakarami|first9=Farnoosh|date=2022-07-07|title=TP53 copy number and protein expression inform mutation status across risk categories in acute myeloid leukemia|url=https://pubmed.ncbi.nlm.nih.gov/35390143|journal=Blood|volume=140|issue=1|pages=58–72|doi=10.1182/blood.2021013983|issn=1528-0020|pmc=9346958|pmid=35390143}}</ref><ref>{{Cite journal|last=Saft|first=Leonie|last2=Karimi|first2=Mohsen|last3=Ghaderi|first3=Mehran|last4=Matolcsy|first4=András|last5=Mufti|first5=Ghulam J.|last6=Kulasekararaj|first6=Austin|last7=Göhring|first7=Gudrun|last8=Giagounidis|first8=Aristoteles|last9=Selleslag|first9=Dominik|date=2014-06|title=p53 protein expression independently predicts outcome in patients with lower-risk myelodysplastic syndromes with del(5q)|url=https://pubmed.ncbi.nlm.nih.gov/24682512|journal=Haematologica|volume=99|issue=6|pages=1041–1049|doi=10.3324/haematol.2013.098103|issn=1592-8721|pmc=4040908|pmid=24682512}}</ref><ref>{{Cite journal|last=Loghavi|first=Sanam|last2=Al-Ibraheemi|first2=Alyaa|last3=Zuo|first3=Zhuang|last4=Garcia-Manero|first4=Guillermo|last5=Yabe|first5=Mariko|last6=Wang|first6=Sa A.|last7=Kantarjian|first7=Hagop M.|last8=Yin|first8=Cameron C.|last9=Miranda|first9=Roberto N.|date=2015-10|title=TP53 overexpression is an independent adverse prognostic factor in de novo myelodysplastic syndromes with fibrosis|url=https://pubmed.ncbi.nlm.nih.gov/26123119|journal=British Journal of Haematology|volume=171|issue=1|pages=91–99|doi=10.1111/bjh.13529|issn=1365-2141|pmc=5577911|pmid=26123119}}</ref><ref>{{Cite journal|last=Ruzinova|first=Marianna B.|last2=Lee|first2=Yi-Shan|last3=Duncavage|first3=Eric J.|last4=Welch|first4=John S.|date=2019-08|title=TP53 immunohistochemistry correlates with TP53 mutation status and clearance in decitabine-treated patients with myeloid malignancies|url=https://pubmed.ncbi.nlm.nih.gov/30792212|journal=Haematologica|volume=104|issue=8|pages=e345–e348|doi=10.3324/haematol.2018.205302|issn=1592-8721|pmc=6669137|pmid=30792212}}</ref><ref>{{Cite journal|last=Kubbutat|first=M. H.|last2=Jones|first2=S. N.|last3=Vousden|first3=K. H.|date=1997-05-15|title=Regulation of p53 stability by Mdm2|url=https://pubmed.ncbi.nlm.nih.gov/9153396|journal=Nature|volume=387|issue=6630|pages=299–303|doi=10.1038/387299a0|issn=0028-0836|pmid=9153396}}</ref> Complete absence of TP53 expression demonstrable by immunohistochemistry has similarly been associated with ''TP53'' mutation (typically frameshift, nonsense, and splice site, often with coexisting copy loss).<ref name=":3" />
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| <br />
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| [[File:TP53 IHC panel.tif|thumb|1300x1300px|Immunohistochemical evaluation of TP53 expression correlates with ''TP53'' mutation status in MDS-bi''TP53''. Left: Normal TP53 expression in MDS without ''TP53'' mutation; cells show variable nuclear staining. Center: TP53 overexpression in MDS with biallelic ''TP53'' inactivation resulting from a missense mutation and loss of 17p; the majority of cells show excessive nuclear staining. Right: Absence of TP53 expression in MDS with biallelic ''TP53'' inactivation resulting from a truncating mutation and loss of 17p; the great majority of cells show absence of any detectable TP53 staining.|alt=|none]]
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| {| class="wikitable"
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| |'''Positive (universal)'''
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| |N/A
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| |-
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| |'''Positive (subset)'''
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| |N/A
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| |-
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| |'''Negative (universal)'''
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| |N/A
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| |-
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| |'''Negative (subset)'''
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| |N/A
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| |}
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|
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| ==WHO Essential and Desirable Genetic Diagnostic Criteria==
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| <span style="color:#0070C0">(''Instructions: The table will have the diagnostic criteria from the WHO book <u>autocompleted</u>; remove any <u>non</u>-genetics related criteria. If applicable, add text about other classification'' ''systems that define this entity and specify how the genetics-related criteria differ.'')</span>
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| {| class="wikitable"
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| |+
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| |WHO Essential Criteria (Genetics)*
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| |-
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| |WHO Desirable Criteria (Genetics)*
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| |
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| |-
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| |Other Classification
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| |
| |
| |}
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| <nowiki>*</nowiki>Note: These are only the genetic/genomic criteria. Additional diagnostic criteria can be found in the [https://tumourclassification.iarc.who.int/home <u>WHO Classification of Tumours</u>].
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| ==Related Terminology==
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| <span style="color:#0070C0">(''Instructions: The table will have the related terminology from the WHO <u>autocompleted</u>.)''</span>
| |
| {| class="wikitable" | | {| class="wikitable" |
| |+ | | |+ |
| |Acceptable | | |Acceptable |
| | | | |Myelodysplastic neoplasm with muti-hit TP53 inactivation |
| |- | | |- |
| |Not Recommended | | |Not Recommended |
| | | | |N/A |
| |} | | |} |
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| !Clinical Relevance Details/Other Notes | | !Clinical Relevance Details/Other Notes |
| |- | | |- |
| | | | |N/A |
| | | | |N/A |
| | | | |N/A |
| | | | |N/A |
| | | | |N/A |
| | | | |N/A |
| | | | |N/A |
| | | | |N/A |
| |} | | |} |
|
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| <br />
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| ==Individual Region Genomic Gain/Loss/LOH== | | ==Individual Region Genomic Gain/Loss/LOH== |
| Put your text here and fill in the table <span style="color:#0070C0">(''Instructions: Includes aberrations not involving gene rearrangements. Details on clinical significance such as prognosis and other important information can be provided in the notes section. Can refer to CGC workgroup tables as linked on the homepage if applicable. Please include references throughout the table. Do not delete the table.'') </span>
| | MDS bi-''TP53'' is strongly associated with karyotype complexity, with a higher average number of cytogenetic abnormalities (rearrangements, copy gains, and copy losses) relative to MDS with unmutated ''TP53'' or with monoallelic mutation, with particular predilection for recurrent copy number losses.<ref name=":1">{{Cite journal|last=Haase|first=Detlef|last2=Stevenson|first2=Kristen E.|last3=Neuberg|first3=Donna|last4=Maciejewski|first4=Jaroslaw P.|last5=Nazha|first5=Aziz|last6=Sekeres|first6=Mikkael A.|last7=Ebert|first7=Benjamin L.|last8=Garcia-Manero|first8=Guillermo|last9=Haferlach|first9=Claudia|date=2019-07|title=TP53 mutation status divides myelodysplastic syndromes with complex karyotypes into distinct prognostic subgroups|url=https://pubmed.ncbi.nlm.nih.gov/30635634|journal=Leukemia|volume=33|issue=7|pages=1747–1758|doi=10.1038/s41375-018-0351-2|issn=1476-5551|pmc=6609480|pmid=30635634}}</ref><ref name=":0">{{Cite journal|last=Bernard|first=Elsa|last2=Nannya|first2=Yasuhito|last3=Hasserjian|first3=Robert P.|last4=Devlin|first4=Sean M.|last5=Tuechler|first5=Heinz|last6=Medina-Martinez|first6=Juan S.|last7=Yoshizato|first7=Tetsuichi|last8=Shiozawa|first8=Yusuke|last9=Saiki|first9=Ryunosuke|date=2020-10|title=Implications of TP53 allelic state for genome stability, clinical presentation and outcomes in myelodysplastic syndromes|url=https://pubmed.ncbi.nlm.nih.gov/32747829|journal=Nature Medicine|volume=26|issue=10|pages=1549–1556|doi=10.1038/s41591-020-1008-z|issn=1546-170X|pmc=8381722|pmid=32747829}}</ref> Recurrent chromosomal gains, losses, and regions of LOH described which have been observed at higher frequency in MDS-bi''TP53'' include<ref name=":0" /><ref name=":2">Germing U., Claudi M., Zerbini N., et al. Myelodysplastic neoplasm with biallelic TP53 inactivation. In: WHO Classification of Tumours Editorial Board. Haematolymphoid tumours [Internet; beta version ahead of print]. Lyon (France): International Agency for Research on Cancer; 2022 [cited YYYY Mmm D]. (WHO classification of tumours series, 5th ed.; vol. 11). Available from: <nowiki>https://tumourclassification.iarc.who.int/chapters/63</nowiki>.</ref><ref name=":1" /> |
| {| class="wikitable sortable"
| |
| |-
| |
| !Chr #!!'''Gain, Loss, Amp, LOH'''!!'''Minimal Region Cytoband and/or Genomic Coordinates [Genome Build; Size]'''!!'''Relevant Gene(s)'''
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| !'''Diagnostic, Prognostic, and Therapeutic Significance - D, P, T'''
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| !'''Established Clinical Significance Per Guidelines - Yes or No (Source)'''
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| !'''Clinical Relevance Details/Other Notes'''
| |
| |-
| |
| |<span class="blue-text">EXAMPLE:</span>
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| 7
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| |<span class="blue-text">EXAMPLE:</span> Loss | |
| |<span class="blue-text">EXAMPLE:</span> | |
| chr7
| |
| |<span class="blue-text">EXAMPLE:</span> | |
| Unknown
| |
| |<span class="blue-text">EXAMPLE:</span> D, P | |
| |<span class="blue-text">EXAMPLE:</span> No | |
| |<span class="blue-text">EXAMPLE:</span> | |
| Presence of monosomy 7 (or 7q deletion) is sufficient for a diagnosis of AML with MDS-related changes when there is ≥20% blasts and no prior therapy (add reference). Monosomy 7/7q deletion is associated with a poor prognosis in AML (add references).
| |
| |- | |
| |<span class="blue-text">EXAMPLE:</span> | |
| 8
| |
| |<span class="blue-text">EXAMPLE:</span> Gain | |
| |<span class="blue-text">EXAMPLE:</span> | |
| chr8
| |
| |<span class="blue-text">EXAMPLE:</span> | |
| Unknown
| |
| |<span class="blue-text">EXAMPLE:</span> D, P | |
| | | |
| |<span class="blue-text">EXAMPLE:</span>
| |
| Common recurrent secondary finding for t(8;21) (add references).
| |
| |- | |
| |<span class="blue-text">EXAMPLE:</span> | |
| 17
| |
| |<span class="blue-text">EXAMPLE:</span> Amp | |
| |<span class="blue-text">EXAMPLE:</span> | |
| 17q12; chr17:39,700,064-39,728,658 [hg38; 28.6 kb]
| |
| |<span class="blue-text">EXAMPLE:</span> | |
| ''ERBB2''
| |
| |<span class="blue-text">EXAMPLE:</span> D, P, T
| |
| | | |
| |<span class="blue-text">EXAMPLE:</span> | |
| Amplification of ''ERBB2'' is associated with HER2 overexpression in HER2 positive breast cancer (add references). Add criteria for how amplification is defined.
| |
| |- | |
| | | |
| | | |
| | | |
| | | |
| | | |
| | | |
| | | |
| |} | |
| | |
| MDS bi-''TP53'' is strongly associated with karyotype complexity, with a higher average number of cytogenetic abnormalities (rearrangements, copy gains, and copy losses) relative to MDS with unmutated ''TP53'' or with monoallelic mutation, with particular predilection for recurrent copy number losses.<ref name=":1" /><ref name=":0" /> Recurrent chromosomal gains, losses, and regions of LOH described which have been observed at higher frequency in MDS-bi''TP53'' include<ref name=":0" /><ref name=":2" /><ref name=":1" />:
| |
| | |
| '''Loss / Deletion'''
| |
| | |
| *Deletion 5q (most common co-occurring abnormality)
| |
| *Loss of chromosome 7 or deletion 7q (second most common co-occurring abnormality)
| |
| *Deletion 17p
| |
| *Deletion 12p
| |
| *Losses involving chromosome 13
| |
| *Losses involving chromosome 18
| |
| *Deletion 20q
| |
| | |
| '''Gain'''
| |
| | |
| *Trisomy 8
| |
| *Trisomy 21
| |
| *Gain of 1p
| |
| *Trisomy 22
| |
| *Gain of 11q
| |
| | |
|
| |
|
| Copy-neutral LOH involving chromosome 17p and the ''TP53'' locus is a component of the diagnostic definition of MDS-bi''TP53'' and has been reported to occur in 21% of patients with this disease, usually in the setting of a single ''TP53'' mutation (i.e. not typically in association with more than one distinct ''TP53'' mutation).<ref name=":0" /> It is not currently known whether other instances of recurrent copy-neutral LOH in myeloid neoplasms are observed at significantly higher frequency in MDS-bi''TP53''. | | Copy-neutral LOH involving chromosome 17p and the ''TP53'' locus is a component of the diagnostic definition of MDS-bi''TP53'' and has been reported to occur in 21% of patients with this disease, usually in the setting of a single ''TP53'' mutation (i.e. not typically in association with more than one distinct ''TP53'' mutation).<ref name=":0" /> It is not currently known whether other instances of recurrent copy-neutral LOH in myeloid neoplasms are observed at significantly higher frequency in MDS-bi''TP53''. |
| Line 262: |
Line 62: |
| |'''Chr #''' | | |'''Chr #''' |
| |'''Gain/Loss/Amp/LOH''' | | |'''Gain/Loss/Amp/LOH''' |
| |'''Minimal Region Genomic Coordinates [Genome Build]'''
| | !Minimal Region Cytoband and/or Genomic Coordinates [Genome Build; Size] |
| |'''Minimal Region Cytoband''' | | |'''Relevant Gene(s)''' |
| |'''Diagnostic Significance (Yes, No or Unknown)'''
| | !Diagnostic, Prognostic, and Therapeutic Significance - D, P, T |
| |'''Prognostic Significance'''
| | |'''Established Clinical Significance Per Guidelines - Yes or No (Source)''' |
| | | !Clinical Relevance Details/Other Notes |
| '''(Yes, No or Unknown)'''
| |
| |'''Therapeutic Significance''' | |
| | |
| '''(Yes, No or Unknown)'''
| |
| |'''Notes'''
| |
| |- | | |- |
| |1 | | |1 |
| |Gain | | |Gain |
| | |1p |
| | | | | |
| |1p
| |
| |No
| |
| |No* | | |No* |
| |No | | |No |
| Line 284: |
Line 78: |
| |5 | | |5 |
| |Loss | | |Loss |
| | |5q |
| | | | | |
| |5q
| |
| |No
| |
| |No* | | |No* |
| |No | | |No |
| Line 293: |
Line 86: |
| |7 | | |7 |
| |Loss | | |Loss |
| | |chr7 / 7q |
| | | | | |
| |chr7 / 7q
| |
| |No
| |
| |No* | | |No* |
| |No | | |No |
| Line 302: |
Line 94: |
| |8 | | |8 |
| |Gain | | |Gain |
| | |chr8 |
| | | | | |
| |chr8
| |
| |No
| |
| |No* | | |No* |
| |No | | |No |
| Line 311: |
Line 102: |
| |11 | | |11 |
| |Gain | | |Gain |
| | |11q |
| | | | | |
| |11q
| |
| |No
| |
| |No* | | |No* |
| |No | | |No |
| Line 320: |
Line 110: |
| |12 | | |12 |
| |Loss | | |Loss |
| | |12p |
| | | | | |
| |12p
| |
| |No
| |
| |No* | | |No* |
| |No | | |No |
| Line 329: |
Line 118: |
| |13 | | |13 |
| |Loss | | |Loss |
| | |13q |
| | | | | |
| |13q
| |
| |No
| |
| |No* | | |No* |
| |No | | |No |
| Line 338: |
Line 126: |
| |17 | | |17 |
| |Loss / LOH | | |Loss / LOH |
| |
| |
| |17p | | |17p |
| |Yes | | |''TP53'' |
| |Yes** | | |D,P,T |
| |Yes | | |Yes (WHO/ICC/NCCN) |
| |Key component of entity classification | | |Key component of entity classification |
| |- | | |- |
| Line 349: |
Line 136: |
| | | | | |
| | | | | |
| |No
| |
| |No* | | |No* |
| |No | | |No |
| Line 356: |
Line 142: |
| |20 | | |20 |
| |Loss | | |Loss |
| | |20q |
| | | | | |
| |20q
| |
| |No
| |
| |No* | | |No* |
| |No | | |No |
| Line 365: |
Line 150: |
| |21 | | |21 |
| |Gain | | |Gain |
| | |chr21 |
| | | | | |
| |chr21
| |
| |No
| |
| |No* | | |No* |
| |No | | |No |
| Line 374: |
Line 158: |
| |22 | | |22 |
| |Gain | | |Gain |
| | |chr22 |
| | | | | |
| |chr22
| |
| |No
| |
| |No* | | |No* |
| |No | | |No |
| Line 386: |
Line 169: |
|
| |
|
| ==Characteristic Chromosomal or Other Global Mutational Patterns== | | ==Characteristic Chromosomal or Other Global Mutational Patterns== |
| Put your text here and fill in the table <span style="color:#0070C0">(I''nstructions: Included in this category are alterations such as hyperdiploid; gain of odd number chromosomes including typically chromosome 1, 3, 5, 7, 11, and 17; co-deletion of 1p and 19q; complex karyotypes without characteristic genetic findings; chromothripsis; microsatellite instability; homologous recombination deficiency; mutational signature pattern; etc. Details on clinical significance such as prognosis and other important information can be provided in the notes section. Please include references throughout the table. Do not delete the table.'')</span>
| |
| {| class="wikitable sortable"
| |
| |-
| |
| !Chromosomal Pattern
| |
| !Molecular Pathogenesis
| |
| !'''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'''
| |
| |-
| |
| |<span class="blue-text">EXAMPLE:</span>
| |
| Co-deletion of 1p and 18q
| |
| |<span class="blue-text">EXAMPLE:</span> See chromosomal rearrangements table as this pattern is due to an unbalanced derivative translocation associated with oligodendroglioma (add reference).
| |
| |<span class="blue-text">EXAMPLE:</span> Common (Oligodendroglioma)
| |
| |<span class="blue-text">EXAMPLE:</span> D, P
| |
| |
| |
| |
| |
| |-
| |
| |<span class="blue-text">EXAMPLE:</span>
| |
| Microsatellite instability - hypermutated
| |
| |
| |
| |<span class="blue-text">EXAMPLE:</span> Common (Endometrial carcinoma)
| |
| |<span class="blue-text">EXAMPLE:</span> P, T
| |
| |
| |
| |
| |
| |-
| |
| |
| |
| |
| |
| |
| |
| |
| |
| |
| |
| |
| |
| |}
| |
|
| |
| MDS-bi''TP53'' is strongly associated with complex (and monosomal) karyotypes; patients with biallelic inactivation of ''TP53'' showed significantly higher numbers of distinct cytogenetic abnormalities (median six excluding chromosome 17) relative to patients with monoallelic inactivation (median one), and a large majority of these tend to be accounted for by abnormalities associated with genomic loss (deletion/monosomy), with a median of four such abnormalities in MDS-bi''TP53'', which are particularly enriched for deletions involving chromosome 5q (identified in 85% of patients).<ref name=":0" /><ref name=":2" /><ref name=":1" /> Abnormalities involving chromosome 17p resulting in ''TP53'' loss are, by virtue of diagnostic criteria, present in approximately one third of MDS bi-''TP53'', in which they may result from simple deletion or unbalanced rearrangement, and which may in cases be submicroscopic/cryptic to analysis of banded chromosomes.<ref name=":0" />
| |
| [[File:Complex karyotype with loss of 17p in MDS with biTP53.tif|thumb|1300x1300px|MDS-bi''TP53'' is strongly associated with complex and monosomal karyotypes. Left: Cytogenetic analysis of bone marrow cells in MDS showing a complex karyotype with deletion of 17p and characteristic recurrent abnormalities, including del(5q), del(7q), del(20q), and loss of chromosome 18. Center: Interphase FISH showing deletion of one ''TP53'' locus resulting from the del(17p). Right: Loss of 17p material resulting in deletion of ''TP53'' often results from unbalanced rearrangements involving 17p (top) or deletion of 17p (bottom) in the context of a complex karyotype.
| |
|
| |
| Image from: Eric McGinnis, Vancouver General Hospital|alt=|none]]
| |
| {| class="wikitable" | | {| class="wikitable" |
| |'''Chromosomal Pattern''' | | |'''Chromosomal Pattern''' |
| |'''Diagnostic Significance (Yes, No or Unknown)''' | | |'''Molecular Pathogenesis''' |
| |'''Prognostic Significance''' | | |'''Prevalence''' |
| | | |Diagnostic, Prognostic, and Therapeutic Significance - D, P, T |
| '''(Yes, No or Unknown)'''
| | !Established Clinical Significance Per Guidelines - Yes or No (Source) |
| |'''Therapeutic Significance'''
| | !Clinical Relevance Details/Other Notes |
| | |
| '''(Yes, No or Unknown)'''
| |
| |'''Notes'''
| |
| |- | | |- |
| |Complex karyotype | | |Complex karyotype |
| |No (see note) | | | |
| | |Common |
| | |D,P,T (see note) |
| |Yes (see note) | | |Yes (see note) |
| |No (see note)
| |
| |Often with abnormalities resulting in chromosomal losses, especially involving chromosome 5q and chromosome 7 | | |Often with abnormalities resulting in chromosomal losses, especially involving chromosome 5q and chromosome 7 |
| Complex karyotypes are strongly associated with MDS-bi''TP53'' and, in the absence of available data for identification of LOH at the ''TP53'' locus, may be suggestive of biallelic inactivation and may be associated with similarly poor prognosis | | Complex karyotypes are strongly associated with MDS-bi''TP53'' and, in the absence of available data for identification of LOH at the ''TP53'' locus, may be suggestive of biallelic inactivation and may be associated with similarly poor prognosis |
| |} | | |} |
| | MDS-bi''TP53'' is strongly associated with complex (and monosomal) karyotypes; patients with biallelic inactivation of ''TP53'' showed significantly higher numbers of distinct cytogenetic abnormalities (median six excluding chromosome 17) relative to patients with monoallelic inactivation (median one), and a large majority of these tend to be accounted for by abnormalities associated with genomic loss (deletion/monosomy), with a median of four such abnormalities in MDS-bi''TP53'', which are particularly enriched for deletions involving chromosome 5q (identified in 85% of patients).<ref name=":0" /><ref name=":2" /><ref name=":1" /> Abnormalities involving chromosome 17p resulting in ''TP53'' loss are, by virtue of diagnostic criteria, present in approximately one third of MDS bi-''TP53'', in which they may result from simple deletion or unbalanced rearrangement, and which may in cases be submicroscopic/cryptic to analysis of banded chromosomes.<ref name=":0" /> |
|
| |
|
| ==Gene Mutations (SNV/INDEL)==
| | [[File:Complex karyotype with loss of 17p in MDS with biTP53.tif|thumb|1300x1300px|MDS-bi''TP53'' is strongly associated with complex and monosomal karyotypes. Left: Cytogenetic analysis of bone marrow cells in MDS showing a complex karyotype with deletion of 17p and characteristic recurrent abnormalities, including del(5q), del(7q), del(20q), and loss of chromosome 18. Center: Interphase FISH showing deletion of one ''TP53'' locus resulting from the del(17p). Right: Loss of 17p material resulting in deletion of ''TP53'' often results from unbalanced rearrangements involving 17p (top) or deletion of 17p (bottom) in the context of a complex karyotype. |
| Put your text here and fill in the table <span style="color:#0070C0">(''Instructions: This table is not meant to be an exhaustive list; please include only genes/alterations that are recurrent or common as well either disease defining and/or clinically significant. If a gene has multiple mechanisms depending on the type or site of the alteration, add multiple entries in the table. For clinical significance, denote associations with FDA-approved therapy (not an extensive list of applicable drugs) and NCCN or other national guidelines if applicable; Can also refer to CGC workgroup tables as linked on the homepage if applicable as well as any high impact papers or reviews of gene mutations in this entity. Details on clinical significance such as prognosis and other important information such as concomitant and mutually exclusive mutations can be provided in the notes section. Please include references throughout the table. Do not delete the table.'') </span>
| |
| {| class="wikitable sortable"
| |
| |- | |
| !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'''
| |
| |-
| |
| |<span class="blue-text">EXAMPLE:</span>''EGFR''
| |
|
| |
|
| <br />
| | Image from: Eric McGinnis, Vancouver General Hospital|alt=|none]] |
| |<span class="blue-text">EXAMPLE:</span> Exon 18-21 activating mutations
| |
| |<span class="blue-text">EXAMPLE:</span> Oncogene
| |
| |<span class="blue-text">EXAMPLE:</span> Common (lung cancer)
| |
| |<span class="blue-text">EXAMPLE:</span> T
| |
| |<span class="blue-text">EXAMPLE:</span> Yes (NCCN)
| |
| |<span class="blue-text">EXAMPLE:</span> Exons 18, 19, and 21 mutations are targetable for therapy. Exon 20 T790M variants cause resistance to first generation TKI therapy and are targetable by second and third generation TKIs (add references).
| |
| |-
| |
| |<span class="blue-text">EXAMPLE:</span> ''TP53''; Variable LOF mutations
| |
| <br />
| |
| |<span class="blue-text">EXAMPLE:</span> Variable LOF mutations
| |
| |<span class="blue-text">EXAMPLE:</span> Tumor Supressor Gene
| |
| |<span class="blue-text">EXAMPLE:</span> Common (breast cancer)
| |
| |<span class="blue-text">EXAMPLE:</span> P
| |
| |
| |
| |<span class="blue-text">EXAMPLE:</span> >90% are somatic; rare germline alterations associated with Li-Fraumeni syndrome (add reference). Denotes a poor prognosis in breast cancer.
| |
| |-
| |
| |<span class="blue-text">EXAMPLE:</span> ''BRAF''; Activating mutations
| |
| |<span class="blue-text">EXAMPLE:</span> Activating mutations
| |
| |<span class="blue-text">EXAMPLE:</span> Oncogene
| |
| |<span class="blue-text">EXAMPLE:</span> Common (melanoma)
| |
| |<span class="blue-text">EXAMPLE:</span> T | |
| | | |
| |
| |
| |-
| |
| |
| |
| |
| |
| |
| |
| |
| |
| |
| |
| |
| |
| |
| |
| |}Note: A more extensive list of mutations can be found in [https://www.cbioportal.org/ <u>cBioportal</u>], [https://cancer.sanger.ac.uk/cosmic <u>COSMIC</u>], and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content.
| |
|
| |
|
| At least one mutation involving ''[[TP53]]'' is required to establish a diagnosis of MDS bi''TP53''; a second distinct mutation involving ''TP53'', fulfilling diagnostic criteria without deletion or copy neutral LOH, is identified in approximately one third of patients with MDS-bi''TP53''.<ref name=":2" /><ref name=":0" /> ''TP53'' mutations reported in MDS-bi''TP53'' show a similar pattern of distribution to those previously reported, primarily clustering in the DNA-binding domain with smaller numbers of (primarily truncating) mutations upstream (extending to the transactivation domain) or downstream (extending downstream of the oligomerization domain); available data suggest approximately 70% of mutations to be missense variants, 28% (a higher frequency than was observed in MDS with monoallelic ''TP53'' mutation) to be truncating (including nonsense, frameshift, splice site, and nonstop variants), and a small fraction to be in-frame deletions or insertions.<ref name=":0" /> In MDS-bi''TP53'', 20% of ''TP53'' variants identified were accounted for by hotspot mutations affecting amino acids 273, 220, 248, and 175 (in order of descending frequency). Variants identified in the context of multiple distinct ''TP53'' mutations have been reported with a median VAF of 32% (range: 2% to 52%) while those associated with a second hit resulting from ''TP53'' locus deletion or copy-neutral LOH have a reported median VAF of 41% (2% to 92% with a bimodal distribution) and 71% (2% to 98%), respectively.<ref name=":0" />
| | ==Gene Mutations (SNV/INDEL)== |
| | |
| ''TP53''-mutated MDS, in general, tends to carry fewer cooperating somatic mutations that MDS without ''TP53'' mutation; MDS bi-''TP53'' is further associated with fewer cooperating somatic mutations than MDS with monoallelic inactivation of ''TP53'', with 40% of MDS-bi''TP53'' reported to show no additional identifiable driver mutations.<ref name=":0" /><ref name=":1" /> Genes recurrently mutated in this group are similar to those described in MDS in general, and include ''DNMT3A'', ''TET2'', ''ASXL1'', ''U2AF1'', ''PPM1D'', ''EZH2'', ''SF3B1'', ''NF1''; infrequently, comutations identified include ''BCOR'', ''JAK2'', and ''CBL''. MDS carrying at least one mutation in ''TP53'', as a whole, has been observed to less frequently carry mutations in ''ASXL1'', ''U2AF1'', and ''RUNX1'', while MDS-bi''TP53'' has been observed to have lower rates of ''TET2'', ''SF3B1'', ''ASXL1'', ''SRSF2'', and ''RUNX1'' mutation relative to MDS with a single ''TP53'' mutation.<ref name=":0" /><ref name=":1" />
| |
| | |
| Note: A more extensive list of mutations can be found in cBioportal (https://www.cbioportal.org/), COSMIC (https://cancer.sanger.ac.uk/cosmic), ICGC (https://dcc.icgc.org/) and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content.
| |
| {| class="wikitable" | | {| class="wikitable" |
| |'''Gene; Genetic Alteration''' | | |'''Gene; Genetic Alteration''' |
| |'''Presumed Mechanism (Tumor Suppressor Gene (TSG)/Oncogene/Other)''' | | |'''Genetic Alteration''' |
| |'''Prevalence (COSMIC/ TCGA/Other)'''
| | !Tumor Suppressor Gene, Oncogene, Other |
| |'''Concomitant Mutations'''
| | !Prevalence - |
| |'''Mutually Exclusive Mutations'''
| | Common >20%, Recurrent 5-20% or Rare <5% (Disease) |
| |'''Diagnostic Significance (Yes, No or Unknown)''' | | |'''Diagnostic, Prognostic, and Therapeutic Significance - D, P, T''' |
| |'''Prognostic Significance'''
| | |'''Established Clinical Significance Per Guidelines - Yes or No (Source)''' |
| | | |'''Clinical Relevance Details/Other Notes''' |
| '''(Yes, No or Unknown)'''
| |
| |'''Therapeutic Significance''' | |
| | |
| '''(Yes, No or Unknown)'''
| |
| |'''Notes''' | |
| |- | | |- |
| |''TP53;'' LOF and/or GOF mutations | | |''[[TP53]]'' |
| | |LOF and/or GOF mutations |
| |Tumor Suppressor Gene / Oncogene (GOF variants) | | |Tumor Suppressor Gene / Oncogene (GOF variants) |
| |100% (entity-defining for MDS-bi''TP53'') | | |100% (entity-defining for MDS-bi''TP53'') |
| |''DNMT3A, TET2, ASXL1, U2AF1, PPM1D, EZH2, SF3B1, NF1'' (see note) | | |D, P, T |
| |None
| | |Yes (WHO/ICC/NCCN) |
| |Yes
| |
| |Yes
| |
| |Yes (see note) | |
| |MDS-bi''TP53'' carries, on average, less cooperating somatic mutations than MDS without ''TP53'' mutation | | |MDS-bi''TP53'' carries, on average, less cooperating somatic mutations than MDS without ''TP53'' mutation |
| MDS-bi''TP53'' is associated with poorer responses to most therapeutic modalities | | MDS-bi''TP53'' is associated with poorer responses to most therapeutic modalities |
| |} | | |} |
|
| |
|
| | At least one mutation involving ''[[TP53]]'' is required to establish a diagnosis of MDS bi''TP53''; a second distinct mutation involving ''TP53'', fulfilling diagnostic criteria without deletion or copy neutral LOH, is identified in approximately one third of patients with MDS-bi''TP53''.<ref name=":2" /><ref name=":0" /> ''TP53'' mutations reported in MDS-bi''TP53'' show a similar pattern of distribution to those previously reported, primarily clustering in the DNA-binding domain with smaller numbers of (primarily truncating) mutations upstream (extending to the transactivation domain) or downstream (extending downstream of the oligomerization domain); available data suggest approximately 70% of mutations to be missense variants, 28% (a higher frequency than was observed in MDS with monoallelic ''TP53'' mutation) to be truncating (including nonsense, frameshift, splice site, and nonstop variants), and a small fraction to be in-frame deletions or insertions.<ref name=":0" /> In MDS-bi''TP53'', 20% of ''TP53'' variants identified were accounted for by hotspot mutations affecting amino acids 273, 220, 248, and 175 (in order of descending frequency). Variants identified in the context of multiple distinct ''TP53'' mutations have been reported with a median VAF of 32% (range: 2% to 52%) while those associated with a second hit resulting from ''TP53'' locus deletion or copy-neutral LOH have a reported median VAF of 41% (2% to 92% with a bimodal distribution) and 71% (2% to 98%), respectively.<ref name=":0" /> |
| | |
| | ''TP53''-mutated MDS, in general, tends to carry fewer cooperating somatic mutations that MDS without ''TP53'' mutation; MDS bi-''TP53'' is further associated with fewer cooperating somatic mutations than MDS with monoallelic inactivation of ''TP53'', with 40% of MDS-bi''TP53'' reported to show no additional identifiable driver mutations.<ref name=":0" /><ref name=":1" /> Genes recurrently mutated in this group are similar to those described in MDS in general, and include ''DNMT3A'', ''TET2'', ''ASXL1'', ''U2AF1'', ''PPM1D'', ''EZH2'', ''SF3B1'', ''NF1''; infrequently, comutations identified include ''BCOR'', ''JAK2'', and ''CBL''. MDS carrying at least one mutation in ''TP53'', as a whole, has been observed to less frequently carry mutations in ''ASXL1'', ''U2AF1'', and ''RUNX1'', while MDS-bi''TP53'' has been observed to have lower rates of ''TET2'', ''SF3B1'', ''ASXL1'', ''SRSF2'', and ''RUNX1'' mutation relative to MDS with a single ''TP53'' mutation.<ref name=":0" /><ref name=":1" /> |
| | |
| | Note: A more extensive list of mutations can be found in cBioportal (https://www.cbioportal.org/), COSMIC (https://cancer.sanger.ac.uk/cosmic), ICGC (https://dcc.icgc.org/) and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content. |
| ==Epigenomic Alterations== | | ==Epigenomic Alterations== |
| Similar to other MDS entities, mutations in chromatin-modifying/epigenetic regulator genes (e.g. ''TET2'', ''EZH2'', ''DNMT3A'', ''ASXL1'') are recurrent in MDS-bi''TP53'', albeit at a lower frequency. Certain ''TP53'' mutations, including hotspot mutations identified in MDS-bi''TP53'', have been demonstrated to confer gain-of-function effects to the mutant TP53, some of which appear to be mediated through modification of the activities of chromatin regulatory/epigenetic modifier genes such as ''KMT2A'', ''KMT2D'', and ''EZH2''.<ref>{{Cite journal|last=Zhu|first=Jiajun|last2=Sammons|first2=Morgan A.|last3=Donahue|first3=Greg|last4=Dou|first4=Zhixun|last5=Vedadi|first5=Masoud|last6=Getlik|first6=Matthäus|last7=Barsyte-Lovejoy|first7=Dalia|last8=Al-awar|first8=Rima|last9=Katona|first9=Bryson W.|date=2015-09-10|title=Gain-of-function p53 mutants co-opt chromatin pathways to drive cancer growth|url=https://pubmed.ncbi.nlm.nih.gov/26331536|journal=Nature|volume=525|issue=7568|pages=206–211|doi=10.1038/nature15251|issn=1476-4687|pmc=4568559|pmid=26331536}}</ref><ref>{{Cite journal|last=Chen|first=Sisi|last2=Wang|first2=Qiang|last3=Yu|first3=Hao|last4=Capitano|first4=Maegan L.|last5=Vemula|first5=Sasidhar|last6=Nabinger|first6=Sarah C.|last7=Gao|first7=Rui|last8=Yao|first8=Chonghua|last9=Kobayashi|first9=Michihiro|date=2019-12-11|title=Mutant p53 drives clonal hematopoiesis through modulating epigenetic pathway|url=https://pubmed.ncbi.nlm.nih.gov/31827082|journal=Nature Communications|volume=10|issue=1|pages=5649|doi=10.1038/s41467-019-13542-2|issn=2041-1723|pmc=6906427|pmid=31827082}}</ref> | | Similar to other MDS entities, mutations in chromatin-modifying/epigenetic regulator genes (e.g. ''TET2'', ''EZH2'', ''DNMT3A'', ''ASXL1'') are recurrent in MDS-bi''TP53'', albeit at a lower frequency. Certain ''TP53'' mutations, including hotspot mutations identified in MDS-bi''TP53'', have been demonstrated to confer gain-of-function effects to the mutant TP53, some of which appear to be mediated through modification of the activities of chromatin regulatory/epigenetic modifier genes such as ''KMT2A'', ''KMT2D'', and ''EZH2''.<ref>{{Cite journal|last=Zhu|first=Jiajun|last2=Sammons|first2=Morgan A.|last3=Donahue|first3=Greg|last4=Dou|first4=Zhixun|last5=Vedadi|first5=Masoud|last6=Getlik|first6=Matthäus|last7=Barsyte-Lovejoy|first7=Dalia|last8=Al-awar|first8=Rima|last9=Katona|first9=Bryson W.|date=2015-09-10|title=Gain-of-function p53 mutants co-opt chromatin pathways to drive cancer growth|url=https://pubmed.ncbi.nlm.nih.gov/26331536|journal=Nature|volume=525|issue=7568|pages=206–211|doi=10.1038/nature15251|issn=1476-4687|pmc=4568559|pmid=26331536}}</ref><ref>{{Cite journal|last=Chen|first=Sisi|last2=Wang|first2=Qiang|last3=Yu|first3=Hao|last4=Capitano|first4=Maegan L.|last5=Vemula|first5=Sasidhar|last6=Nabinger|first6=Sarah C.|last7=Gao|first7=Rui|last8=Yao|first8=Chonghua|last9=Kobayashi|first9=Michihiro|date=2019-12-11|title=Mutant p53 drives clonal hematopoiesis through modulating epigenetic pathway|url=https://pubmed.ncbi.nlm.nih.gov/31827082|journal=Nature Communications|volume=10|issue=1|pages=5649|doi=10.1038/s41467-019-13542-2|issn=2041-1723|pmc=6906427|pmid=31827082}}</ref> |
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| *A complex karyotype (at least three distinct abnormalities excluding loss of Y) and/or 17p deletion detected by analysis of banded chromosomes, in the context of one detected ''TP53'' variant, can be considered evidence of biallelic inactivation | | *A complex karyotype (at least three distinct abnormalities excluding loss of Y) and/or 17p deletion detected by analysis of banded chromosomes, in the context of one detected ''TP53'' variant, can be considered evidence of biallelic inactivation |
| *If myeloid blasts account for 10-19% of cellularity in blood or bone marrow then a diagnosis of MDS/AML with mutated ''TP53'' is applied (for which only a single ''TP53'' mutation with VAF ≥10% is required for diagnosis) | | *If myeloid blasts account for 10-19% of cellularity in blood or bone marrow then a diagnosis of MDS/AML with mutated ''TP53'' is applied (for which only a single ''TP53'' mutation with VAF ≥10% is required for diagnosis) |
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