Compendium of Cancer Genome Aberrations

HAEM5:Myelodysplastic neoplasm with biallelic TP53 inactivation: Difference between revisions

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{{DISPLAYTITLE:Myelodysplastic neoplasm with biallelic TP53 inactivation}}
{{DISPLAYTITLE:Myelodysplastic neoplasm with biallelic TP53 inactivation}}
[[HAEM5:Table_of_Contents|Haematolymphoid Tumours (5th ed.)]]
[[HAEM5:Table_of_Contents|Haematolymphoid Tumours (WHO Classification, 5th ed.)]]


{{Under Construction}}
==Primary Author(s)*==
==Primary Author(s)*==
Eric McGinnis, MD, Vancouver General Hospital
==WHO Classification of Disease==


Put your text here<span style="color:#0070C0"> (''Name and affiliation; example:'' Jane Smith, PhD, Institute of Genomics) </span>
{| class="wikitable"
!Structure
!Disease
|-
|Book
|Haematolymphoid Tumours (5th ed.)
|-
|Category
|Myeloid proliferations and neoplasms
|-
|Family
|Myelodysplastic neoplasms
|-
|Type
|Myelodysplastic neoplasms, with defining genetic abnormalities
|-
|Subtype(s)
|Myelodysplastic neoplasm with biallelic TP53 inactivation
|}
==Related Terminology==


__TOC__
==Cancer Category / Type==
Put your text here
==Cancer Sub-Classification / Subtype==
Put your text here
==Definition / Description of Disease==
Put your text here <span style="color:#0070C0">(''Instructions: Brief description of approximately one paragraph - include disease context relative to other WHO classification categories referring to the specific WHO book pages, diagnostic criteria if applicable, and differential diagnosis if applicable'') </span>
==Synonyms / Terminology==
Put your text here <span style="color:#0070C0">(''Instructions: Include currently used terms and major historical ones, adding “(historical)” after the latter.'') </span>
==Epidemiology / Prevalence==
Put your text here
==Clinical Features==
Put your text here and fill in the table <span style="color:#0070C0">(''Instruction: Can include references in the table'') </span>
{| class="wikitable"
{| class="wikitable"
|'''Signs and Symptoms'''
|+
|EXAMPLE Asymptomatic (incidental finding on complete blood counts)
|Acceptable
 
|Myelodysplastic neoplasm with muti-hit TP53 inactivation
EXAMPLE B-symptoms (weight loss, fever, night sweats)
 
EXAMPLE Fatigue
 
EXAMPLE Lymphadenopathy (uncommon)
|-
|-
|'''Laboratory Findings'''
|Not Recommended
|EXAMPLE Cytopenias
|N/A
 
EXAMPLE Lymphocytosis (low level)
|}
|}


==Sites of Involvement==
==Gene Rearrangements==
 
There are no known recurrent rearrangements resulting in gene fusions associated with MDS-bi''TP53''.
Put your text here <span style="color:#0070C0">(''Instruction: Indicate physical sites; Example: nodal, extranodal, bone marrow'') </span>
 
==Morphologic Features==
 
Put your text here
 
==Immunophenotype==
 
Put your text here and fill in the table <span style="color:#0070C0">(''Instruction: Can include references in the table'') </span>
 
{| class="wikitable sortable"
{| class="wikitable sortable"
|-
|-
!Finding!!Marker
!Driver Gene!!Fusion(s) and Common Partner Genes!!Molecular Pathogenesis!!Typical Chromosomal Alteration(s)
!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
|-
|-
|Positive (universal)||EXAMPLE CD1
|N/A
|-
|N/A
|Positive (subset)||EXAMPLE CD2
|N/A
|-
|N/A
|Negative (universal)||EXAMPLE CD3
|N/A
|-
|N/A
|Negative (subset)||EXAMPLE CD4
|N/A
|N/A
|}
|}
==Individual Region Genomic Gain/Loss/LOH==
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" />


==Chromosomal Rearrangements (Gene Fusions)==
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''.
 
{| class="wikitable"
Put your text here and fill in the table
|'''Chr #'''
 
|'''Gain/Loss/Amp/LOH'''
{| class="wikitable sortable"
!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
|-
|1
|Gain
|1p
|
|No*
|No
|
|-
|-
!Chromosomal Rearrangement!!Genes in Fusion (5’ or 3’ Segments)!!Pathogenic Derivative!!Prevalence
|5
!Diagnostic Significance (Yes, No or Unknown)
|Loss
!Prognostic Significance (Yes, No or Unknown)
|5q
!Therapeutic Significance (Yes, No or Unknown)
|
!Notes
|No*
|No
|Most common co-occurring abnormality
|-
|-
|EXAMPLE t(9;22)(q34;q11.2)||EXAMPLE 3'ABL1 / 5'BCR||EXAMPLE der(22)||EXAMPLE 20% (COSMIC)
|7
EXAMPLE 30% (add reference)
|Loss
|Yes
|chr7 / 7q
|
|No*
|No
|No
|Yes
|Second most common co-occurring abnormality
|EXAMPLE
 
The t(9;22) is diagnostic of CML in the appropriate morphology and clinical context (add reference). This fusion is responsive to targeted therapy such as Imatinib (Gleevec) (add reference).
|}
==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 fusions. Can include references in the table. Can refer to CGC workgroup tables as linked on the homepage if applicable.'') </span>
 
{| class="wikitable sortable"
|-
|-
!Chr #!!Gain / Loss / Amp / LOH!!Minimal Region Genomic Coordinates [Genome Build]!!Minimal Region Cytoband
|8
!Diagnostic Significance (Yes, No or Unknown)
|Gain
!Prognostic Significance (Yes, No or Unknown)
|chr8
!Therapeutic Significance (Yes, No or Unknown)
|
!Notes
|No*
|No
|
|-
|-
|EXAMPLE
|11
 
|Gain
7
|11q
|EXAMPLE Loss
|
|EXAMPLE
|No*
 
chr7:1- 159,335,973 [hg38]
|EXAMPLE
 
chr7
|Yes
|Yes
|No
|No
|EXAMPLE
|
 
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 reference).
|-
|-
|EXAMPLE
|12
 
|Loss
8
|12p
|EXAMPLE Gain
|
|EXAMPLE
|No*
 
chr8:1-145,138,636 [hg38]
|EXAMPLE
 
chr8
|No
|No
|
|-
|13
|Loss
|13q
|
|No*
|No
|No
|
|-
|17
|Loss / LOH
|17p
|''TP53''
|D,P,T
|Yes (WHO/ICC/NCCN)
|Key component of entity classification
|-
|18
|Loss
|
|
|No*
|No
|No
|EXAMPLE
|
 
Common recurrent secondary finding for t(8;21) (add reference).
|}
==Characteristic Chromosomal Patterns==
 
Put your text here <span style="color:#0070C0">(''EXAMPLE PATTERNS: 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'')</span>
 
{| class="wikitable sortable"
|-
|-
!Chromosomal Pattern
|20
!Diagnostic Significance (Yes, No or Unknown)
|Loss
!Prognostic Significance (Yes, No or Unknown)
|20q
!Therapeutic Significance (Yes, No or Unknown)
|
!Notes
|No*
|No
|
|-
|-
|EXAMPLE
|21
 
|Gain
Co-deletion of 1p and 18q
|chr21
|Yes
|
|No*
|No
|No
|
|-
|22
|Gain
|chr22
|
|No*
|No
|No
|EXAMPLE:
|
 
See chromosomal rearrangements table as this pattern is due to an unbalanced derivative translocation associated with oligodendroglioma (add reference).
|}
|}
==Gene Mutations (SNV / INDEL)==
<nowiki>*</nowiki>Adverse prognosis associated with MDS-bi''TP53'' appears to persist independent of IPSS-R status


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 and common as well either disease defining and/or clinically significant. Can include references 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.'') </span>
<nowiki>**</nowiki>MDS-bi''TP53'' diagnosis and therefore prognostic stratification is dependent on loss or LOH involving 17p unless multiple mutations are present


{| class="wikitable sortable"
==Characteristic Chromosomal or Other Global Mutational Patterns==
{| class="wikitable"
|'''Chromosomal  Pattern'''
|'''Molecular Pathogenesis'''
|'''Prevalence'''
|Diagnostic, Prognostic, and Therapeutic Significance - D, P, T
!Established Clinical Significance Per Guidelines - Yes or No (Source)
!Clinical Relevance Details/Other Notes
|-
|-
!Gene; Genetic Alteration!!'''Presumed Mechanism (Tumor Suppressor Gene [TSG] / Oncogene / Other)'''!!'''Prevalence (COSMIC /  TCGA / Other)'''!!'''Concomitant Mutations'''!!'''Mutually Exclusive Mutations'''
|Complex karyotype
!'''Diagnostic Significance (Yes, No or Unknown)'''
|
!Prognostic Significance (Yes, No or Unknown)
|Common
!Therapeutic Significance (Yes, No or Unknown)
|D,P,T (see note)
!Notes
|Yes (see note)
|-
|Often with abnormalities resulting in chromosomal losses, especially involving chromosome 5q and chromosome 7
|EXAMPLE: TP53; Variable LOF mutations
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" />


EXAMPLE:
[[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.


EGFR; Exon 20 mutations
Image from: Eric McGinnis, Vancouver General Hospital|alt=|none]]


EXAMPLE: BRAF; Activating mutations
==Gene Mutations (SNV/INDEL)==
|EXAMPLE: TSG
{| class="wikitable"
|EXAMPLE: 20% (COSMIC)
|'''Gene; Genetic Alteration'''
 
|'''Genetic Alteration'''
EXAMPLE: 30% (add Reference)
!Tumor Suppressor Gene, Oncogene, Other
|EXAMPLE: IDH1 R123H
!Prevalence -
|EXAMPLE: EGFR amplification
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'''
|EXAMPLE:  Excludes hairy cell leukemia (HCL) (add reference).
|-
<br />
|''[[TP53]]''
|LOF and/or GOF mutations
|Tumor Suppressor Gene / Oncogene (GOF variants)
|100% (entity-defining for MDS-bi''TP53'')
|D, P, T
|Yes (WHO/ICC/NCCN)  
|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
|}
|}
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==
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" />


Put your text here
''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==
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>
==Genes and Main Pathways Involved==
==Genes and Main Pathways Involved==
 
p53, a tumour repressor transcription factor encoded by the ''TP53'' gene, is central to regulation of a complex network of pathways by which cells respond to intra- or extracellular stressors, including cell cycle progression and response to hyperproliferation signals, cell survival and apoptosis, and maintenance of genome stability.<ref>{{Cite journal|last=Eischen|first=Christine M.|date=2016-06-01|title=Genome Stability Requires p53|url=https://pubmed.ncbi.nlm.nih.gov/27252396|journal=Cold Spring Harbor Perspectives in Medicine|volume=6|issue=6|pages=a026096|doi=10.1101/cshperspect.a026096|issn=2157-1422|pmc=4888814|pmid=27252396}}</ref><ref>{{Cite journal|last=Levine|first=Arnold J.|last2=Oren|first2=Moshe|date=2009-10|title=The first 30 years of p53: growing ever more complex|url=https://pubmed.ncbi.nlm.nih.gov/19776744|journal=Nature Reviews. Cancer|volume=9|issue=10|pages=749–758|doi=10.1038/nrc2723|issn=1474-1768|pmc=2771725|pmid=19776744}}</ref><ref>{{Cite journal|last=Boettcher|first=Steffen|last2=Miller|first2=Peter G.|last3=Sharma|first3=Rohan|last4=McConkey|first4=Marie|last5=Leventhal|first5=Matthew|last6=Krivtsov|first6=Andrei V.|last7=Giacomelli|first7=Andrew O.|last8=Wong|first8=Waihay|last9=Kim|first9=Jesi|date=2019-08-09|title=A dominant-negative effect drives selection of TP53 missense mutations in myeloid malignancies|url=https://pubmed.ncbi.nlm.nih.gov/31395785|journal=Science (New York, N.Y.)|volume=365|issue=6453|pages=599–604|doi=10.1126/science.aax3649|issn=1095-9203|pmc=7327437|pmid=31395785}}</ref> Mutations inactivating ''TP53'' typically result in disruption of normal tumour suppressor activities of the protein and, depending on the cell state and mutational profile, may exert dominant negative effects on residual wild-type p53 and/or may confer neomorphic oncogenic function to the protein.<ref>{{Cite journal|last=Stein|first=Yan|last2=Aloni-Grinstein|first2=Ronit|last3=Rotter|first3=Varda|date=2020-12-31|title=Mutant p53 oncogenicity: dominant-negative or gain-of-function?|url=https://pubmed.ncbi.nlm.nih.gov/33159515|journal=Carcinogenesis|volume=41|issue=12|pages=1635–1647|doi=10.1093/carcin/bgaa117|issn=1460-2180|pmid=33159515}}</ref><ref>{{Cite journal|last=Boettcher|first=Steffen|last2=Miller|first2=Peter G.|last3=Sharma|first3=Rohan|last4=McConkey|first4=Marie|last5=Leventhal|first5=Matthew|last6=Krivtsov|first6=Andrei V.|last7=Giacomelli|first7=Andrew O.|last8=Wong|first8=Waihay|last9=Kim|first9=Jesi|date=2019-08-09|title=A dominant-negative effect drives selection of TP53 missense mutations in myeloid malignancies|url=https://pubmed.ncbi.nlm.nih.gov/31395785|journal=Science (New York, N.Y.)|volume=365|issue=6453|pages=599–604|doi=10.1126/science.aax3649|issn=1095-9203|pmc=7327437|pmid=31395785}}</ref> p53 is required for genomic stability and mutations affecting ''TP53'' are among the most frequent abnormalities identified in human malignancies, in which they are strongly associated with genomic instability (in the form of increased frequency of aneuploidy, polyploidy/tetraploidy, and chromosomal rearrangements).<ref name=":0" /><ref>{{Cite journal|last=Eischen|first=Christine M.|date=2016-06-01|title=Genome Stability Requires p53|url=https://pubmed.ncbi.nlm.nih.gov/27252396|journal=Cold Spring Harbor Perspectives in Medicine|volume=6|issue=6|pages=a026096|doi=10.1101/cshperspect.a026096|issn=2157-1422|pmc=4888814|pmid=27252396}}</ref>
Put your text here and fill in the table <span style="color:#0070C0">(''Instructions: Can include references in the table.'')</span>
{| class="wikitable"
{| class="wikitable sortable"
|'''Gene; Genetic Alteration'''
|'''Pathway'''
|'''Pathophysiologic Outcome'''
|-
|-
!Gene; Genetic Alteration!!Pathway!!Pathophysiologic Outcome
|''TP53''; Inactivating +/- Gain of abnormal function mutations
|-
|TP53 signaling network; cell cycle arrest, DNA repair, cell senescence, apoptosis in response to DNA damage, oncogene activation, cell stressors
|EXAMPLE: BRAF and MAP2K1; Activating mutations
|Failures of DNA repair, cell cycle arrest, apoptosis in response to DNA damage, hyperproliferation, or cell stressors
|EXAMPLE: MAPK signaling
|EXAMPLE: Increased cell growth and proliferation
|-
|EXAMPLE: CDKN2A; Inactivating mutations
|EXAMPLE: Cell cycle regulation
|EXAMPLE: Unregulated cell division
|-
|EXAMPLE:  KMT2C and ARID1A; Inactivating mutations
|EXAMPLE:  Histone modification, chromatin remodeling
|EXAMPLE:  Abnormal gene expression program
|}
|}
==Genetic Diagnostic Testing Methods==
==Genetic Diagnostic Testing Methods==
As classification of MDS-bi''TP53'' requires demonstration of at least one ''TP53'' mutation, sequencing analysis is required in all cases (i.e. cytogenetic evidence supportive of ''TP53'' loss without detection of a mutation by sequencing is not considered diagnostic of this entity); at a minimum, coverage of exons 4 to 11 (the regions in which the majority of variants are detected) has been recommended.<ref name=":2" /> If a second variant is not detected by sequencing analysis (in which case diagnostic criteria are considered fulfilled, assuming the mutations are not known to affect the same allele) then a technique to assess for copy number loss and/or copy neutral LOH at the ''TP53'' locus is generally required. Fluorescence in situ hybridization with a probe set designed to detect deletions of this locus is a common approach to copy loss detection; alternatives include (but are not limited to) chromosome microarray analysis or next generation sequencing (both of which may also allow for detection of copy neutral LOH) and optical genome mapping. If a qualifying copy number loss or copy neutral LOH cannot be demonstrated, a variant allele fraction above 49% can be considered presumptive evidence of one of these phenomena for diagnostic purposes, presuming a germline ''TP53'' variant is excluded.<ref name=":2" />
[[File:OGM TP53 loss.tif|thumb|1300x1300px|Identification of copy number loss involving the ''TP53'' locus by optical genome mapping. Left: Detailed copy number track demonstrating loss of 17p (black arrow), including the ''TP53'' locus (red arrow). Right: Circos plot showing the same copy number loss of 17p (black arrow), including the ''TP53'' locus (red arrow), in the context of a complex unbalanced rearrangement involving chromosomes 8, 17, and 20.


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Image from: Eric McGinnis, Vancouver General Hospital|alt=|none]]
 
==Familial Forms==
==Familial Forms==
Individuals with germline ''TP53'' variants (as in Li-Fraumeni syndrome) are predisposed to a range of malignancies, including hematologic malignancies. Myeloid malignancies in this population have been reported to commonly occur after cytotoxic therapy for an alternative cancer and to, relatively frequently, also carry a somatic ''TP53'' mutation resulting in biallelic inactivation.<ref name=":2" /><ref>{{Cite journal|last=Swaminathan|first=Mahesh|last2=Bannon|first2=Sarah A.|last3=Routbort|first3=Mark|last4=Naqvi|first4=Kiran|last5=Kadia|first5=Tapan M.|last6=Takahashi|first6=Koichi|last7=Alvarado|first7=Yesid|last8=Ravandi-Kashani|first8=Farhad|last9=Patel|first9=Keyur P.|date=2019-02|title=Hematologic malignancies and Li-Fraumeni syndrome|url=https://pubmed.ncbi.nlm.nih.gov/30709875|journal=Cold Spring Harbor Molecular Case Studies|volume=5|issue=1|pages=a003210|doi=10.1101/mcs.a003210|issn=2373-2873|pmc=6371746|pmid=30709875}}</ref><ref>{{Cite journal|last=Gonzalez|first=Kelly D.|last2=Noltner|first2=Katie A.|last3=Buzin|first3=Carolyn H.|last4=Gu|first4=Dongqing|last5=Wen-Fong|first5=Cindy Y.|last6=Nguyen|first6=Vu Q.|last7=Han|first7=Jennifer H.|last8=Lowstuter|first8=Katrina|last9=Longmate|first9=Jeffrey|date=2009-03-10|title=Beyond Li Fraumeni Syndrome: clinical characteristics of families with p53 germline mutations|url=https://pubmed.ncbi.nlm.nih.gov/19204208|journal=Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology|volume=27|issue=8|pages=1250–1256|doi=10.1200/JCO.2008.16.6959|issn=1527-7755|pmid=19204208}}</ref>


Put your text here <span style="color:#0070C0">(''Instructions: Include associated hereditary conditions/syndromes that cause this entity or are caused by this entity.'') </span>
Should a myeloid neoplasm meeting diagnostic criteria for MDS-bi''TP53'' develop in an individual with germline predisposition to development of myeloid neoplasms, the appropriate germline predisposition disorder should be added as a diagnostic qualifier: e.g., MDS-bi''TP53'' associated with germline ''TP53'' variant.<ref name=":2" />
 
==Additional Information==
==Additional Information==
In the proposed International Consensus Classification system (in which myeloid neoplasms with mutated ''TP53'' were separated as a distinct category), entities meeting diagnostic criteria for MDS-bi''TP53'' using WHO 5th Edition classification standards will generally be compatible with either: myelodysplastic syndrome with mutated ''TP53'', or; myelodysplastic syndrome/acute myeloid leukemia (MDS/AML) with mutated ''TP53''. Key distinctions from WHO 5th Edition diagnostic criteria include:<ref>{{Cite journal|last=Arber|first=Daniel A.|last2=Orazi|first2=Attilio|last3=Hasserjian|first3=Robert P.|last4=Borowitz|first4=Michael J.|last5=Calvo|first5=Katherine R.|last6=Kvasnicka|first6=Hans-Michael|last7=Wang|first7=Sa A.|last8=Bagg|first8=Adam|last9=Barbui|first9=Tiziano|date=2022-09-15|title=International Consensus Classification of Myeloid Neoplasms and Acute Leukemias: integrating morphologic, clinical, and genomic data|url=https://pubmed.ncbi.nlm.nih.gov/35767897|journal=Blood|volume=140|issue=11|pages=1200–1228|doi=10.1182/blood.2022015850|issn=1528-0020|pmc=9479031|pmid=35767897}}</ref><ref>{{Cite journal|last=Hasserjian|first=Robert P.|last2=Orazi|first2=Attilio|last3=Orfao|first3=Alberto|last4=Rozman|first4=Maria|last5=Wang|first5=Sa A.|date=2023-01|title=The International Consensus Classification of myelodysplastic syndromes and related entities|url=https://pubmed.ncbi.nlm.nih.gov/36287260|journal=Virchows Archiv: An International Journal of Pathology|volume=482|issue=1|pages=39–51|doi=10.1007/s00428-022-03417-1|issn=1432-2307|pmid=36287260}}</ref><ref>{{Cite journal|last=Weinberg|first=Olga K.|last2=Porwit|first2=Anna|last3=Orazi|first3=Attilio|last4=Hasserjian|first4=Robert P.|last5=Foucar|first5=Kathryn|last6=Duncavage|first6=Eric J.|last7=Arber|first7=Daniel A.|date=2023-01|title=The International Consensus Classification of acute myeloid leukemia|url=https://pubmed.ncbi.nlm.nih.gov/36264379|journal=Virchows Archiv: An International Journal of Pathology|volume=482|issue=1|pages=27–37|doi=10.1007/s00428-022-03430-4|issn=1432-2307|pmid=36264379}}</ref>


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*A VAF threshold of ≥10% is required for each ''TP53'' variant applied in diagnostic criteria
 
*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)
==Links==
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==References==
==References==
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#Arber DA, et al., (2017). Acute myeloid leukaemia with recurrent genetic abnormalities, in World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, Revised 4th 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, p129-171.
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==Notes==
       
<nowiki>*</nowiki>Primary authors will typically be those that initially create and complete the content of a page.  If a subsequent user modifies the content and feels the effort put forth is of high enough significance to warrant listing in the authorship section, please contact the CCGA coordinators (contact information provided on the homepage).  Additional global feedback or concerns are also welcome.
<nowiki>*</nowiki>''Citation of this Page'': “Myelodysplastic neoplasm with biallelic TP53 inactivation”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated {{REVISIONMONTH}}/{{REVISIONDAY}}/{{REVISIONYEAR}}, <nowiki>https://ccga.io/index.php/HAEM5:Myelodysplastic_neoplasm_with_biallelic_TP53_inactivation</nowiki>.
<nowiki>*</nowiki>''Citation of this Page'': “Myelodysplastic neoplasm with biallelic TP53 inactivation”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated {{REVISIONMONTH}}/{{REVISIONDAY}}/{{REVISIONYEAR}}, <nowiki>https://ccga.io/index.php/HAEM5:Myelodysplastic_neoplasm_with_biallelic_TP53_inactivation</nowiki>.
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