Compendium of Cancer Genome Aberrations

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

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Updated gene mutations section to WHO5 format table (previously missed)
 
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|''TP53''
|''TP53''
|D,P,T
|D,P,T
|Yes (WHO/ICC/ELN)
|Yes (WHO/ICC/NCCN)
|Key component of entity classification
|Key component of entity classification
|-
|-
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==Gene Mutations (SNV/INDEL)==
==Gene Mutations (SNV/INDEL)==
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 />
|<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" />
''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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