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

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Haematolymphoid Tumours (WHO Classification, 5th ed.)

Primary Author(s)*

Eric McGinnis, MD, Vancouver General Hospital

WHO Classification of Disease

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

Definition / Description of Disease

Myelodysplastic neoplasm with biallelic TP53 inactivation (MDS-biTP53) 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.^[1]^[2]

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.^[2]

Synonyms / Terminology

Myelodysplastic neoplasm with multi-hit TP53 inactivation, MDS-biTP53

Epidemiology / Prevalence

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%).^[3] 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).^[3] The incidence of MDS-biTP53 has been estimated to be approximately 0.03 persons per 100,000 per year.^[2]

Clinical Features

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.^[3]^[4]

Anemia (hemoglobin < 130 g/L in males, < 120 g/L in females)
- Pallor, fatigue
Neutropenia (absolute neutrophil count < 1.8x10⁹/L)
- Infection
Thrombocytopenia (platelet count < 150x10⁹/L)
- Bruising, petechiae, bleeding

MDS-biTP53 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-biTP53.^[3]^[2]^[5]^[6]

Signs and Symptoms	Pallor Fatigue Infection Bruising Bleeding Petechiae
Laboratory Findings	Anemia (hemoglobin < 130 g/L in males, < 120 g/L in females) Neutropenia (neutrophils < 1.8x10⁹/L) Thrombocytopenia (platelets < 150x10⁹/L) Circulating blasts (+/-) Elevated lactate dehydrogenase (+/-)

Sites of Involvement

Bone marrow and peripheral blood; rarely, extramedullary proliferations occur.^[7]

Morphologic Features

Morphologic dysplasia is the hallmark of MDS, including MDS-biTP53; 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.^[3]^[4]^[8] TP53 mutations are enriched in MDS associated with bone marrow fibrosis.^[9]^[10]

Hematopoietic lineage	Characteristic dysplastic features
Erythroid	Nuclear budding Internuclear bridging Multinuclearity Karyorrhexis Megaloblastosis Cytoplasmic vacuolation Ring sideroblasts Periodic acid Schiff positivity
Granulocytic	Nuclear hyposegmentation (Pelgeroid changes) Nuclear hypersegmentation Cytoplasmic hypogranularity Abnormally small cell size Auer rods Pseudo-Chédiak–Higashi granules
Megakaryocytic	Nuclear hypolobation Widely separated nuclear lobes Micromegakaryocytes

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

MDS-biTP53 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

Immunophenotype

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-biTP53 and are not formalized in current diagnostic criteria.^[2]^[11]

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.^[12]^[13]^[14]^[15]^[16] 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).^[12]

Immunohistochemical evaluation of TP53 expression correlates with TP53 mutation status in MDS-biTP53. 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.

Positive (universal)	N/A
Positive (subset)	N/A
Negative (universal)	N/A
Negative (subset)	N/A

Chromosomal Rearrangements (Gene Fusions)

There are no known recurrent rearrangements resulting in gene fusions associated with MDS-biTP53.

Chromosomal Rearrangement	Genes in Fusion (5’ or 3’ Segments)	Pathogenic Derivative	Prevalence	Diagnostic Significance (Yes, No or Unknown)	Prognostic Significance (Yes, No or Unknown)	Therapeutic Significance (Yes, No or Unknown)	Notes
EXAMPLE: t(9;22)(q34;q11.2)	EXAMPLE: 3'ABL1 / 5'BCR	EXAMPLE: der(22)	EXAMPLE: 20% (COSMIC) EXAMPLE: 30% (add reference)	Yes	No	Yes	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

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.^[4]^[3] Recurrent chromosomal gains, losses, and regions of LOH described which have been observed at higher frequency in MDS-biTP53 include^[3]^[2]^[4]:

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-biTP53 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).^[3] It is not currently known whether other instances of recurrent copy-neutral LOH in myeloid neoplasms are observed at significantly higher frequency in MDS-biTP53.

Chr #	Gain/Loss/Amp/LOH	Minimal Region Genomic Coordinates [Genome Build]	Minimal Region Cytoband	Diagnostic Significance (Yes, No or Unknown)	Prognostic Significance (Yes, No or Unknown)	Therapeutic Significance (Yes, No or Unknown)	Notes
1	Gain		1p	No	No*	No
5	Loss		5q	No	No*	No	Most common co-occurring abnormality
7	Loss		chr7 / 7q	No	No*	No	Second most common co-occurring abnormality
8	Gain		chr8	No	No*	No
11	Gain		11q	No	No*	No
12	Loss		12p	No	No*	No
13	Loss		13q	No	No*	No
17	Loss / LOH		17p	Yes	Yes**	Yes	Key component of entity classification
18	Loss			No	No*	No
20	Loss		20q	No	No*	No
21	Gain		chr21	No	No*	No
22	Gain		chr22	No	No*	No

*Adverse prognosis associated with MDS-biTP53 appears to persist independent of IPSS-R status

**MDS-biTP53 diagnosis and therefore prognostic stratification is dependent on loss or LOH involving 17p unless multiple mutations are present

Characteristic Chromosomal Patterns

MDS-biTP53 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-biTP53, which are particularly enriched for deletions involving chromosome 5q (identified in 85% of patients).^[3]^[2]^[4] 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.^[3]

MDS-biTP53 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

Chromosomal Pattern	Diagnostic Significance (Yes, No or Unknown)	Prognostic Significance (Yes, No or Unknown)	Therapeutic Significance (Yes, No or Unknown)	Notes
Complex karyotype	No (see note)	Yes (see note)	No (see note)	Often with abnormalities resulting in chromosomal losses, especially involving chromosome 5q and chromosome 7 Complex karyotypes are strongly associated with MDS-biTP53 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

Gene Mutations (SNV/INDEL)

At least one mutation involving TP53 is required to establish a diagnosis of MDS biTP53; 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-biTP53.^[2]^[3] TP53 mutations reported in MDS-biTP53 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.^[3] In MDS-biTP53, 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.^[3]

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-biTP53 reported to show no additional identifiable driver mutations.^[3]^[4] 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-biTP53 has been observed to have lower rates of TET2, SF3B1, ASXL1, SRSF2, and RUNX1 mutation relative to MDS with a single TP53 mutation.^[3]^[4]

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.

Gene; Genetic Alteration	Presumed Mechanism (Tumor Suppressor Gene (TSG)/Oncogene/Other)	Prevalence (COSMIC/ TCGA/Other)	Concomitant Mutations	Mutually Exclusive Mutations	Diagnostic Significance (Yes, No or Unknown)	Prognostic Significance (Yes, No or Unknown)	Therapeutic Significance (Yes, No or Unknown)	Notes
TP53; LOF and/or GOF mutations	Tumor Suppressor Gene / Oncogene (GOF variants)	100% (entity-defining for MDS-biTP53)	DNMT3A, TET2, ASXL1, U2AF1, PPM1D, EZH2, SF3B1, NF1 (see note)	None	Yes	Yes	Yes (see note)	MDS-biTP53 carries, on average, less cooperating somatic mutations than MDS without TP53 mutation MDS-biTP53 is associated with poorer responses to most therapeutic modalities

Epigenomic Alterations

Similar to other MDS entities, mutations in chromatin-modifying/epigenetic regulator genes (e.g. TET2, EZH2, DNMT3A, ASXL1) are recurrent in MDS-biTP53, albeit at a lower frequency. Certain TP53 mutations, including hotspot mutations identified in MDS-biTP53, 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.^[17]^[18]

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.^[19]^[20]^[21] 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.^[22]^[23] 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).^[3]^[24]

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	Failures of DNA repair, cell cycle arrest, apoptosis in response to DNA damage, hyperproliferation, or cell stressors

Genetic Diagnostic Testing Methods

As classification of MDS-biTP53 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.^[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.^[2]

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. Image from: Eric McGinnis, Vancouver General Hospital

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.^[2]^[25]^[26]

Should a myeloid neoplasm meeting diagnostic criteria for MDS-biTP53 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-biTP53 associated with germline TP53 variant.^[2]

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-biTP53 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:^[27]^[28]^[29]

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)

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References

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↑ Gonzalez, Kelly D.; et al. (2009-03-10). "Beyond Li Fraumeni Syndrome: clinical characteristics of families with p53 germline mutations". Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology. 27 (8): 1250–1256. doi:10.1200/JCO.2008.16.6959. ISSN 1527-7755. PMID 19204208.
↑ Arber, Daniel A.; et al. (2022-09-15). "International Consensus Classification of Myeloid Neoplasms and Acute Leukemias: integrating morphologic, clinical, and genomic data". Blood. 140 (11): 1200–1228. doi:10.1182/blood.2022015850. ISSN 1528-0020. PMC 9479031 Check |pmc= value (help). PMID 35767897 Check |pmid= value (help).
↑ Hasserjian, Robert P.; et al. (2023-01). "The International Consensus Classification of myelodysplastic syndromes and related entities". Virchows Archiv: An International Journal of Pathology. 482 (1): 39–51. doi:10.1007/s00428-022-03417-1. ISSN 1432-2307. PMID 36287260 Check |pmid= value (help). Check date values in: |date= (help)
↑ Weinberg, Olga K.; et al. (2023-01). "The International Consensus Classification of acute myeloid leukemia". Virchows Archiv: An International Journal of Pathology. 482 (1): 27–37. doi:10.1007/s00428-022-03430-4. ISSN 1432-2307. PMID 36264379 Check |pmid= value (help). Check date values in: |date= (help)

Notes

*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. *Citation of this Page: “Myelodysplastic neoplasm with biallelic TP53 inactivation”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated 09/6/2024, https://ccga.io/index.php/HAEM5:Myelodysplastic_neoplasm_with_biallelic_TP53_inactivation.

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[:2-2] 2.00 ^2.01 ^2.02 ^2.03 ^2.04 ^2.05 ^2.06 ^2.07 ^2.08 ^2.09 ^2.10 ^2.11 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: https://tumourclassification.iarc.who.int/chapters/63.

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[26] Gonzalez, Kelly D.; et al. (2009-03-10). "Beyond Li Fraumeni Syndrome: clinical characteristics of families with p53 germline mutations". Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology. 27 (8): 1250–1256. doi:10.1200/JCO.2008.16.6959. ISSN 1527-7755. PMID 19204208.

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[28] Hasserjian, Robert P.; et al. (2023-01). "The International Consensus Classification of myelodysplastic syndromes and related entities". Virchows Archiv: An International Journal of Pathology. 482 (1): 39–51. doi:10.1007/s00428-022-03417-1. ISSN 1432-2307. PMID 36287260 Check |pmid= value (help). Check date values in: |date= (help)

[29] Weinberg, Olga K.; et al. (2023-01). "The International Consensus Classification of acute myeloid leukemia". Virchows Archiv: An International Journal of Pathology. 482 (1): 27–37. doi:10.1007/s00428-022-03430-4. ISSN 1432-2307. PMID 36264379 Check |pmid= value (help). Check date values in: |date= (help)

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