Childhood myelodysplastic neoplasm with increased blasts

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Haematolymphoid Tumours (WHO Classification, 5th ed.)

editContent Update To WHO 5th Edition Classification Is In Process; Content Below is Based on WHO 4th Edition Classification
This page was converted to the new template on 2023-12-07. The original page can be found at HAEM4:Refractory Cytopenia of Childhood.

(General Instructions – The focus of these pages is the clinically significant genetic alterations in each disease type. This is based on up-to-date knowledge from multiple resources such as PubMed and the WHO classification books. The CCGA is meant to be a supplemental resource to the WHO classification books; the CCGA captures in a continually updated wiki-stye manner the current genetics/genomics knowledge of each disease, which evolves more rapidly than books can be revised and published. If the same disease is described in multiple WHO classification books, the genetics-related information for that disease will be consolidated into a single main page that has this template (other pages would only contain a link to this main page). Use HUGO-approved gene names and symbols (italicized when appropriate), HGVS-based nomenclature for variants, as well as generic names of drugs and testing platforms or assays if applicable. Please complete tables whenever possible and do not delete them (add N/A if not applicable in the table and delete the examples); to add (or move) a row or column in a table, click nearby within the table and select the > symbol that appears. Please do not delete or alter the section headings. The use of bullet points alongside short blocks of text rather than only large paragraphs is encouraged. Additional instructions below in italicized blue text should not be included in the final page content. Please also see Author_Instructions and FAQs as well as contact your Associate Editor or Technical Support.)

Primary Author(s)*

Xiaoli Du, Ph.D; Teresa A. Smolarek, Ph.D, FACMG

Division of Human Genetics, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH, 45229, USA.

WHO Classification of Disease

Structure Disease
Book Haematolymphoid Tumours (5th ed.)
Category Myeloid proliferations and neoplasms
Family Myelodysplastic neoplasms
Type Myelodysplastic neoplasms of childhood
Subtype(s) Childhood myelodysplastic neoplasm with increased blasts

WHO Essential and Desirable Genetic Diagnostic Criteria

(Instructions: The table will have the diagnostic criteria from the WHO book autocompleted; remove any non-genetics related criteria. If applicable, add text about other classification systems that define this entity and specify how the genetics-related criteria differ.)

WHO Essential Criteria (Genetics)*
WHO Desirable Criteria (Genetics)*
Other Classification

*Note: These are only the genetic/genomic criteria. Additional diagnostic criteria can be found in the WHO Classification of Tumours.

Related Terminology

(Instructions: The table will have the related terminology from the WHO autocompleted.)

Acceptable
Not Recommended

Gene Rearrangements

Put your text here and fill in the table (Instructions: 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.)

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
EXAMPLE: ABL1 EXAMPLE: BCR::ABL1 EXAMPLE: The pathogenic derivative is the der(22) resulting in fusion of 5’ BCR and 3’ABL1. EXAMPLE: t(9;22)(q34;q11.2) EXAMPLE: Common (CML) EXAMPLE: D, P, T EXAMPLE: Yes (WHO, NCCN) 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). BCR::ABL1 is generally favorable in CML (add reference).

EXAMPLE: CIC EXAMPLE: CIC::DUX4 EXAMPLE: Typically, the last exon of CIC is fused to DUX4. The fusion breakpoint in CIC is usually intra-exonic and removes an inhibitory sequence, upregulating PEA3 genes downstream of CIC including ETV1, ETV4, and ETV5. EXAMPLE: t(4;19)(q25;q13) EXAMPLE: Common (CIC-rearranged sarcoma) EXAMPLE: D EXAMPLE:

DUX4 has many homologous genes; an alternate translocation in a minority of cases is t(10;19), but this is usually indistinguishable from t(4;19) by short-read sequencing (add references).

EXAMPLE: ALK EXAMPLE: ELM4::ALK


Other fusion partners include KIF5B, NPM1, STRN, TFG, TPM3, CLTC, KLC1

EXAMPLE: Fusions result in constitutive activation of the ALK tyrosine kinase. The most common ALK fusion is EML4::ALK, with breakpoints in intron 19 of ALK. At the transcript level, a variable (5’) partner gene is fused to 3’ ALK at exon 20. Rarely, ALK fusions contain exon 19 due to breakpoints in intron 18. EXAMPLE: N/A EXAMPLE: Rare (Lung adenocarcinoma) EXAMPLE: T EXAMPLE:

Both balanced and unbalanced forms are observed by FISH (add references).

EXAMPLE: ABL1 EXAMPLE: N/A EXAMPLE: Intragenic deletion of exons 2–7 in EGFR removes the ligand-binding domain, resulting in a constitutively active tyrosine kinase with downstream activation of multiple oncogenic pathways. EXAMPLE: N/A EXAMPLE: Recurrent (IDH-wildtype Glioblastoma) EXAMPLE: D, P, T
editv4:Chromosomal Rearrangements (Gene Fusions)
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No

End of V4 Section


editv4:Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications).
Please incorporate this section into the relevant tables found in:
  • Chromosomal Rearrangements (Gene Fusions)
  • Individual Region Genomic Gain/Loss/LOH
  • Characteristic Chromosomal Patterns
  • Gene Mutations (SNV/INDEL)
  • Diagnosis: <2% blood blasts and <5% bone marrow blasts and persistent cytopenia
  • Prognosis: In RCC, patients with monosomy 7 have a higher probability of progression[1][2][3]. Patients with trisomy 8 or a normal karyotype are unlikely to progress to advanced MDS.
  • Therapeutic: Hematopoietic stem cell transplantation (HSCT) is the only curative therapy for RCC patients. This treatment is suitable for patients with monosomy 7 or a complex karyotype in the early stage of the process. Some of the RCC patients benefit from immunosuppressive therapy, although it is unclear whether the immunosuppressive therapy has the risk of relapse long-term[4][5].
End of V4 Section

Individual Region Genomic Gain/Loss/LOH

Put your text here and fill in the table (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.)

Chr # Gain, Loss, Amp, LOH Minimal Region Cytoband and/or Genomic Coordinates [Genome Build; Size] Relevant Gene(s) Diagnostic, Prognostic, and Therapeutic Significance - D, P, T Established Clinical Significance Per Guidelines - Yes or No (Source) Clinical Relevance Details/Other Notes
EXAMPLE:

7

EXAMPLE: Loss EXAMPLE:

chr7

EXAMPLE:

Unknown

EXAMPLE: D, P EXAMPLE: 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 references).

EXAMPLE:

8

EXAMPLE: Gain EXAMPLE:

chr8

EXAMPLE:

Unknown

EXAMPLE: D, P EXAMPLE:

Common recurrent secondary finding for t(8;21) (add references).

EXAMPLE:

17

EXAMPLE: Amp EXAMPLE:

17q12; chr17:39,700,064-39,728,658 [hg38; 28.6 kb]

EXAMPLE:

ERBB2

EXAMPLE: D, P, T EXAMPLE:

Amplification of ERBB2 is associated with HER2 overexpression in HER2 positive breast cancer (add references). Add criteria for how amplification is defined.

editv4:Genomic Gain/Loss/LOH
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Monosomy 7 is the most frequent cytogenetic abnormality of RCC patients, followed by trisomy 8 and other abnormalities, including complex karyotypes[6][7][8].

End of V4 Section

Characteristic Chromosomal or Other Global Mutational Patterns

Put your text here and fill in the table (Instructions: 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.)

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
EXAMPLE:

Co-deletion of 1p and 18q

EXAMPLE: See chromosomal rearrangements table as this pattern is due to an unbalanced derivative translocation associated with oligodendroglioma (add reference). EXAMPLE: Common (Oligodendroglioma) EXAMPLE: D, P
EXAMPLE:

Microsatellite instability - hypermutated

EXAMPLE: Common (Endometrial carcinoma) EXAMPLE: P, T
editv4:Characteristic Chromosomal Aberrations / Patterns
The content below was from the old template. Please incorporate above.

Monosomy 7 (CCHMC), trisomy 8 and other abnormalities, including complex karyotypes.

Pictures are needed to be upload!!

End of V4 Section

Gene Mutations (SNV/INDEL)

Put your text here and fill in the table (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.)

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
EXAMPLE:EGFR


EXAMPLE: Exon 18-21 activating mutations EXAMPLE: Oncogene EXAMPLE: Common (lung cancer) EXAMPLE: T EXAMPLE: Yes (NCCN) EXAMPLE: 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).
EXAMPLE: TP53; Variable LOF mutations


EXAMPLE: Variable LOF mutations EXAMPLE: Tumor Supressor Gene EXAMPLE: Common (breast cancer) EXAMPLE: P EXAMPLE: >90% are somatic; rare germline alterations associated with Li-Fraumeni syndrome (add reference). Denotes a poor prognosis in breast cancer.
EXAMPLE: BRAF; Activating mutations EXAMPLE: Activating mutations EXAMPLE: Oncogene EXAMPLE: Common (melanoma) EXAMPLE: T

Note: A more extensive list of mutations can be found in cBioportal, COSMIC, and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content.

editv4:Gene Mutations (SNV/INDEL)
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  • Mutations are less common than in adult MDS with a different profile
  • Most frequent mutations: RAS/MAPK, SAMD9/SAMD9L, GATA2[9][10].

Other Mutations

No

End of V4 Section

Epigenomic Alterations

No

Genes and Main Pathways Involved

Put your text here and fill in the table (Instructions: Please include references throughout the table. Do not delete the table.)

Gene; Genetic Alteration Pathway Pathophysiologic Outcome
EXAMPLE: BRAF and MAP2K1; Activating mutations 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
editv4:Genes and Main Pathways Involved
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  • RAS/MAPK: involved in MAPK tyrosine Kinase pathway
  • SAMD9/SAMD9L: involved in regulating the growth and proliferation and differentiation of cells
  • GATA2: involved in regulating transcription of genes related with the development and proliferation of hematopoietic and endocrine cell lineages
End of V4 Section

Genetic Diagnostic Testing Methods

Bone marrow minimal histological criteria for refractory cytopenia of childhood[11][12]. Refractory cytopenia of childhood is defined as persistent cytopenia with <5% blasts in bone marrow and <2% blasts in peripheral blood. The criteria of dysplasia must be fulfilled in ≥2 cell lineages or ≥10% of cells within one cell lineage on bone marrow aspirate smears. See table:

Cellularity Erythropoiesis Granulopoiesis Megakaryopoiesis
Variable A few clusters of ≥20 erythroid precursors.

Arrest in maturation, with increased number of proerythroblasts.

Increased number of mitoses.

No minimal diagnostic criteria. Unequivocal micromegakaryocytes;

immunohistochemistry is obligatory (CD61, CD41, CD42b);

other dysplastic changes in variable numbers.

In addition, RCC must be differentiated from aplastic anemia, bone marrow failure syndromes, infection, nutritional deficiencies, and metabolic diseases.

Familial Forms

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Additional Information

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Links

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References

(use the "Cite" icon at the top of the page) (Instructions: Add each reference into the text above by clicking where you want to insert the reference, selecting the “Cite” icon at the top of the wiki page, and using the “Automatic” tab option to search by PMID to select the reference to insert. If a PMID is not available, such as for a book, please use the “Cite” icon, select “Manual” and then “Basic Form”, and include the entire reference. To insert the same reference again later in the page, select the “Cite” icon and “Re-use” to find the reference; DO NOT insert the same reference twice using the “Automatic” tab as it will be treated as two separate references. The reference list in this section will be automatically generated and sorted.)

  1. Passmore, S. Jane; et al. (2003-06). "Paediatric myelodysplastic syndromes and juvenile myelomonocytic leukaemia in the UK: a population-based study of incidence and survival". British Journal of Haematology. 121 (5): 758–767. doi:10.1046/j.1365-2141.2003.04361.x. ISSN 0007-1048. PMID 12780790. Check date values in: |date= (help)
  2. Pui, Ching-Hon; et al. (2004). "Childhood and adolescent lymphoid and myeloid leukemia". Hematology. American Society of Hematology. Education Program: 118–145. doi:10.1182/asheducation-2004.1.118. ISSN 1520-4391. PMID 15561680.
  3. Kardos, Gabriela; et al. (2003-09-15). "Refractory anemia in childhood: a retrospective analysis of 67 patients with particular reference to monosomy 7". Blood. 102 (6): 1997–2003. doi:10.1182/blood-2002-11-3444. ISSN 0006-4971. PMID 12763938.
  4. Hasegawa, Daisuke; et al. (2009-12). "Treatment of children with refractory anemia: the Japanese Childhood MDS Study Group trial (MDS99)". Pediatric Blood & Cancer. 53 (6): 1011–1015. doi:10.1002/pbc.22121. ISSN 1545-5017. PMID 19499580. Check date values in: |date= (help)
  5. Yoshimi, Ayami; et al. (2014-04). "Comparison of horse and rabbit antithymocyte globulin in immunosuppressive therapy for refractory cytopenia of childhood". Haematologica. 99 (4): 656–663. doi:10.3324/haematol.2013.095786. ISSN 1592-8721. PMC 3971075. PMID 24162791. Check date values in: |date= (help)
  6. Kardos, Gabriela; et al. (2003-09-15). "Refractory anemia in childhood: a retrospective analysis of 67 patients with particular reference to monosomy 7". Blood. 102 (6): 1997–2003. doi:10.1182/blood-2002-11-3444. ISSN 0006-4971. PMID 12763938.
  7. Niemeyer, Charlotte M.; et al. (2011). "Classification of childhood aplastic anemia and myelodysplastic syndrome". Hematology. American Society of Hematology. Education Program. 2011: 84–89. doi:10.1182/asheducation-2011.1.84. ISSN 1520-4383. PMID 22160017.
  8. Gupta, Ruchi; et al. (2018-10). "Prevalence of Chromosome 7 Abnormalities in Myelodysplastic Syndrome and Acute Myeloid Leukemia: A Single Center Study and Brief Literature Review". Indian Journal of Hematology & Blood Transfusion: An Official Journal of Indian Society of Hematology and Blood Transfusion. 34 (4): 602–611. doi:10.1007/s12288-018-0941-1. ISSN 0971-4502. PMC 6186231. PMID 30369728. Check date values in: |date= (help)
  9. Schwartz, Jason R.; et al. (2017-11-16). "The genomic landscape of pediatric myelodysplastic syndromes". Nature Communications. 8 (1): 1557. doi:10.1038/s41467-017-01590-5. ISSN 2041-1723. PMC 5691144. PMID 29146900.
  10. Wlodarski, Marcin W.; et al. (2016-03-17). "Prevalence, clinical characteristics, and prognosis of GATA2-related myelodysplastic syndromes in children and adolescents". Blood. 127 (11): 1387–1397, quiz 1518. doi:10.1182/blood-2015-09-669937. ISSN 1528-0020. PMID 26702063.
  11. Arber DA, et al., (2016). WHO 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 Editors. IARC Press: Lyon, France, p106-109.
  12. Iwafuchi, Hideto (2018). "The histopathology of bone marrow failure in children". Journal of clinical and experimental hematopathology: JCEH. 58 (2): 68–86. doi:10.3960/jslrt.18018. ISSN 1880-9952. PMC 6413145. PMID 29998978.


Notes

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Prior Author(s):


*Citation of this Page: “Childhood myelodysplastic neoplasm with increased blasts”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated 02/11/2025, https://ccga.io/index.php/HAEM5:Childhood_myelodysplastic_neoplasm_with_increased_blasts.