Myelodysplastic neoplasm with low blasts and 5q deletion

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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
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Primary Author(s)*

Xiaolin Hu, Ph.D; Teresa Smolarek, Ph.D, FACMG

del(5)(q15q33)

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 low blasts and 5q deletion

Definition / Description of Disease

MDS with isolated del(5q) is a type of MDS with defining cytogenetic abnormality of del(5q). The World Health Organization named it as isolated del 5q, but occasionally the deletion can occur with an additional cytogenetic abnormality other than monosomy 7 or del(7q). The 5q- syndrome was first described by Van den Berghe et al as a distinct type of MDS featured with macrocytic anemia, hypolobulated megakaryocytes, a normal or increased platelet count [1]. Deletion of 5q is the most common recurrent cytogenetic abnormality in myeloid neoplasm and it was commonly seen in 10-15% of patients with MDS[2]. A ~1.5 Mb common deleted region (CDR) at 5q32-q33 was identified in 5q- syndrome patients and was associated with good prognosis [3]. This disease has a good respond to lenalidomide treatment (See Clinical Significance).

Synonyms / Terminology

Myelodysplastic syndromes with 5q deletion; 5q minus syndrome

Epidemiology / Prevalence

  • Median age 67 years [4]
  • Women versus male about 2:1

Clinical Features

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Signs and Symptoms EXAMPLE: Asymptomatic (incidental finding on complete blood counts)

EXAMPLE: B-symptoms (weight loss, fever, night sweats)

EXAMPLE: Fatigue

EXAMPLE: Lymphadenopathy (uncommon)

Laboratory Findings EXAMPLE: Cytopenias

EXAMPLE: Lymphocytosis (low level)


editv4:Clinical Features
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  • Macrocytic anemia most common, usually severe and can be transfusion dependent.
  • Thrombocytosis can be seen in 1/3 to 1/2 of cases, whereas thrombocytopenia or neutropenia are uncommon.
  • Pancytopenia is rare. If pancytopenia with isolated 5q-, MDS with unclassifiable should be considered. [WHO]
  • Good prognosis and low risk to progress to AML.

Sites of Involvement

Blood or bone marrow

Morphologic Features

On bone marrow examination, cellularity is usually normal or hypercellular. Erythroid hypoplasia may be seen. Blasts cells are < 5% in the bone marrow and < 1% in the peripheral blood. The most characteristic feature of isolated 5q- is the presence of micromegakaryocytes with hypolobated nuclei [insert pic micromegakaryocyte]. The erythroid dysplasia may be seen but not predominant. Granulocytic dysplasia is uncommon.

Hypolobated micromegakaryocytes are also seen in CML, which is characterized by leukocytosis, basophilia, and myeloid hyperplasia with leftward shift. Platelet count increase can be seen in essential thrombocythemia (ET), but ET has large megakaryocytes with hyperlobulated nuclei rather than microkaryocytes with hypolobulation in MDS with isolated del(5q).

Immunophenotype

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Finding Marker
Positive (universal) EXAMPLE: CD1
Positive (subset) EXAMPLE: CD2
Negative (universal) EXAMPLE: CD3
Negative (subset) EXAMPLE: CD4


editv4:Immunophenotype
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There is no distinct immunophenotypic profile specific for myelodysplastic syndrome (MDS) with isolated del(5q). Currently, morphologic evaluation remains the gold standard in diagnosis of MDS. Immunophenotyping provides supportive evidence to clarify the blasts nature and percentage [5].

Chromosomal Rearrangements (Gene Fusions)

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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).


editv4:Chromosomal Rearrangements (Gene Fusions)
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NA

Chromosomal Rearrangement Genes in Fusion (5’ or 3’ Segments) Pathogenic Derivative Prevalence
EXAMPLE: t(9;22)(q34;q11.2) EXAMPLE: 3'ABL1 / 5'BCR EXAMPLE: der(22) EXAMPLE: 5%
EXAMPLE: t(8;21)(q22;q22) EXAMPLE: 5'RUNX1 / 3'RUNXT1 EXAMPLE: der(8) EXAMPLE: 5%


editv4:Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications).
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  • Chromosomal Rearrangements (Gene Fusions)
  • Individual Region Genomic Gain/Loss/LOH
  • Characteristic Chromosomal Patterns
  • Gene Mutations (SNV/INDEL)

Diagnosis:

  • Cytopenia in 1 to 2 lineages. Cytopenias are defined as hemoglobin concentration < 10 g/dL, platelet count < 100 x 109/L and absolute neutrophil count < 1.8 x 109/L; mild degree of anemia (hemoglobin < 13 g/dL in men or < 12 g/dL in women) or thrombocytopenia (platelets < 150 x109/L) are allowed if defining cytogenetic abnormality is present. Thrombocytosis (platelet count ≥ 450 x 109/L) is allowed in MDS with isolated del(5q). PB monocytes must be < 1 x109/L.
  • Dysplasia in 1 to 3 lineages. Micromegakaryocytes with hypolobation are characteristic dysplasia. Ring sideroblasts are not common.
  • Blasts percentage: BM <5%, PB <1%, no Auer rods.
  • Interstitial deletion of 5q alone or with an additional abnormality other than loss of chromosome 7 or deletion of 7q.
  • Chromosome 7 loss or del(7q), more than one additional cytogenetic abnormality, excess blasts need to be excluded from the diagnosis.

Prognosis:

  • According to IPSS‐R good‐risk group with low rates of leukemic transformation [6].
  • The median survival of MDS with isolated del(5q) is 66 to 145 months.
  • About less than 10% of cases progress to acute myeloid leukemia [7].
  • Mutations of TP53 may function as an independent prognostic factor in associated with leukemic progression and resistant to lenalidomide[8][9].

Therapeutic Implications:

Lenalidomide is an analogue of thalidomide which functions as an immunomodulatory agent. Treatment with lenalidomide has shown great potential in reducing the abnormal clone as well as transfusion dependency irrespective of cytogenetic complexity [10][11]. FDA approved Lenalidomide on December 2005 for treating MDS with del(5q) with or without additional cytogenetic abnormalities.

Individual Region Genomic Gain / Loss / LOH

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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
EXAMPLE:

7

EXAMPLE: Loss EXAMPLE:

chr7:1- 159,335,973 [hg38]

EXAMPLE:

chr7

Yes Yes 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:

8

EXAMPLE: Gain EXAMPLE:

chr8:1-145,138,636 [hg38]

EXAMPLE:

chr8

No No No EXAMPLE:

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

editv4:Genomic Gain/Loss/LOH
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Chromosome Number Gain/Loss/Amp/LOH Region
EXAMPLE: 8 EXAMPLE: Gain EXAMPLE: chr8:0-1000000
EXAMPLE: 7 EXAMPLE: Loss EXAMPLE: chr7:0-1000000

Characteristic Chromosomal Patterns

Put your text here (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. Do not delete table.)

Chromosomal Pattern Diagnostic Significance (Yes, No or Unknown) Prognostic Significance (Yes, No or Unknown) Therapeutic Significance (Yes, No or Unknown) Notes
EXAMPLE:

Co-deletion of 1p and 18q

Yes No No EXAMPLE:

See chromosomal rearrangements table as this pattern is due to an unbalanced derivative translocation associated with oligodendroglioma (add reference).

editv4:Characteristic Chromosomal Aberrations / Patterns
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The most characteristic cytogenetic abnormality is an interstitial deletion on the long arm of chromosome 5 or del(5q)[1] The break point is not fixed but the region between bands q31 and q33 is generally deleted. Several candidates genes were thought to contribute to the haploinsufficiency effect of the deleted region, including RPS14 [12], CSNK1A1 [13], miR-145 and miR-146a [14]. Identification of del(5q) has clinical significance because patients with this cytogenetic abnormality have a good prognosis and they respond well to lenalidomide treatment.

Gene Mutations (SNV / INDEL)

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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
EXAMPLE: TP53; Variable LOF mutations

EXAMPLE:

EGFR; Exon 20 mutations

EXAMPLE: BRAF; Activating mutations

EXAMPLE: TSG EXAMPLE: 20% (COSMIC)

EXAMPLE: 30% (add Reference)

EXAMPLE: IDH1 R123H EXAMPLE: EGFR amplification EXAMPLE:  Excludes hairy cell leukemia (HCL) (add reference).


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.


editv4:Gene Mutations (SNV/INDEL)
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Somatic mutations in JAK2 and MPL have been reported in a small subset patients with isolated del(5q), but these mutations seem not confer diagnostic or prognostic value [15]. A subset of cases could have SF3B1 mutations, which needs to be differentiated with MDS-RS.

Gene Mutation Oncogene/Tumor Suppressor/Other Presumed Mechanism (LOF/GOF/Other; Driver/Passenger) Prevalence (COSMIC/TCGA/Other)
EXAMPLE: TP53 EXAMPLE: R273H EXAMPLE: Tumor Suppressor EXAMPLE: LOF EXAMPLE: 20%

Other Mutations

Type Gene/Region/Other
Concomitant Mutations JAK2 V617F, MPL W515L
Secondary Mutations
Mutually Exclusive

Epigenomic Alterations

Genes involved in epigenetic regulation are frequently mutated in MDS such as TET2, DNMT3A, IDH1, IDH2, AXSL1, and EZH2 [16]. These genes play a role in DNA methylation and chromatin modification as well as regulating gene expression.

Genes and Main Pathways Involved

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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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Several candidate genes in the common deleted region of 5q have been reported to contribute to the molecular pathogenesis.

RPS14: Encodes for ribosomal subunit of 40S. Inactivation of RPS14 results in ineffective erythroid differentiation and increased apoptosis in a p53 dependent way [17].

CSNK1A1: Encodes for CK1α, a serine/threonine protein kinase activity. Mutations in CSNK1A1 lead to clonal expansion of hematopoietic stem cells through activation of β-catenin [13].

miR-145 and miR146α: These two micro RNA genes are thought to be associated with thrombocytosis and hypolobulated megakaryocytes [18].

Genetic Diagnostic Testing Methods

  • Bone marrow morphology and peripheral blood test are standard in diagnosis of MDS.
  • FISH probes targeting the CDR are commonly incorporated into MDS panel to assess -5/5q-.
  • Conventional cytogenetics are also helpful in diagnosis.
    Fluorescent in situ hybridization (FISH) with a dual color DNA probe specific for the EGR1 (5q31.2) locus and to a distal short arm locus (5p15.31) of chromosome 5 detected two green and one red signal pattern that consistents with 5q deletion in 51% of patient's cells.

Familial Forms

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Additional Information

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Links

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References

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  1. ↑ 1.0 1.1 Van Den Berghe, Herman; et al. (1974). "Distinct haematological disorder with deletion of long arm of No. 5 chromosome". Nature. 251 (5474): 437–438. doi:10.1038/251437a0. ISSN 0028-0836.
  2. ↑ Hosono, Naoko; et al. (2017). "Recurrent genetic defects on chromosome 5q in myeloid neoplasms". Oncotarget. 8 (4): 6483–6495. doi:10.18632/oncotarget.14130. ISSN 1949-2553. PMC 5351647. PMID 28031539.CS1 maint: PMC format (link)
  3. ↑ Boultwood, J.; et al. (1994). "Molecular Mapping of Uncharacteristically Small 5q Deletions in Two Patients with the 5q- Syndrome: Delineation of the Critical Region on 5q and Identification of a 5q- Breakpoint". Genomics. 19 (3): 425–432. doi:10.1006/geno.1994.1090.
  4. ↑ Giagounidis, A.A.N.; et al. (2004). "Hematological Malignancies". Hematology. 9 (4): 271–277. doi:10.1080/10245330410001723824. ISSN 1607-8454.
  5. ↑ Zini, Gina (2017). "Diagnostics and Prognostication of Myelodysplastic Syndromes". Annals of Laboratory Medicine. 37 (6): 465. doi:10.3343/alm.2017.37.6.465. ISSN 2234-3806. PMC 5587818. PMID 28840983.CS1 maint: PMC format (link)
  6. ↑ Mallo, M; et al. (2011). "Impact of adjunct cytogenetic abnormalities for prognostic stratification in patients with myelodysplastic syndrome and deletion 5q". Leukemia. 25 (1): 110–120. doi:10.1038/leu.2010.231. ISSN 0887-6924.
  7. ↑ Boultwood, Jacqueline; et al. (2010). "Advances in the 5q− syndrome". Blood. 116 (26): 5803–5811. doi:10.1182/blood-2010-04-273771. ISSN 0006-4971.
  8. ↑ Jädersten, Martin; et al. (2011). "TP53 Mutations in Low-Risk Myelodysplastic Syndromes With del(5q) Predict Disease Progression". Journal of Clinical Oncology. 29 (15): 1971–1979. doi:10.1200/JCO.2010.31.8576. ISSN 0732-183X.
  9. ↑ Kulasekararaj, Austin G.; et al. (2013). "TP53 mutations in myelodysplastic syndrome are strongly correlated with aberrations of chromosome 5, and correlate with adverse prognosis". British Journal of Haematology. 160 (5): 660–672. doi:10.1111/bjh.12203.
  10. ↑ Giagounidis, A. A. N.; et al. (2005). "Prognosis of patients with del(5q) MDS and complex karyotype and the possible role of lenalidomide in this patient subgroup". Annals of Hematology. 84 (9): 569–571. doi:10.1007/s00277-005-1054-0. ISSN 0939-5555.
  11. ↑ List, Alan; et al. (2006). "Lenalidomide in the Myelodysplastic Syndrome with Chromosome 5q Deletion". New England Journal of Medicine. 355 (14): 1456–1465. doi:10.1056/NEJMoa061292. ISSN 0028-4793.
  12. ↑ Ebert, Benjamin L.; et al. (2008). "Identification of RPS14 as a 5q- syndrome gene by RNA interference screen". Nature. 451 (7176): 335–339. doi:10.1038/nature06494. ISSN 0028-0836. PMC 3771855. PMID 18202658.CS1 maint: PMC format (link)
  13. ↑ 13.0 13.1 Schneider, Rebekka K.; et al. (2014). "Role of Casein Kinase 1A1 in the Biology and Targeted Therapy of del(5q) MDS". Cancer Cell. 26 (4): 509–520. doi:10.1016/j.ccr.2014.08.001. PMC 4199102. PMID 25242043.CS1 maint: PMC format (link)
  14. ↑ Starczynowski, Daniel T; et al. (2010). "Identification of miR-145 and miR-146a as mediators of the 5q– syndrome phenotype". Nature Medicine. 16 (1): 49–58. doi:10.1038/nm.2054. ISSN 1078-8956.
  15. ↑ Patnaik, M M; et al. (2010). "WHO-defined 'myelodysplastic syndrome with isolated del(5q)' in 88 consecutive patients: survival data, leukemic transformation rates and prevalence of JAK2, MPL and IDH mutations". Leukemia. 24 (7): 1283–1289. doi:10.1038/leu.2010.105. ISSN 0887-6924. PMC 3035970. PMID 20485371.CS1 maint: PMC format (link)
  16. ↑ Heuser, Michael; et al. (2018). "Epigenetics in myelodysplastic syndromes". Seminars in Cancer Biology. 51: 170–179. doi:10.1016/j.semcancer.2017.07.009.
  17. ↑ Barlow, Jillian L; et al. (2010). "A p53-dependent mechanism underlies macrocytic anemia in a mouse model of human 5q– syndrome". Nature Medicine. 16 (1): 59–66. doi:10.1038/nm.2063. ISSN 1078-8956. PMC 2803774. PMID 19966810.CS1 maint: PMC format (link)
  18. ↑ Starczynowski, Daniel T; et al. (2010). "Identification of miR-145 and miR-146a as mediators of the 5q– syndrome phenotype". Nature Medicine. 16 (1): 49–58. doi:10.1038/nm.2054. ISSN 1078-8956.

Notes

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