B-lymphoblastic leukaemia/lymphoma with high hyperdiploidy

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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:B-Lymphoblastic Leukemia/Lymphoma with Hyperdiploidy.

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Primary Author(s)*

Miguel Gonzalez Mancera, MD

WHO Classification of Disease

Structure Disease
Book Haematolymphoid Tumours (5th ed.)
Category B-cell lymphoid proliferations and lymphomas
Family Precursor B-cell neoplasms
Type B-lymphoblastic leukaemias/lymphomas
Subtype(s) B-lymphoblastic leukaemia/lymphoma with high hyperdiploidy

Related Terminology

Acceptable N/A
Not Recommended N/A

Gene Rearrangements

No recurrent gene rearrangements have been described[1].

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: BCR::ABL1 EXAMPLE: The pathogenic derivative is the der(22) resulting in fusion of 5’ BCR and 3’ABL1.
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.

Individual Region Genomic Gain/Loss/LOH

This entity is defined by a hyperdiploid pattern with recurrent, non-random gains of one or more copies of entire chromosomes. Below are the typical chromosomal gains described.

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
21 Gain Chr21 RUNX1 No established significance No Chromosome 21 is universally gained in high-hyperdiploid B-ALL/LBL [2]; therefore, the presence of multiple (three to five) discrete RUNX1 signals seen when using ETV6::RUNX1 FISH probes suggests the presence of high hyperdiploidy.
X Gain ChrX None No established significance No N/A
6 Gain Chr6 None No established significance No N/A
14 Gain Chr14 None No established significance No N/A
18 Gain Chr18 None Prognostic significance: has been correlated with a lower risk of relapse[3]. No N/A
4 Gain Chr4 None The prognostic impact of the “triple trisomies”, i.e., concurrent rent +4, +10, and +17, is debated; they have been reported to be associated with low risk by the Children’s Oncology Group (COG)[4], but not in UK trials[3]. No N/A
17 Gain Chr17 None See prognosis section for +4 above No N/A
10 Gain Chr10 None See prognosis section for +4 above No N/A
8 Gain Chr8 None No established significance No

Characteristic Chromosomal or Other Global Mutational Patterns

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
Hyperdiploid Although pathogenetic mechanisms are poorly understood, chromosomal gains are early events in the pathogenesis of B-ALL/LBL with high hyperdiploidy and are the main driver[1][5]. It was suggested that the aneuploidy in these cases likely arises by an initial tripolar mitosis in a diploid cell followed by clonal evolution[6]. D: Needs demonstration of high-hyperdiploidy status (comprising 51–65 chromosomes) by karyotyping and/or FISH

P: B-ALL/LBL with high-hyperdiploidy has a very favorable prognosis, with long-term overall survival in > 90% of children[7].

T: N/A

No (NCCN) High event-free survival (EFS) was associated with trisomy 4, 6, 17, 18, and 22, presence of triple trisomies (4, 10, 17), and high modal numbers ( > 50 chromosomes)[7].

Patients with low hyperdiploidy have been reported to have a 49% EFS at 5 years compared to those with high hyperdiploidy with a five-year EFS of 71%. Negative prognostic features include > 10 years of age, male gender, and bone marrow fibrosis[7].

More recent studies have validated a risk profile determining that outcome appears to be linked to specific chromosomal gains[8].

Gene Mutations (SNV/INDEL)

Nine genes have been found to be recurrently mutated and were also either mutated more frequently than expected by chance or targeted by structural events[9].

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
KRAS


Nonsynonymous single nucleotide variant (SNV) in known codon 12 and 13 hotspot region, and additional mutations in codons 116 and 146[10] Oncogene Common No No KRAS codons 117 and 146 may be new recurrent mutational hotspots in high hyperdiploid ALL.
NRAS


Nonsynonymous SNV Oncogene Recurrent No No N/A
FLT3 Nonsynonymous SNV, nonframeshift insertion, nonframeshift deletion, nonframeshift substitution Tyrosine kinase receptor Recurrent No No N/A
PTPN11 Nonsynonymous SNV Protein tyrosine phosphatase Recurrent No No N/A
CREBBP Nonsynonymous SNV, frameshift insertion, splice site Histone acetyltransferase Recurrent No No CREBBP has been reported to be mutated in a high proportion of relapsing high hyperdiploid childhood ALLs[11].
WHSC1 Nonsynonymous SNV Histone methyltransferase Recurrent No No N/A
SUV420H1 Nonsynonymous SNV Histone methyltransferase Rare No No N/A
SETD2 Frameshift insertion Histone methyltransferase Rare No No N/A
EZH2 Nonsynonymous SNV Histone methyltransferase Rarre No No N/A

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.

Epigenomic Alterations

No relevant epigenomic alterations have been described.

Genes and Main Pathways Involved

Gene; Genetic Alteration Pathway Pathophysiologic Outcome
FLT3, NRAS, KRAS and PTPN11[5]; Activating mutations Receptor tyrosine kinase (RTK)-RAS signaling Increased proliferation, differentiation, and survival

Genetic Diagnostic Testing Methods

Hyperdiploidy is readily identifiable by conventional chromosome studies, FISH and CMA. CMA studies have shown that approximately 80% of hyperdiploid cases have additional genomic abnormalities with chromosomes commonly involved being 1, 9, 11, 12, and X[9] [12][13][14].

Familial Forms

No familial forms have been described.

Additional Information

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Links

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References

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  1. ↑ 1.0 1.1 WHO Classification of Tumours: Haematolymphoid Tumours [Internet; Beta Version Ahead of Print] (5th ed.), International Agency for Research on Cancer (2022) https://tumourclassification.iarc.who.int/chapters/63
  2. ↑ Harrison, Christine J.; et al. (2010-10). "Detection of prognostically relevant genetic abnormalities in childhood B-cell precursor acute lymphoblastic leukaemia: recommendations from the Biology and Diagnosis Committee of the International Berlin-Frankfürt-Münster study group". British Journal of Haematology. 151 (2): 132–142. doi:10.1111/j.1365-2141.2010.08314.x. ISSN 1365-2141. PMID 20701601. Check date values in: |date= (help)
  3. ↑ 3.0 3.1 Moorman, Anthony V.; et al. (2010-05). "Prognostic effect of chromosomal abnormalities in childhood B-cell precursor acute lymphoblastic leukaemia: results from the UK Medical Research Council ALL97/99 randomised trial". The Lancet. Oncology. 11 (5): 429–438. doi:10.1016/S1470-2045(10)70066-8. ISSN 1474-5488. PMID 20409752. Check date values in: |date= (help)
  4. ↑ Schultz, Kirk R.; et al. (2007-02-01). "Risk- and response-based classification of childhood B-precursor acute lymphoblastic leukemia: a combined analysis of prognostic markers from the Pediatric Oncology Group (POG) and Children's Cancer Group (CCG)". Blood. 109 (3): 926–935. doi:10.1182/blood-2006-01-024729. ISSN 0006-4971. PMC 1785141. PMID 17003380.
  5. ↑ 5.0 5.1 Paulsson, Kajsa; et al. (2015-06). "The genomic landscape of high hyperdiploid childhood acute lymphoblastic leukemia". Nature Genetics. 47 (6): 672–676. doi:10.1038/ng.3301. ISSN 1546-1718. PMID 25961940. Check date values in: |date= (help)
  6. ↑ Woodward, Eleanor L.; et al. (2023-03-25). "Clonal origin and development of high hyperdiploidy in childhood acute lymphoblastic leukaemia". Nature Communications. 14 (1): 1658. doi:10.1038/s41467-023-37356-5. ISSN 2041-1723. PMC 10039905 Check |pmc= value (help). PMID 36966135 Check |pmid= value (help).
  7. ↑ 7.0 7.1 7.2 Paulsson, Kajsa; et al. (2013-09). "High modal number and triple trisomies are highly correlated favorable factors in childhood B-cell precursor high hyperdiploid acute lymphoblastic leukemia treated according to the NOPHO ALL 1992/2000 protocols". Haematologica. 98 (9): 1424–1432. doi:10.3324/haematol.2013.085852. ISSN 1592-8721. PMC 3762100. PMID 23645689. Check date values in: |date= (help)
  8. ↑ Enshaei, Amir; et al. (2021-11). "Defining low-risk high hyperdiploidy in patients with paediatric acute lymphoblastic leukaemia: a retrospective analysis of data from the UKALL97/99 and UKALL2003 clinical trials". The Lancet. Haematology. 8 (11): e828–e839. doi:10.1016/S2352-3026(21)00304-5. ISSN 2352-3026. PMC 8567211 Check |pmc= value (help). PMID 34715050 Check |pmid= value (help). Check date values in: |date= (help)
  9. ↑ 9.0 9.1 Paulsson, Kajsa; et al. (2010-12-14). "Genetic landscape of high hyperdiploid childhood acute lymphoblastic leukemia". Proceedings of the National Academy of Sciences of the United States of America. 107 (50): 21719–21724. doi:10.1073/pnas.1006981107. ISSN 1091-6490. PMC 3003126. PMID 21098271.
  10. ↑ Paulsson, Kajsa; et al. (2009-08). "High hyperdiploid childhood acute lymphoblastic leukemia". Genes, Chromosomes & Cancer. 48 (8): 637–660. doi:10.1002/gcc.20671. ISSN 1098-2264. PMID 19415723. Check date values in: |date= (help)
  11. ↑ Inthal, A.; et al. (2012-08). "CREBBP HAT domain mutations prevail in relapse cases of high hyperdiploid childhood acute lymphoblastic leukemia". Leukemia. 26 (8): 1797–1803. doi:10.1038/leu.2012.60. ISSN 1476-5551. PMC 4194312. PMID 22388726. Check date values in: |date= (help)
  12. ↑ Schraders, Margit; et al. (2009-05). "High-resolution genomic profiling of pediatric lymphoblastic lymphomas reveals subtle differences with pediatric acute lymphoblastic leukemias in the B-lineage". Cancer Genetics and Cytogenetics. 191 (1): 27–33. doi:10.1016/j.cancergencyto.2009.01.002. ISSN 1873-4456. PMID 19389505. Check date values in: |date= (help)
  13. ↑ Steeghs, Elisabeth M. P.; et al. (03 15, 2019). "Copy number alterations in B-cell development genes, drug resistance, and clinical outcome in pediatric B-cell precursor acute lymphoblastic leukemia". Scientific Reports. 9 (1): 4634. doi:10.1038/s41598-019-41078-4. ISSN 2045-2322. PMC 6420659. PMID 30874617. Check date values in: |date= (help)
  14. ↑ Lejman, Monika; et al. (08 2019). "Microarray testing as an efficient tool to redefine hyperdiploid paediatric B-cell precursor acute lymphoblastic leukaemia patients". Leukemia Research. 83: 106163. doi:10.1016/j.leukres.2019.05.013. ISSN 1873-5835. PMID 31202078. Check date values in: |date= (help)


Notes

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[[Copy Number and cn-LOH Abnormalities in ALL]

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