Compendium of Cancer Genome Aberrations

B-lymphoblastic leukaemia/lymphoma with high hyperdiploidy

Haematolymphoid Tumours (WHO Classification, 5th ed.)

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
N/A N/A N/A N/A N/A N/A N/A N/A

Individual Region Genomic Gain/Loss/LOH

Highly homogeneous genomes are seen for most of the leukemias, with predominantly whole chromosome gains being present in all cells[2]. 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 (NCCN) Chromosome 21 is universally gained in high-hyperdiploid B-ALL/LBL [3]; therefore, the presence of multiple (three to five) discrete RUNX1 signals seen when using ETV6::RUNX1 FISH probes suggests the presence of high hyperdiploidy.
6 Gain Chr6 None No established significance No (NCCN) N/A
8 Gain Chr8 None No established significance No (NCCN)
14 Gain Chr14 None No established significance No (NCCN) N/A
18 Gain Chr18 None Prognostic significance: has been correlated with a lower risk of relapse[4]. No (NCCN) N/A
4, 10, 17 Gain Chr4, Chr10, Chr17 None Prognostic impact of “triple trisomies” (ie. concurrent +4, +10, and +17) is debated; reported to be associated with low risk by the Children’s Oncology Group (COG)[5], but not in UK trials[4]. No (NCCN) N/A
X Gain ChrX None No established significance No (NCCN) N/A

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: 51-65 chromosomes with recurrent, non-random gains of one or more copies of entire chromosomes[1] Although pathogenetic mechanisms are poorly understood, chromosomal gains are early events in the pathogenesis, possibly already before birth, and are the main driver[1][6][7][8][9]. Aneuploidy in these cases likely arises by an initial tripolar mitosis in a diploid cell followed by clonal evolution.

During clonal evolution, chromosomes that change in copy number typically are X, 8, 9, 14, 16, 17, and 21[2].

Common (defining) D: Needs demonstration of high-hyperdiploidy status by karyotyping and/or FISH

P: B-ALL/LBL with high-hyperdiploidy has a very favorable prognosis; long-term overall survival in >90% of children[10].

No (NCCN) Recent studies have validated a risk profile linked to specific chromosomal gains[11].

High event-free survival (EFS) associated with trisomy 4, 6, 17, 18, and 22; presence of triple trisomies (4, 10, 17); and high modal numbers (>50 chromosomes)[10]. Patients with low hyperdiploidy reported to have a 49% 5-year EFS compared to those with high hyperdiploidy who have a 71% 5-year EFS. Negative prognostic features include age >10 years, male gender, and bone marrow fibrosis[10].

Gain of chromosome 21 Common (universal) N/A No (NCCN) Chromosome 21 is universally gained in high-hyperdiploid B-ALL/LBL[3]; therefore, the presence of multiple (3-5) discrete RUNX1 signals seen when using ETV6::RUNX1 FISH probes suggests the presence of high hyperdiploidy.
Triple trisomies in chromosomes 4, 10 and 17 P: Favorable Yes (COG) Prognostic impact of “triple trisomies” (ie. concurrent +4, +10, and +17) is debated; reported to be associated with low risk by the Children’s Oncology Group (COG)[5], but not in UK trials[4].

Gene Mutations (SNV/INDEL)

Recurrently mutated genes have been identified[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[9] Oncogene Common No No KRAS codons 117 and 146 may be new recurrent mutational hotspots in high hyperdiploid ALL[9].
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; loss of function Epigenetic tumor suppressor gene Recurrent No No CREBBP has been reported to be mutated in a high proportion of relapsing high hyperdiploid childhood ALLs[12].
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[1].

Genes and Main Pathways Involved

Gene; Genetic Alteration Pathway Pathophysiologic Outcome
Aneuploid gene dosage effect Global transcriptional amplification Increased expression of multiple survival genes
FLT3, NRAS, KRAS and PTPN11[9]; Activating mutations Receptor tyrosine kinase (RTK)-RAS signaling Increased proliferation, differentiation, and survival

Genetic Diagnostic Testing Methods

  • Conventional cytogenetics - detects hyperdiploidy; excludes other recurrent genetic abnormalities that classify B-ALL/LBL subtypes.
  • FISH - detects hyperdiploidy; excludes other recurrent genetic abnormalities that classify B-ALL/LBL subtypes.
  • Chromosomal microarray (CMA) - detects hyperdiploidy and additional genomic abnormalities commonly affecting chromosomes 1, 9, 11, 12, and X[13][14][15][16], see in 80% of cases.
  • NGS: excludes other recurrent genetic abnormalities that classify B-ALL/LBL subtypes; identifies variants seen with progression of disease.

Familial Forms

No familial forms have been described[1].

Additional Information

N/A

Links

N/A

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 WHO Classification of Tumours: Haematolymphoid Tumours [Internet; Beta Version Ahead of Print](5th ed.), International Agency for Research on Cancer (2022)
  2. ↑ 2.0 2.1 Woodward, Eleanor L.; Yang, Minjun; Moura-Castro, Larissa H.; van den Bos, Hilda; Gunnarsson, Rebeqa; Olsson-Arvidsson, Linda; Spierings, Diana C. J.; Castor, Anders; Duployez, Nicolas (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. PMID 36966135.
  3. ↑ 3.0 3.1 Harrison, Christine J.; Haas, Oskar; Harbott, Jochen; Biondi, Andrea; Stanulla, Martin; Trka, Jan; Izraeli, Shai; Biology and Diagnosis Committee of International Berlin-Frankfürt-Münster study group (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. {{cite journal}}: Check date values in: |date= (help)
  4. ↑ 4.0 4.1 4.2 Moorman, Anthony V.; Ensor, Hannah M.; Richards, Sue M.; Chilton, Lucy; Schwab, Claire; Kinsey, Sally E.; Vora, Ajay; Mitchell, Chris D.; Harrison, Christine J. (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. {{cite journal}}: Check date values in: |date= (help)
  5. ↑ 5.0 5.1 Schultz, Kirk R.; Pullen, D. Jeanette; Sather, Harland N.; Shuster, Jonathan J.; Devidas, Meenakshi; Borowitz, Michael J.; Carroll, Andrew J.; Heerema, Nyla A.; Rubnitz, Jeffrey E. (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.
  6. ↑ Szczepański, T.; Willemse, M. J.; van Wering, E. R.; van Weerden, J. F.; Kamps, W. A.; van Dongen, J. J. (2001-09). "Precursor-B-ALL with D(H)-J(H) gene rearrangements have an immature immunogenotype with a high frequency of oligoclonality and hyperdiploidy of chromosome 14". Leukemia. 15 (9): 1415–1423. doi:10.1038/sj.leu.2402206. ISSN 0887-6924. PMID 11516102. {{cite journal}}: Check date values in: |date= (help)
  7. ↑ Maia, A. T.; van der Velden, V. H. J.; Harrison, C. J.; Szczepanski, T.; Williams, M. D.; Griffiths, M. J.; van Dongen, J. J. M.; Greaves, M. F. (2003-11). "Prenatal origin of hyperdiploid acute lymphoblastic leukemia in identical twins". Leukemia. 17 (11): 2202–2206. doi:10.1038/sj.leu.2403101. ISSN 0887-6924. PMID 12931229. {{cite journal}}: Check date values in: |date= (help)
  8. ↑ Maia, Ana Teresa; Tussiwand, Roxane; Cazzaniga, Giovanni; Rebulla, Paolo; Colman, Susan; Biondi, Andrea; Greaves, Mel (2004-05). "Identification of preleukemic precursors of hyperdiploid acute lymphoblastic leukemia in cord blood". Genes, Chromosomes & Cancer. 40 (1): 38–43. doi:10.1002/gcc.20010. ISSN 1045-2257. PMID 15034866. {{cite journal}}: Check date values in: |date= (help)
  9. ↑ 9.0 9.1 9.2 9.3 9.4 Paulsson, Kajsa; Lilljebjörn, Henrik; Biloglav, Andrea; Olsson, Linda; Rissler, Marianne; Castor, Anders; Barbany, Gisela; Fogelstrand, Linda; Nordgren, Ann (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. {{cite journal}}: Check date values in: |date= (help)
  10. ↑ 10.0 10.1 10.2 Paulsson, Kajsa; Forestier, Erik; Andersen, Mette K.; Autio, Kirsi; Barbany, Gisela; Borgström, Georg; Cavelier, Lucia; Golovleva, Irina; Heim, Sverre (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. {{cite journal}}: Check date values in: |date= (help)
  11. ↑ Enshaei, Amir; Vora, Ajay; Harrison, Christine J.; Moppett, John; Moorman, Anthony V. (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. PMID 34715050. {{cite journal}}: Check date values in: |date= (help)
  12. ↑ Inthal, A.; Zeitlhofer, P.; Zeginigg, M.; Morak, M.; Grausenburger, R.; Fronkova, E.; Fahrner, B.; Mann, G.; Haas, O. A. (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. {{cite journal}}: Check date values in: |date= (help)
  13. ↑ Paulsson, Kajsa; Forestier, Erik; Lilljebjörn, Henrik; Heldrup, Jesper; Behrendtz, Mikael; Young, Bryan D.; Johansson, Bertil (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.
  14. ↑ Schraders, Margit; van Reijmersdal, Simon V.; Kamping, Eveline J.; van Krieken, Johan H. J. M.; van Kessel, Ad Geurts; Groenen, Patricia J. T. A.; Hoogerbrugge, Peter M.; Kuiper, Roland P. (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. {{cite journal}}: Check date values in: |date= (help)
  15. ↑ Steeghs, Elisabeth M. P.; Boer, Judith M.; Hoogkamer, Alex Q.; Boeree, Aurélie; de Haas, Valerie; de Groot-Kruseman, Hester A.; Horstmann, Martin A.; Escherich, Gabriele; Pieters, Rob (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. {{cite journal}}: Check date values in: |date= (help)
  16. ↑ Lejman, Monika; Zawitkowska, Joanna; Styka, Borys; Babicz, Mariusz; Winnicka, Dorota; Zaucha-Prażmo, Agnieszka; Pastorczak, Agata; Taha, Joanna; Młynarski, Wojciech (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. {{cite journal}}: Check date values in: |date= (help)


Notes

*Citation of this Page: Mancera MG. “B-lymphoblastic leukaemia/lymphoma with high hyperdiploidy”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated 02/17/2026, https://ccga.io/index.php/HAEM5:B-lymphoblastic_leukaemia/lymphoma_with_high_hyperdiploidy.

*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.

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