HAEM5:B-lymphoblastic leukaemia/lymphoma with high hyperdiploidy

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.

(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)*

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.

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 a karyotype comprising 51–65 chromosomes with recurrent, non-random gains of one or more copies of entire chromosomes.
• Highly homogeneous genomes are seen for most of the leukemias, with predominantly whole chromosome gains being present in all cells. 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 ; 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 (NCCN)	N/A
6	Gain	Chr6	None	No established significance	No (NCCN)	N/A
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.	No (NCCN)	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), but not in UK trials.	No (NCCN)	N/A
17	Gain	Chr17	None	See "prognostic significance" section for +4 above	No (NCCN)	N/A
10	Gain	Chr10	None	See prognostic significance" section for +4 above	No (NCCN)	N/A
8	Gain	Chr8	None	No established significance	No (NCCN)	N/A

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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, possibly already before birth, and are the main driver. It was suggested that the aneuploidy in these cases likely arises by an initial tripolar mitosis in a diploid cell followed by clonal evolution. During the clonal evolution, chromosomes that changed in copy number comprised X, 8, 9, 14, 16, 17, and 21.	Ubiquitous	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. 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). 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. More recent studies have validated a risk profile determining that outcome appears to be linked to specific chromosomal gains.

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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.

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	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.
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; 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.

Familial Forms

No familial forms have been described.

Additional Information

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Links

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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.

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

*Citation of this Page: “B-lymphoblastic leukaemia/lymphoma with high hyperdiploidy”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated 11/21/2025, https://ccga.io/index.php/HAEM5:B-lymphoblastic_leukaemia/lymphoma_with_high_hyperdiploidy.