HAEM5:B-lymphoblastic leukaemia/lymphoma with high hyperdiploidy: Difference between revisions

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{{DISPLAYTITLE:B-lymphoblastic leukaemia/lymphoma with high hyperdiploidy}}
{{DISPLAYTITLE:B-lymphoblastic leukaemia/lymphoma with high hyperdiploidy}}[[HAEM5:Table_of_Contents|Haematolymphoid Tumours (WHO Classification, 5th ed.)]]
[[HAEM5:Table_of_Contents|Haematolymphoid Tumours (5th ed.)]]


{{Under Construction}}
<blockquote class='blockedit'>{{Box-round|title=HAEM5 Conversion Notes|This page was converted to the new template on 2023-11-03. The original page can be found at [[HAEM4:B-Lymphoblastic Leukemia/Lymphoma with Hyperdiploidy]].
}}</blockquote>
==Primary Author(s)*==
==Primary Author(s)*==


Afia Hasnain, MBBS, PhD; Yassmine Akkari, PhD, FACMG
Miguel Gonzalez Mancera, MD
 
==WHO Classification of Disease==
__TOC__
 
==Cancer Category/Type==
 
B-Lymphoblastic Leukemia/Lymphoma
 
==Cancer Sub-Classification / Subtype==
 
B-Lymphoblastic Leukemia/Lymphoma with hyperdiploidy
 
==Definition / Description of Disease==
 
B-ALL with hyperdiploidy is a neoplasm of lymphoblasts committed to the B-cell lineage whose blasts contain >50 chromosome (usually <66), typically without translocations or other structural alterations.  


{| class="wikitable"
!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
|}


In the context of B-ALL, hyperdiploidy is further subdivided into two groups including low hyperdiploidy (47–50 chromosomes) and high hyperdiploidy ( > 50 chromosomes) with some studies further defining the high hyperdiploid subgroup as those with a modal chromosome number of 51–68. <ref>{{Cite journal|last=Groeneveld-Krentz|first=Stefanie|last2=Schroeder|first2=Michael P.|last3=Reiter|first3=Michael|last4=Pogodzinski|first4=Malwine J.|last5=Pimentel-Gutiérrez|first5=Helia J.|last6=Vagkopoulou|first6=Renia|last7=Hof|first7=Jana|last8=Chen-Santel|first8=Christiane|last9=Nebral|first9=Karin|date=04 2019|title=Aneuploidy in children with relapsed B-cell precursor acute lymphoblastic leukaemia: clinical importance of detecting a hypodiploid origin of relapse|url=https://pubmed.ncbi.nlm.nih.gov/30714092|journal=British Journal of Haematology|volume=185|issue=2|pages=266–283|doi=10.1111/bjh.15770|issn=1365-2141|pmid=30714092}}</ref> <ref>{{Cite journal|last=Chessels|first=J. M.|last2=Swansbury|first2=G. J.|last3=Reeves|first3=B.|last4=Bailey|first4=C. C.|last5=Richards|first5=S. M.|date=1997-10|title=Cytogenetics and prognosis in childhood lymphoblastic leukaemia: results of MRC UKALL X. Medical Research Council Working Party in Childhood Leukaemia|url=https://pubmed.ncbi.nlm.nih.gov/9359508|journal=British Journal of Haematology|volume=99|issue=1|pages=93–100|doi=10.1046/j.1365-2141.1997.3493163.x|issn=0007-1048|pmid=9359508}}</ref> <ref>{{Cite journal|last=Reismüller|first=Bettina|last2=Steiner|first2=Manuel|last3=Pichler|first3=Herbert|last4=Dworzak|first4=Michael|last5=Urban|first5=Christian|last6=Meister|first6=Bernhard|last7=Schmitt|first7=Klaus|last8=Pötschger|first8=Ulrike|last9=König|first9=Margit|date=06 2017|title=High hyperdiploid acute lymphoblastic leukemia (ALL)-A 25-year population-based survey of the Austrian ALL-BFM (Berlin-Frankfurt-Münster) Study Group|url=https://pubmed.ncbi.nlm.nih.gov/27804199|journal=Pediatric Blood & Cancer|volume=64|issue=6|doi=10.1002/pbc.26327|issn=1545-5017|pmid=27804199}}</ref> <ref>{{Cite journal|last=Paulsson|first=Kajsa|last2=Lilljebjörn|first2=Henrik|last3=Biloglav|first3=Andrea|last4=Olsson|first4=Linda|last5=Rissler|first5=Marianne|last6=Castor|first6=Anders|last7=Barbany|first7=Gisela|last8=Fogelstrand|first8=Linda|last9=Nordgren|first9=Ann|date=2015-06|title=The genomic landscape of high hyperdiploid childhood acute lymphoblastic leukemia|url=https://pubmed.ncbi.nlm.nih.gov/25961940|journal=Nature Genetics|volume=47|issue=6|pages=672–676|doi=10.1038/ng.3301|issn=1546-1718|pmid=25961940}}</ref>
==Related Terminology==


==Synonyms / Terminology==
Put your text here <span style="color:#0070C0">(''Instructions: Include currently used terms and major historical ones, adding “(historical)” after the latter.'') </span>
==Epidemiology / Prevalence==
The incidence of hyperdiploidy in B-ALL decreases with age: <ref>{{Cite journal|last=Paulsson|first=Kajsa|last2=Forestier|first2=Erik|last3=Andersen|first3=Mette K.|last4=Autio|first4=Kirsi|last5=Barbany|first5=Gisela|last6=Borgström|first6=Georg|last7=Cavelier|first7=Lucia|last8=Golovleva|first8=Irina|last9=Heim|first9=Sverre|date=2013-09|title=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|url=https://pubmed.ncbi.nlm.nih.gov/23645689|journal=Haematologica|volume=98|issue=9|pages=1424–1432|doi=10.3324/haematol.2013.085852|issn=1592-8721|pmc=3762100|pmid=23645689}}</ref><ref>{{Cite journal|last=Paulsson|first=Kajsa|last2=Forestier|first2=Erik|last3=Lilljebjörn|first3=Henrik|last4=Heldrup|first4=Jesper|last5=Behrendtz|first5=Mikael|last6=Young|first6=Bryan D.|last7=Johansson|first7=Bertil|date=2010-12-14|title=Genetic landscape of high hyperdiploid childhood acute lymphoblastic leukemia|url=https://pubmed.ncbi.nlm.nih.gov/21098271|journal=Proceedings of the National Academy of Sciences of the United States of America|volume=107|issue=50|pages=21719–21724|doi=10.1073/pnas.1006981107|issn=1091-6490|pmc=3003126|pmid=21098271}}</ref><ref>{{Cite journal|last=Paulsson|first=Kajsa|last2=Johansson|first2=Bertil|date=2009-08|title=High hyperdiploid childhood acute lymphoblastic leukemia|url=https://pubmed.ncbi.nlm.nih.gov/19415723|journal=Genes, Chromosomes & Cancer|volume=48|issue=8|pages=637–660|doi=10.1002/gcc.20671|issn=1098-2264|pmid=19415723}}</ref><ref>{{Cite journal|last=Mullighan|first=Charles G.|date=2014-12-05|title=The genomic landscape of acute lymphoblastic leukemia in children and young adults|url=https://pubmed.ncbi.nlm.nih.gov/25696852|journal=Hematology. American Society of Hematology. Education Program|volume=2014|issue=1|pages=174–180|doi=10.1182/asheducation-2014.1.174|issn=1520-4383|pmid=25696852}}</ref><ref>{{Cite journal|last=Okamoto|first=Ryoko|last2=Ogawa|first2=Seishi|last3=Nowak|first3=Daniel|last4=Kawamata|first4=Norihiko|last5=Akagi|first5=Tadayuki|last6=Kato|first6=Motohiro|last7=Sanada|first7=Masashi|last8=Weiss|first8=Tamara|last9=Haferlach|first9=Claudia|date=2010-09|title=Genomic profiling of adult acute lymphoblastic leukemia by single nucleotide polymorphism oligonucleotide microarray and comparison to pediatric acute lymphoblastic leukemia|url=https://pubmed.ncbi.nlm.nih.gov/20435627|journal=Haematologica|volume=95|issue=9|pages=1481–1488|doi=10.3324/haematol.2009.011114|issn=1592-8721|pmc=2930948|pmid=20435627}}</ref>
* approximately 25% of pediatric patients (ages 1–9 years)
* approximately 10% of adolescents (ages 10–15 years)
* approximately 5–7% of adults (age > 19 years)   
==Clinical Features==
Put your text here and fill in the table <span style="color:#0070C0">(''Instruction: Can include references in the table'') </span>
{| class="wikitable"
{| class="wikitable"
|'''Signs and Symptoms'''
|Acceptable
|EXAMPLE Asymptomatic (incidental finding on complete blood counts)
|N/A
|-
|Not Recommended
|N/A
|}


EXAMPLE B-symptoms (weight loss, fever, night sweats)
==Gene Rearrangements==


EXAMPLE Fatigue
No recurrent gene rearrangements have been described<ref name=":3" />.
 
{| class="wikitable sortable"
EXAMPLE Lymphadenopathy (uncommon)
|-
!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
|-
|-
|'''Laboratory Findings'''
|N/A
|EXAMPLE Cytopenias
|N/A
 
|N/A
EXAMPLE Lymphocytosis (low level)
|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<ref name=":6">{{Cite journal|last=Woodward|first=Eleanor L.|last2=Yang|first2=Minjun|last3=Moura-Castro|first3=Larissa H.|last4=van den Bos|first4=Hilda|last5=Gunnarsson|first5=Rebeqa|last6=Olsson-Arvidsson|first6=Linda|last7=Spierings|first7=Diana C. J.|last8=Castor|first8=Anders|last9=Duployez|first9=Nicolas|date=2023-03-25|title=Clonal origin and development of high hyperdiploidy in childhood acute lymphoblastic leukaemia|url=https://pubmed.ncbi.nlm.nih.gov/36966135|journal=Nature Communications|volume=14|issue=1|pages=1658|doi=10.1038/s41467-023-37356-5|issn=2041-1723|pmc=10039905|pmid=36966135}}</ref>. Below are the typical chromosomal gains described.
<blockquote class='blockedit'>{{Box-round|title=v4:Clinical Features|The content below was from the old template. Please incorporate above.}}
 
The presenting features are generally similar to those seen in patients with other ALLs.
 
</blockquote>
==Sites of Involvement==
 
Put your text here <span style="color:#0070C0">(''Instruction: Indicate physical sites; Example: nodal, extranodal, bone marrow'') </span>
 
==Morphologic Features==
 
Put your text here
 
==Immunophenotype==
 
Put your text here and/or fill in the table
 
{| class="wikitable sortable"
{| class="wikitable sortable"
|-
|-
!Finding!!Marker
!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 <ref name=":5">{{Cite journal|last=Harrison|first=Christine J.|last2=Haas|first2=Oskar|last3=Harbott|first3=Jochen|last4=Biondi|first4=Andrea|last5=Stanulla|first5=Martin|last6=Trka|first6=Jan|last7=Izraeli|first7=Shai|last8=Biology and Diagnosis Committee of International Berlin-Frankfürt-Münster study group|date=2010-10|title=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|url=https://pubmed.ncbi.nlm.nih.gov/20701601|journal=British Journal of Haematology|volume=151|issue=2|pages=132–142|doi=10.1111/j.1365-2141.2010.08314.x|issn=1365-2141|pmid=20701601}}</ref>; 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)
|
|-
|-
|Positive (universal)||CD19, CD10
|14
|Gain
|Chr14
|None
|No established significance
|No (NCCN)
|N/A
|-
|-
|Positive (subset)||CD34
|18
|Gain
|Chr18
|None
|Prognostic significance: has been correlated with a lower risk of relapse<ref name=":1">{{Cite journal|last=Moorman|first=Anthony V.|last2=Ensor|first2=Hannah M.|last3=Richards|first3=Sue M.|last4=Chilton|first4=Lucy|last5=Schwab|first5=Claire|last6=Kinsey|first6=Sally E.|last7=Vora|first7=Ajay|last8=Mitchell|first8=Chris D.|last9=Harrison|first9=Christine J.|date=2010-05|title=Prognostic effect of chromosomal abnormalities in childhood B-cell precursor acute lymphoblastic leukaemia: results from the UK Medical Research Council ALL97/99 randomised trial|url=https://pubmed.ncbi.nlm.nih.gov/20409752|journal=The Lancet. Oncology|volume=11|issue=5|pages=429–438|doi=10.1016/S1470-2045(10)70066-8|issn=1474-5488|pmid=20409752}}</ref>.
|No (NCCN)
|N/A
|-
|-
|Negative (universal)||CD45
|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)<ref name=":7">{{Cite journal|last=Schultz|first=Kirk R.|last2=Pullen|first2=D. Jeanette|last3=Sather|first3=Harland N.|last4=Shuster|first4=Jonathan J.|last5=Devidas|first5=Meenakshi|last6=Borowitz|first6=Michael J.|last7=Carroll|first7=Andrew J.|last8=Heerema|first8=Nyla A.|last9=Rubnitz|first9=Jeffrey E.|date=2007-02-01|title=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)|url=https://pubmed.ncbi.nlm.nih.gov/17003380|journal=Blood|volume=109|issue=3|pages=926–935|doi=10.1182/blood-2006-01-024729|issn=0006-4971|pmc=1785141|pmid=17003380}}</ref>, but not in UK trials<ref name=":1" />.
|No (NCCN)
|N/A
|-
|-
|Negative (subset)||EXAMPLE CD4
|X
|Gain
|ChrX
|None
|No established significance
|No (NCCN)
|N/A
|}
|}
 
==Characteristic Chromosomal or Other Global Mutational Patterns==
==Chromosomal Rearrangements (Gene Fusions)==
 
Put your text here and fill in the table


{| class="wikitable sortable"
{| class="wikitable sortable"
|-
|-
!Chromosomal Rearrangement!!Genes in Fusion (5’ or 3’ Segments)!!Pathogenic Derivative!!Prevalence
!Chromosomal Pattern
!Diagnostic Significance (Yes, No or Unknown)
!Molecular Pathogenesis
!Prognostic Significance (Yes, No or Unknown)
!Prevalence -
!Therapeutic Significance (Yes, No or Unknown)
Common >20%, Recurrent 5-20% or Rare <5% (Disease)
!Notes
!Diagnostic, Prognostic, and Therapeutic Significance - D, P, T
!Established Clinical Significance Per Guidelines - Yes or No (Source)
!Clinical Relevance Details/Other Notes
|-
|-
|EXAMPLE t(9;22)(q34;q11.2)||EXAMPLE 3'ABL1 / 5'BCR||EXAMPLE der(22)||EXAMPLE 20% (COSMIC)
|Hyperdiploid: 51-65 chromosomes with recurrent, non-random gains of one or more copies of entire chromosomes<ref name=":3" />
EXAMPLE 30% (add reference)
| rowspan="3" |Although pathogenetic mechanisms are poorly understood, chromosomal gains are early events in the pathogenesis, possibly already before birth, and are the main driver<ref name=":3">WHO Classification of Tumours: Haematolymphoid Tumours [Internet; Beta Version Ahead of Print](5th ed.), International Agency for Research on Cancer (2022)</ref><ref>{{Cite journal|last=Szczepański|first=T.|last2=Willemse|first2=M. J.|last3=van Wering|first3=E. R.|last4=van Weerden|first4=J. F.|last5=Kamps|first5=W. A.|last6=van Dongen|first6=J. J.|date=2001-09|title=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|url=https://pubmed.ncbi.nlm.nih.gov/11516102|journal=Leukemia|volume=15|issue=9|pages=1415–1423|doi=10.1038/sj.leu.2402206|issn=0887-6924|pmid=11516102}}</ref><ref>{{Cite journal|last=Maia|first=A. T.|last2=van der Velden|first2=V. H. J.|last3=Harrison|first3=C. J.|last4=Szczepanski|first4=T.|last5=Williams|first5=M. D.|last6=Griffiths|first6=M. J.|last7=van Dongen|first7=J. J. M.|last8=Greaves|first8=M. F.|date=2003-11|title=Prenatal origin of hyperdiploid acute lymphoblastic leukemia in identical twins|url=https://pubmed.ncbi.nlm.nih.gov/12931229|journal=Leukemia|volume=17|issue=11|pages=2202–2206|doi=10.1038/sj.leu.2403101|issn=0887-6924|pmid=12931229}}</ref><ref>{{Cite journal|last=Maia|first=Ana Teresa|last2=Tussiwand|first2=Roxane|last3=Cazzaniga|first3=Giovanni|last4=Rebulla|first4=Paolo|last5=Colman|first5=Susan|last6=Biondi|first6=Andrea|last7=Greaves|first7=Mel|date=2004-05|title=Identification of preleukemic precursors of hyperdiploid acute lymphoblastic leukemia in cord blood|url=https://pubmed.ncbi.nlm.nih.gov/15034866|journal=Genes, Chromosomes & Cancer|volume=40|issue=1|pages=38–43|doi=10.1002/gcc.20010|issn=1045-2257|pmid=15034866}}</ref><ref name=":2" />. Aneuploidy in these cases likely arises by an initial tripolar mitosis in a diploid cell followed by clonal evolution.
|Yes
During clonal evolution, chromosomes that change in copy number typically are X, 8, 9, 14, 16, 17, and 21<ref name=":6" />.
|No
|Common (defining)
|Yes
|D: Needs demonstration of high-hyperdiploidy status by karyotyping and/or FISH
|EXAMPLE
P: B-ALL/LBL with high-hyperdiploidy has a very favorable prognosis; long-term overall survival in >90% of children<ref name=":0">{{Cite journal|last=Paulsson|first=Kajsa|last2=Forestier|first2=Erik|last3=Andersen|first3=Mette K.|last4=Autio|first4=Kirsi|last5=Barbany|first5=Gisela|last6=Borgström|first6=Georg|last7=Cavelier|first7=Lucia|last8=Golovleva|first8=Irina|last9=Heim|first9=Sverre|date=2013-09|title=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|url=https://pubmed.ncbi.nlm.nih.gov/23645689|journal=Haematologica|volume=98|issue=9|pages=1424–1432|doi=10.3324/haematol.2013.085852|issn=1592-8721|pmc=3762100|pmid=23645689}}</ref>.
 
|No (NCCN)
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).
|Recent studies have validated a risk profile linked to specific chromosomal gains<ref>{{Cite journal|last=Enshaei|first=Amir|last2=Vora|first2=Ajay|last3=Harrison|first3=Christine J.|last4=Moppett|first4=John|last5=Moorman|first5=Anthony V.|date=2021-11|title=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|url=https://pubmed.ncbi.nlm.nih.gov/34715050|journal=The Lancet. Haematology|volume=8|issue=11|pages=e828–e839|doi=10.1016/S2352-3026(21)00304-5|issn=2352-3026|pmc=8567211|pmid=34715050}}</ref>.
|}
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)<ref name=":0" />.
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<ref name=":0" />.
 
|-
<blockquote class='blockedit'>{{Box-round|title=v4:Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications).|Please incorporate this section into the relevant tables found in:
|Gain of chromosome 21
* Chromosomal Rearrangements (Gene Fusions)
|Common (universal)
* Individual Region Genomic Gain/Loss/LOH
|N/A
* Characteristic Chromosomal Patterns
|No (NCCN)
* Gene Mutations (SNV/INDEL)}}
|Chromosome 21 is universally gained in high-hyperdiploid B-ALL/LBL<ref name=":5" />; therefore, the presence of multiple (3-5) discrete ''RUNX1'' signals seen when using ''ETV6''::''RUNX1'' FISH probes suggests the presence of high hyperdiploidy.
 
|-
* Pediatric patients with high hyperdiploidy have been reported to have a favorable prognosis with cure seen in >90% of children <ref>{{Cite journal|last=Paulsson|first=Kajsa|last2=Forestier|first2=Erik|last3=Andersen|first3=Mette K.|last4=Autio|first4=Kirsi|last5=Barbany|first5=Gisela|last6=Borgström|first6=Georg|last7=Cavelier|first7=Lucia|last8=Golovleva|first8=Irina|last9=Heim|first9=Sverre|date=2013-09|title=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|url=https://pubmed.ncbi.nlm.nih.gov/23645689|journal=Haematologica|volume=98|issue=9|pages=1424–1432|doi=10.3324/haematol.2013.085852|issn=1592-8721|pmc=3762100|pmid=23645689}}</ref>
|Triple trisomies in chromosomes 4, 10 and 17
* 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) <ref>{{Cite journal|last=Paulsson|first=Kajsa|last2=Forestier|first2=Erik|last3=Andersen|first3=Mette K.|last4=Autio|first4=Kirsi|last5=Barbany|first5=Gisela|last6=Borgström|first6=Georg|last7=Cavelier|first7=Lucia|last8=Golovleva|first8=Irina|last9=Heim|first9=Sverre|date=2013-09|title=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|url=https://pubmed.ncbi.nlm.nih.gov/23645689|journal=Haematologica|volume=98|issue=9|pages=1424–1432|doi=10.3324/haematol.2013.085852|issn=1592-8721|pmc=3762100|pmid=23645689}}</ref>
|
* Negative prognostic features include > 10 years of age, male gender, and bone marrow fibrosis <ref>{{Cite journal|last=Paulsson|first=Kajsa|last2=Forestier|first2=Erik|last3=Andersen|first3=Mette K.|last4=Autio|first4=Kirsi|last5=Barbany|first5=Gisela|last6=Borgström|first6=Georg|last7=Cavelier|first7=Lucia|last8=Golovleva|first8=Irina|last9=Heim|first9=Sverre|date=2013-09|title=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|url=https://pubmed.ncbi.nlm.nih.gov/23645689|journal=Haematologica|volume=98|issue=9|pages=1424–1432|doi=10.3324/haematol.2013.085852|issn=1592-8721|pmc=3762100|pmid=23645689}}</ref>
|P: Favorable
* 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% <ref>{{Cite journal|last=Chessels|first=J. M.|last2=Swansbury|first2=G. J.|last3=Reeves|first3=B.|last4=Bailey|first4=C. C.|last5=Richards|first5=S. M.|date=1997-10|title=Cytogenetics and prognosis in childhood lymphoblastic leukaemia: results of MRC UKALL X. Medical Research Council Working Party in Childhood Leukaemia|url=https://pubmed.ncbi.nlm.nih.gov/9359508|journal=British Journal of Haematology|volume=99|issue=1|pages=93–100|doi=10.1046/j.1365-2141.1997.3493163.x|issn=0007-1048|pmid=9359508}}</ref>  
|Yes (COG)
* Familial Forms
|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)<ref name=":7" />, but not in UK trials<ref name=":1" />.
 
|}
</blockquote>
==Gene Mutations (SNV/INDEL)==
==Individual Region Genomic Gain/Loss/LOH==
 
Put your text here and fill in the table <span style="color:#0070C0">(''Instructions: Includes aberrations not involving gene fusions. Can include references in the table. Can refer to CGC workgroup tables as linked on the homepage if applicable.'') </span>


Recurrently mutated genes have been identified<ref name=":2" />.
{| class="wikitable sortable"
{| class="wikitable sortable"
|-
|-
!Chr #!!Gain / Loss / Amp / LOH!!Minimal Region Genomic Coordinates [Genome Build]!!Minimal Region Cytoband
!Gene!!Genetic Alteration!!Tumor Suppressor Gene, Oncogene, Other!!Prevalence -
!Diagnostic Significance (Yes, No or Unknown)
Common >20%, Recurrent 5-20% or Rare <5% (Disease)
!Prognostic Significance (Yes, No or Unknown)
!Diagnostic, Prognostic, and Therapeutic Significance - D, P, T  
!Therapeutic Significance (Yes, No or Unknown)
!Established Clinical Significance Per Guidelines - Yes or No (Source)
!Notes
!Clinical Relevance Details/Other Notes
|-
|-
|EXAMPLE
|''KRAS''<br />
 
|Nonsynonymous single nucleotide variant (SNV) in known codon 12 and 13 hotspot region, and additional mutations in codons 116 and 146<ref name=":2" />
7
|Oncogene
|EXAMPLE Loss
|Common
|EXAMPLE
|No
 
chr7:1- 159,335,973 [hg38]
|EXAMPLE
 
chr7
|Yes
|Yes
|No
|No
|EXAMPLE
|''KRAS'' codons 117 and 146 may be new recurrent mutational hotspots in high hyperdiploid ALL<ref name=":2" />.
 
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
|''NRAS''
 
|Nonsynonymous SNV
8
|Oncogene
|EXAMPLE Gain
|Recurrent
|EXAMPLE
|No
 
chr8:1-145,138,636 [hg38]
|EXAMPLE
 
chr8
|No
|No
|N/A
|-
|''FLT3''
|Nonsynonymous SNV, nonframeshift insertion, nonframeshift deletion, nonframeshift substitution
|Tyrosine kinase receptor
|Recurrent
|No
|No
|No
|No
|EXAMPLE
|N/A
 
Common recurrent secondary finding for t(8;21) (add reference).
|}
 
<blockquote class='blockedit'>{{Box-round|title=v4:Genomic Gain/Loss/LOH|The content below was from the old template. Please incorporate above.}}
 
* Gains of chromosomes X, 4, 6, 10, 14, 17, 18 and 21 are most common with the following frequencies:
** 21 (98%)
** X (90%)
** 6 (83%)
** 14 (83%)
** 18 (78%)
** 4 (77%)
** 17 (73%)
** 10 (71%)
** 8 (38%)
 
<ref>{{Cite journal|last=Paulsson|first=Kajsa|last2=Forestier|first2=Erik|last3=Andersen|first3=Mette K.|last4=Autio|first4=Kirsi|last5=Barbany|first5=Gisela|last6=Borgström|first6=Georg|last7=Cavelier|first7=Lucia|last8=Golovleva|first8=Irina|last9=Heim|first9=Sverre|date=2013-09|title=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|url=https://pubmed.ncbi.nlm.nih.gov/23645689|journal=Haematologica|volume=98|issue=9|pages=1424–1432|doi=10.3324/haematol.2013.085852|issn=1592-8721|pmc=3762100|pmid=23645689}}</ref> <ref>{{Cite journal|last=Paulsson|first=Kajsa|last2=Forestier|first2=Erik|last3=Lilljebjörn|first3=Henrik|last4=Heldrup|first4=Jesper|last5=Behrendtz|first5=Mikael|last6=Young|first6=Bryan D.|last7=Johansson|first7=Bertil|date=2010-12-14|title=Genetic landscape of high hyperdiploid childhood acute lymphoblastic leukemia|url=https://pubmed.ncbi.nlm.nih.gov/21098271|journal=Proceedings of the National Academy of Sciences of the United States of America|volume=107|issue=50|pages=21719–21724|doi=10.1073/pnas.1006981107|issn=1091-6490|pmc=3003126|pmid=21098271}}</ref> <ref>{{Cite journal|last=Paulsson|first=Kajsa|last2=Johansson|first2=Bertil|date=2009-08|title=High hyperdiploid childhood acute lymphoblastic leukemia|url=https://pubmed.ncbi.nlm.nih.gov/19415723|journal=Genes, Chromosomes & Cancer|volume=48|issue=8|pages=637–660|doi=10.1002/gcc.20671|issn=1098-2264|pmid=19415723}}</ref>
{| class="wikitable sortable"
|-
|-
!Chromosome Number!!Gain/Loss/Amp/LOH!!Region
|''PTPN11''
|Nonsynonymous SNV
|Protein tyrosine phosphatase
|Recurrent
|No
|No
|N/A
|-
|-
|EXAMPLE 8||EXAMPLE Gain||EXAMPLE chr8:0-1000000
|''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<ref>{{Cite journal|last=Inthal|first=A.|last2=Zeitlhofer|first2=P.|last3=Zeginigg|first3=M.|last4=Morak|first4=M.|last5=Grausenburger|first5=R.|last6=Fronkova|first6=E.|last7=Fahrner|first7=B.|last8=Mann|first8=G.|last9=Haas|first9=O. A.|date=2012-08|title=CREBBP HAT domain mutations prevail in relapse cases of high hyperdiploid childhood acute lymphoblastic leukemia|url=https://pubmed.ncbi.nlm.nih.gov/22388726|journal=Leukemia|volume=26|issue=8|pages=1797–1803|doi=10.1038/leu.2012.60|issn=1476-5551|pmc=4194312|pmid=22388726}}</ref>.
|-
|-
|EXAMPLE 7||EXAMPLE Loss||EXAMPLE chr7:0-1000000
|''WHSC1''
|}
|Nonsynonymous SNV
|Histone methyltransferase
</blockquote>
|Recurrent
==Characteristic Chromosomal Patterns==
|No
 
|No
Put your text here <span style="color:#0070C0">(''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'')</span>
|N/A
 
{| class="wikitable sortable"
|-
|-
!Chromosomal Pattern
|''SUV420H1''
!Diagnostic Significance (Yes, No or Unknown)
|Nonsynonymous SNV
!Prognostic Significance (Yes, No or Unknown)
|Histone methyltransferase
!Therapeutic Significance (Yes, No or Unknown)
|Rare
!Notes
|No
|No
|N/A
|-
|-
|EXAMPLE
|''SETD2''
 
|Frameshift insertion
Co-deletion of 1p and 18q
|Histone methyltransferase
|Yes
|Rare
|No
|No
|No
|No
|EXAMPLE:
|N/A
 
See chromosomal rearrangements table as this pattern is due to an unbalanced derivative translocation associated with oligodendroglioma (add reference).
|}
 
<blockquote class='blockedit'>{{Box-round|title=v4:Characteristic Chromosomal Aberrations / Patterns|The content below was from the old template. Please incorporate above.}}
 
* Numerical increase in chromosomes usually without structural abnormalities
 
* Extra copies of chromosomes are non-random.
 
</blockquote>
==Gene Mutations (SNV/INDEL)==
 
Put your text here and fill in the table <span style="color:#0070C0">(''Instructions: This table is not meant to be an exhaustive list; please include only genes/alterations that are recurrent and common as well either disease defining and/or clinically significant. Can include references 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.'') </span>
 
{| class="wikitable sortable"
|-
|-
!Gene; Genetic Alteration!!'''Presumed Mechanism (Tumor Suppressor Gene [TSG] / Oncogene / Other)'''!!'''Prevalence (COSMIC /  TCGA / Other)'''!!'''Concomitant Mutations'''!!'''Mutually Exclusive Mutations'''
|''EZH2''
!'''Diagnostic Significance (Yes, No or Unknown)'''
|Nonsynonymous SNV
!Prognostic Significance (Yes, No or Unknown)
|Histone methyltransferase
!Therapeutic Significance (Yes, No or Unknown)
|Rarre
!Notes
|No
|-
|No
|EXAMPLE: TP53; Variable LOF mutations
|N/A
 
|}Note: A more extensive list of mutations can be found in [https://www.cbioportal.org/ <u>cBioportal</u>], [https://cancer.sanger.ac.uk/cosmic <u>COSMIC</u>], and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content.
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).
<br />
|}
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.
 
==Epigenomic Alterations==
==Epigenomic Alterations==


Put your text here
No relevant epigenomic alterations have been described<ref name=":3" />.
 
==Genes and Main Pathways Involved==
==Genes and Main Pathways Involved==
Put your text here and fill in the table <span style="color:#0070C0">(''Instructions: Can include references in the table.'')</span>
{| class="wikitable sortable"
{| class="wikitable sortable"
|-
|-
!Gene; Genetic Alteration!!Pathway!!Pathophysiologic Outcome
!Gene; Genetic Alteration!!Pathway!!Pathophysiologic Outcome
|-
|-
|EXAMPLE: BRAF and MAP2K1; Activating mutations
|Aneuploid gene dosage effect
|EXAMPLE: MAPK signaling
|Global transcriptional amplification
|EXAMPLE: Increased cell growth and proliferation
|Increased expression of multiple survival genes
|-
|EXAMPLE: CDKN2A; Inactivating mutations
|EXAMPLE: Cell cycle regulation
|EXAMPLE: Unregulated cell division
|-
|-
|EXAMPLE:  KMT2C and ARID1A; Inactivating mutations
|''FLT3, NRAS, KRAS'' and ''PTPN11''<ref name=":2">{{Cite journal|last=Paulsson|first=Kajsa|last2=Lilljebjörn|first2=Henrik|last3=Biloglav|first3=Andrea|last4=Olsson|first4=Linda|last5=Rissler|first5=Marianne|last6=Castor|first6=Anders|last7=Barbany|first7=Gisela|last8=Fogelstrand|first8=Linda|last9=Nordgren|first9=Ann|date=2015-06|title=The genomic landscape of high hyperdiploid childhood acute lymphoblastic leukemia|url=https://pubmed.ncbi.nlm.nih.gov/25961940|journal=Nature Genetics|volume=47|issue=6|pages=672–676|doi=10.1038/ng.3301|issn=1546-1718|pmid=25961940}}</ref>; Activating mutations
|EXAMPLE:  Histone modification, chromatin remodeling
|Receptor tyrosine kinase (RTK)-RAS signaling
|EXAMPLE:  Abnormal gene expression program
|Increased proliferation, differentiation, and survival
|}
|}
==Genetic Diagnostic Testing Methods==
==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.
* 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.
<ref>{{Cite journal|last=Paulsson|first=Kajsa|last2=Forestier|first2=Erik|last3=Lilljebjörn|first3=Henrik|last4=Heldrup|first4=Jesper|last5=Behrendtz|first5=Mikael|last6=Young|first6=Bryan D.|last7=Johansson|first7=Bertil|date=2010-12-14|title=Genetic landscape of high hyperdiploid childhood acute lymphoblastic leukemia|url=https://pubmed.ncbi.nlm.nih.gov/21098271|journal=Proceedings of the National Academy of Sciences of the United States of America|volume=107|issue=50|pages=21719–21724|doi=10.1073/pnas.1006981107|issn=1091-6490|pmc=3003126|pmid=21098271}}</ref> <ref>{{Cite journal|last=Schraders|first=Margit|last2=van Reijmersdal|first2=Simon V.|last3=Kamping|first3=Eveline J.|last4=van Krieken|first4=Johan H. J. M.|last5=van Kessel|first5=Ad Geurts|last6=Groenen|first6=Patricia J. T. A.|last7=Hoogerbrugge|first7=Peter M.|last8=Kuiper|first8=Roland P.|date=2009-05|title=High-resolution genomic profiling of pediatric lymphoblastic lymphomas reveals subtle differences with pediatric acute lymphoblastic leukemias in the B-lineage|url=https://pubmed.ncbi.nlm.nih.gov/19389505|journal=Cancer Genetics and Cytogenetics|volume=191|issue=1|pages=27–33|doi=10.1016/j.cancergencyto.2009.01.002|issn=1873-4456|pmid=19389505}}</ref><ref>{{Cite journal|last=Steeghs|first=Elisabeth M. P.|last2=Boer|first2=Judith M.|last3=Hoogkamer|first3=Alex Q.|last4=Boeree|first4=Aurélie|last5=de Haas|first5=Valerie|last6=de Groot-Kruseman|first6=Hester A.|last7=Horstmann|first7=Martin A.|last8=Escherich|first8=Gabriele|last9=Pieters|first9=Rob|date=03 15, 2019|title=Copy number alterations in B-cell development genes, drug resistance, and clinical outcome in pediatric B-cell precursor acute lymphoblastic leukemia|url=https://pubmed.ncbi.nlm.nih.gov/30874617|journal=Scientific Reports|volume=9|issue=1|pages=4634|doi=10.1038/s41598-019-41078-4|issn=2045-2322|pmc=6420659|pmid=30874617}}</ref><ref>{{Cite journal|last=Lejman|first=Monika|last2=Zawitkowska|first2=Joanna|last3=Styka|first3=Borys|last4=Babicz|first4=Mariusz|last5=Winnicka|first5=Dorota|last6=Zaucha-Prażmo|first6=Agnieszka|last7=Pastorczak|first7=Agata|last8=Taha|first8=Joanna|last9=Młynarski|first9=Wojciech|date=08 2019|title=Microarray testing as an efficient tool to redefine hyperdiploid paediatric B-cell precursor acute lymphoblastic leukaemia patients|url=https://pubmed.ncbi.nlm.nih.gov/31202078|journal=Leukemia Research|volume=83|pages=106163|doi=10.1016/j.leukres.2019.05.013|issn=1873-5835|pmid=31202078}}</ref>
* Chromosomal microarray (CMA) - detects hyperdiploidy and additional genomic abnormalities commonly affecting chromosomes 1, 9, 11, 12, and X<ref name=":4">{{Cite journal|last=Paulsson|first=Kajsa|last2=Forestier|first2=Erik|last3=Lilljebjörn|first3=Henrik|last4=Heldrup|first4=Jesper|last5=Behrendtz|first5=Mikael|last6=Young|first6=Bryan D.|last7=Johansson|first7=Bertil|date=2010-12-14|title=Genetic landscape of high hyperdiploid childhood acute lymphoblastic leukemia|url=https://pubmed.ncbi.nlm.nih.gov/21098271|journal=Proceedings of the National Academy of Sciences of the United States of America|volume=107|issue=50|pages=21719–21724|doi=10.1073/pnas.1006981107|issn=1091-6490|pmc=3003126|pmid=21098271}}</ref><ref>{{Cite journal|last=Schraders|first=Margit|last2=van Reijmersdal|first2=Simon V.|last3=Kamping|first3=Eveline J.|last4=van Krieken|first4=Johan H. J. M.|last5=van Kessel|first5=Ad Geurts|last6=Groenen|first6=Patricia J. T. A.|last7=Hoogerbrugge|first7=Peter M.|last8=Kuiper|first8=Roland P.|date=2009-05|title=High-resolution genomic profiling of pediatric lymphoblastic lymphomas reveals subtle differences with pediatric acute lymphoblastic leukemias in the B-lineage|url=https://pubmed.ncbi.nlm.nih.gov/19389505|journal=Cancer Genetics and Cytogenetics|volume=191|issue=1|pages=27–33|doi=10.1016/j.cancergencyto.2009.01.002|issn=1873-4456|pmid=19389505}}</ref><ref>{{Cite journal|last=Steeghs|first=Elisabeth M. P.|last2=Boer|first2=Judith M.|last3=Hoogkamer|first3=Alex Q.|last4=Boeree|first4=Aurélie|last5=de Haas|first5=Valerie|last6=de Groot-Kruseman|first6=Hester A.|last7=Horstmann|first7=Martin A.|last8=Escherich|first8=Gabriele|last9=Pieters|first9=Rob|date=03 15, 2019|title=Copy number alterations in B-cell development genes, drug resistance, and clinical outcome in pediatric B-cell precursor acute lymphoblastic leukemia|url=https://pubmed.ncbi.nlm.nih.gov/30874617|journal=Scientific Reports|volume=9|issue=1|pages=4634|doi=10.1038/s41598-019-41078-4|issn=2045-2322|pmc=6420659|pmid=30874617}}</ref><ref>{{Cite journal|last=Lejman|first=Monika|last2=Zawitkowska|first2=Joanna|last3=Styka|first3=Borys|last4=Babicz|first4=Mariusz|last5=Winnicka|first5=Dorota|last6=Zaucha-Prażmo|first6=Agnieszka|last7=Pastorczak|first7=Agata|last8=Taha|first8=Joanna|last9=Młynarski|first9=Wojciech|date=08 2019|title=Microarray testing as an efficient tool to redefine hyperdiploid paediatric B-cell precursor acute lymphoblastic leukaemia patients|url=https://pubmed.ncbi.nlm.nih.gov/31202078|journal=Leukemia Research|volume=83|pages=106163|doi=10.1016/j.leukres.2019.05.013|issn=1873-5835|pmid=31202078}}</ref>, 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==
==Familial Forms==


Put your text here <span style="color:#0070C0">(''Instructions: Include associated hereditary conditions/syndromes that cause this entity or are caused by this entity.'') </span>
No familial forms have been described<ref name=":3" />.  
 
==Additional Information==
==Additional Information==


Put your text here
N/A


==Links==
==Links==


Put your links here (use link icon at top of page)
N/A


==References==
==References==
(use the "Cite" icon at the top of the page) <span style="color:#0070C0">(''Instructions: Add each reference into the text above by clicking on where you want to insert the reference, selecting the “Cite” icon at the top of the page, and using the “Automatic” tab option to search such as by PMID to select the reference to insert. The reference list in this section will be automatically generated and sorted.''</span> <span style="color:#0070C0">''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''</span><span style="color:#0070C0">''.''</span><span style="color:#0070C0">) </span> <references />
<references />


'''
<br />


==Notes==
==Notes==
<nowiki>*</nowiki>''Citation of this Page'': Mancera MG. “B-lymphoblastic leukaemia/lymphoma with high hyperdiploidy”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated {{REVISIONMONTH}}/{{REVISIONDAY}}/{{REVISIONYEAR}}, <nowiki>https://ccga.io/index.php/HAEM5:B-lymphoblastic_leukaemia/lymphoma_with_high_hyperdiploidy</nowiki>.
<nowiki>*</nowiki>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.
<nowiki>*</nowiki>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.
 
[[Category:HAEM5]]
 
[[Category:DISEASE]]
 
[[Category:Diseases B]]
[[Copy Number and cn-LOH Abnormalities in ALL]
 
<nowiki>*</nowiki>''Citation of this Page'': “B-lymphoblastic leukaemia/lymphoma with high hyperdiploidy”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated {{REVISIONMONTH}}/{{REVISIONDAY}}/{{REVISIONYEAR}}, <nowiki>https://ccga.io/index.php/HAEM5:B-lymphoblastic_leukaemia/lymphoma_with_high_hyperdiploidy</nowiki>.
[[Category:HAEM5]][[Category:DISEASE]][[Category:Diseases B]]

Latest revision as of 22:09, 17 February 2026

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.

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