Compendium of Cancer Genome Aberrations

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

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


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==Primary Author(s)*==
==Primary Author(s)*==


Ashwini Yenamandra PhD FACMG
Miguel Gonzalez Mancera, MD
 
Lisa Smith PhD FACMG
 
Yassmine Akkari PhD FACMG
==WHO Classification of Disease==
==WHO Classification of Disease==


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==Gene Rearrangements==
==Gene Rearrangements==


 
No recurrent gene rearrangements have been described<ref name=":13">WHO Classification of Tumours: Haematolymphoid Tumours [Internet; Beta Version Ahead of Print](5th ed.), International Agency for Research on Cancer (2022)</ref>.
Put your text here and fill in the table <span style="color:#0070C0">(''Instructions: Details on clinical significance such as prognosis and other important information can be provided in the notes section. Please include references throughout the table. Do not delete the table.'')</span>
{| class="wikitable sortable"
{| class="wikitable sortable"
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|<span class="blue-text">EXAMPLE:</span>
|<span class="blue-text">EXAMPLE:</span>
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). BCR::ABL1 is generally favorable in CML (add reference).
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). BCR::ABL1 is generally favorable in CML (add reference).
|-
|<span class="blue-text">EXAMPLE:</span> ''CIC''
|<span class="blue-text">EXAMPLE:</span> ''CIC::DUX4''
|<span class="blue-text">EXAMPLE:</span> 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''.
|<span class="blue-text">EXAMPLE:</span> t(4;19)(q25;q13)
|<span class="blue-text">EXAMPLE:</span> Common (CIC-rearranged sarcoma)
|<span class="blue-text">EXAMPLE:</span> D
|
|<span class="blue-text">EXAMPLE:</span>
''DUX4'' has many homologous genes; an alternate translocation in a minority of cases is t(10;19), but this is usually indistinguishable from t(4;19) by short-read sequencing (add references).
|-
|<span class="blue-text">EXAMPLE:</span> ''ALK''
|<span class="blue-text">EXAMPLE:</span> ''ELM4::ALK''
Other fusion partners include ''KIF5B, NPM1, STRN, TFG, TPM3, CLTC, KLC1''
|<span class="blue-text">EXAMPLE:</span> Fusions result in constitutive activation of the ''ALK'' tyrosine kinase. The most common ''ALK'' fusion is ''EML4::ALK'', with breakpoints in intron 19 of ''ALK''. At the transcript level, a variable (5’) partner gene is fused to 3’ ''ALK'' at exon 20. Rarely, ''ALK'' fusions contain exon 19 due to breakpoints in intron 18.
|<span class="blue-text">EXAMPLE:</span> N/A
|<span class="blue-text">EXAMPLE:</span> Rare (Lung adenocarcinoma)
|<span class="blue-text">EXAMPLE:</span> T
|
|<span class="blue-text">EXAMPLE:</span>
Both balanced and unbalanced forms are observed by FISH (add references).
|-
|<span class="blue-text">EXAMPLE:</span> ''ABL1''
|<span class="blue-text">EXAMPLE:</span> N/A
|<span class="blue-text">EXAMPLE:</span> Intragenic deletion of exons 2–7 in ''EGFR'' removes the ligand-binding domain, resulting in a constitutively active tyrosine kinase with downstream activation of multiple oncogenic pathways.
|<span class="blue-text">EXAMPLE:</span> N/A
|<span class="blue-text">EXAMPLE:</span> Recurrent (IDH-wildtype Glioblastoma)
|<span class="blue-text">EXAMPLE:</span> D, P, T
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<blockquote class="blockedit">{{Box-round|title=v4:Chromosomal Rearrangements (Gene Fusions)|The content below was from the old template. Please incorporate above.}}</blockquote>
N/A


<blockquote class="blockedit">
<blockquote class="blockedit">
<center><span style="color:Maroon">'''End of V4 Section'''</span>
<center>
----
</blockquote>
 
 
<blockquote class="blockedit">{{Box-round|title=v4:Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications).|Please incorporate this section into the relevant tables found in:
* Chromosomal Rearrangements (Gene Fusions)
* Individual Region Genomic Gain/Loss/LOH
* Characteristic Chromosomal Patterns
* Gene Mutations (SNV/INDEL)}}</blockquote>
 
B-lymphoblastic leukemia/lymphoma (B-ALL/LBL) is the most common cause of cancer in pediatric patients. It is characterized by recurrent genetic abnormalities of chromosome number, deletions, duplications and translocations. Hypodiploidy, a neoplasm of lymphoblasts containing less than 46 chromosomes<ref name=":0">Borowitz MJ, et al., (2017). B-Lymphoblastic leukaemia/lymphoma with recurrent genetic abnormalities, in World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, Revised 4th edition. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Arber DA, Hasserjian RP, Le Beau MM, Orazi A, and Siebert R, Editors. IARC Press: Lyon, France, p206.</ref>. Hypodiploid ALL has poor prognosis and near haploid with worst prognosis<ref name=":0" /><ref name=":2" /><ref name=":3">{{Cite journal|last=Nachman|first=James B.|last2=Heerema|first2=Nyla A.|last3=Sather|first3=Harland|last4=Camitta|first4=Bruce|last5=Forestier|first5=Erik|last6=Harrison|first6=Christine J.|last7=Dastugue|first7=Nicole|last8=Schrappe|first8=Martin|last9=Pui|first9=Ching-Hon|date=2007|title=Outcome of treatment in children with hypodiploid acute lymphoblastic leukemia|url=https://www.ncbi.nlm.nih.gov/pubmed/17473063|journal=Blood|volume=110|issue=4|pages=1112–1115|doi=10.1182/blood-2006-07-038299|issn=0006-4971|pmc=1939895|pmid=17473063}}</ref>.
 
Patients with 44 chromosomes had a better event free survival (EFS) than patients with fewer than 44 chromosomes<ref name=":3" />. However, patients with 44 chromosomes and monosomy 7 or a dicentric chromosome had worse EFS<ref name=":3" />. Children and adults with less than 44 chromosomes had poor outcome despite contemporary therapy<ref name=":3" />.
 
In near haploid cases, two-thirds had activation of RAS signaling and P13K signaling pathways; these are sensitive to P13K inhibitors indicating these drugs may offer a new therapeutic option<ref name=":2" />.
 
<blockquote class="blockedit">
<center><span style="color:Maroon">'''End of V4 Section'''</span>
----
----
</blockquote>
</blockquote>
==Individual Region Genomic Gain/Loss/LOH==
==Individual Region Genomic Gain/Loss/LOH==


 
Please refer to section "Characteristic Chromosomal or Other Global Mutational Patterns" below.
Put your text here and fill in the table <span style="color:#0070C0">(''Instructions: Includes aberrations not involving gene rearrangements. Details on clinical significance such as prognosis and other important information can be provided in the notes section. Can refer to CGC workgroup tables as linked on the homepage if applicable. Please include references throughout the table. Do not delete the table.'') </span>
{| class="wikitable sortable"
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|<span class="blue-text">EXAMPLE:</span>
|<span class="blue-text">EXAMPLE:</span>
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 references).
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 references).
|-
|<span class="blue-text">EXAMPLE:</span>
8
|<span class="blue-text">EXAMPLE:</span> Gain
|<span class="blue-text">EXAMPLE:</span>
chr8
|<span class="blue-text">EXAMPLE:</span>
Unknown
|<span class="blue-text">EXAMPLE:</span> D, P
|
|<span class="blue-text">EXAMPLE:</span>
Common recurrent secondary finding for t(8;21) (add references).
|-
|<span class="blue-text">EXAMPLE:</span>
17
|<span class="blue-text">EXAMPLE:</span> Amp
|<span class="blue-text">EXAMPLE:</span>
17q12; chr17:39,700,064-39,728,658 [hg38; 28.6 kb]
|<span class="blue-text">EXAMPLE:</span>
''ERBB2''
|<span class="blue-text">EXAMPLE:</span> D, P, T
|
|<span class="blue-text">EXAMPLE:</span>
Amplification of ''ERBB2'' is associated with HER2 overexpression in HER2 positive breast cancer (add references). Add criteria for how amplification is defined.
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<blockquote class="blockedit">{{Box-round|title=v4:Genomic Gain/Loss/LOH|The content below was from the old template. Please incorporate above.}}</blockquote>
{| class="wikitable sortable"
|-
!Chromosome Number!!Gain/Loss/Amp/LOH!!Region
|-
|17||Gain||SOX9
|-
|9||Loss||CDKN2A/CDKN2B (22-50%)
|}
|}


<blockquote class="blockedit">
<blockquote class="blockedit">
<center><span style="color:Maroon">'''End of V4 Section'''</span>
<center>
----
----
</blockquote>
</blockquote>
==Characteristic Chromosomal or Other Global Mutational Patterns==
==Characteristic Chromosomal or Other Global Mutational Patterns==
 
This entity is defined by the presence of neoplastic lymphoblasts containing less than 46 chromosomes<ref name=":0">Borowitz MJ, et al., (2017). B-Lymphoblastic leukaemia/lymphoma with recurrent genetic abnormalities, in World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, Revised 4th edition. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Arber DA, Hasserjian RP, Le Beau MM, Orazi A, and Siebert R, Editors. IARC Press: Lyon, France, p206.</ref>, and can be subdivided into near-haploid B-ALL/LBL with hypodiploidy (24–31 chromosomes); low-hypodiploid B-ALL/LBL with hypodiploidy (32–39 chromosomes); and high-hypodiploid B-ALL/LBL with hypodiploidy (40–43 chromosomes)<ref name=":13" /><ref name=":18" />. Of note, near-diploid cases (44–45 chromosomes) are not included in the hypodiploid category in clinical therapy–directed classification schemes because they do not share the poor prognosis observed<ref name=":14" />. In a study, for patients with 44 chromosomes, monosomy 7, the presence of a dicentric chromosome, or both predicted a worse event-free survival (EFS) but similar overall survival (OS)<ref name=":3">{{Cite journal|last=Nachman|first=James B.|last2=Heerema|first2=Nyla A.|last3=Sather|first3=Harland|last4=Camitta|first4=Bruce|last5=Forestier|first5=Erik|last6=Harrison|first6=Christine J.|last7=Dastugue|first7=Nicole|last8=Schrappe|first8=Martin|last9=Pui|first9=Ching-Hon|date=2007|title=Outcome of treatment in children with hypodiploid acute lymphoblastic leukemia|url=https://www.ncbi.nlm.nih.gov/pubmed/17473063|journal=Blood|volume=110|issue=4|pages=1112–1115|doi=10.1182/blood-2006-07-038299|issn=0006-4971|pmc=1939895|pmid=17473063}}</ref>.
 
Put your text here and fill in the table <span style="color:#0070C0">(I''nstructions: Included in this category are alterations such as 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; microsatellite instability; homologous recombination deficiency; mutational signature pattern; etc. Details on clinical significance such as prognosis and other important information can be provided in the notes section. Please include references throughout the table. Do not delete the table.'')</span>
{| class="wikitable sortable"
{| class="wikitable sortable"
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!Clinical Relevance Details/Other Notes
!Clinical Relevance Details/Other Notes
|-
|-
|<span class="blue-text">EXAMPLE:</span>
|Near-haploid B-ALL/LBL with hypodiploidy (24–31 chromosomes)
Co-deletion of 1p and 18q
|Near haploidy may be the primary event with loss of chromosomes, followed by a secondary event of doubling of chromosomes indicating uniparental isodisomy (UPID), microdeletions if any may occur after the secondary event<ref name=":5">{{Cite journal|last=Safavi|first=S.|last2=Forestier|first2=E.|last3=Golovleva|first3=I.|last4=Barbany|first4=G.|last5=Nord|first5=K. H.|last6=Moorman|first6=A. V.|last7=Harrison|first7=C. J.|last8=Johansson|first8=B.|last9=Paulsson|first9=K.|date=2013|title=Loss of chromosomes is the primary event in near-haploid and low-hypodiploid acute lymphoblastic leukemia|url=https://www.ncbi.nlm.nih.gov/pubmed/22889820|journal=Leukemia|volume=27|issue=1|pages=248–250|doi=10.1038/leu.2012.227|issn=1476-5551|pmid=22889820}}</ref>. The chromosomal loss alone may be enough for leukemogenesis and the unconserved random chromosomes may contain specific genes that increase the oncogenic potential of leukemic cells<ref name=":15">{{Cite journal|last=Harrison|first=Christine J.|last2=Moorman|first2=Anthony V.|last3=Barber|first3=Kerry E.|last4=Broadfield|first4=Zoë J.|last5=Cheung|first5=Kan L.|last6=Harris|first6=Rachel L.|last7=Jalali|first7=G. Reza|last8=Robinson|first8=Hazel M.|last9=Strefford|first9=Jonathan C.|date=2005-05|title=Interphase molecular cytogenetic screening for chromosomal abnormalities of prognostic significance in childhood acute lymphoblastic leukaemia: a UK Cancer Cytogenetics Group Study|url=https://pubmed.ncbi.nlm.nih.gov/15877734|journal=British Journal of Haematology|volume=129|issue=4|pages=520–530|doi=10.1111/j.1365-2141.2005.05497.x|issn=0007-1048|pmid=15877734}}</ref><ref>{{Cite journal|last=Raimondi|first=Susana C.|last2=Zhou|first2=Yinmei|last3=Mathew|first3=Susan|last4=Shurtleff|first4=Sheila A.|last5=Sandlund|first5=John T.|last6=Rivera|first6=Gaston K.|last7=Behm|first7=Frederick G.|last8=Pui|first8=Ching-Hon|date=2003-12-15|title=Reassessment of the prognostic significance of hypodiploidy in pediatric patients with acute lymphoblastic leukemia|url=https://pubmed.ncbi.nlm.nih.gov/14669294|journal=Cancer|volume=98|issue=12|pages=2715–2722|doi=10.1002/cncr.11841|issn=0008-543X|pmid=14669294}}</ref>.
|<span class="blue-text">EXAMPLE:</span> See chromosomal rearrangements table as this pattern is due to an unbalanced derivative translocation associated with oligodendroglioma (add reference).
|Rare (0.5%)<ref name=":8" />
|<span class="blue-text">EXAMPLE:</span> Common (Oligodendroglioma)
|D: Needs demonstration of hypodiploidy (≤ 43 chromosomes) by karyotyping and/or FISH analysis; flow cytometry DNA index analysis and/or single nucleotide polymorphism (SNP) array analysis to identify masked hypodiploidy.
|<span class="blue-text">EXAMPLE:</span> D, P
P: Associated with poor prognosis<ref name=":3" /><ref name=":1" />. 5-year EFS 25–40%<ref name=":8">{{Cite journal|last=Panuciak|first=Kinga|last2=Nowicka|first2=Emilia|last3=Mastalerczyk|first3=Angelika|last4=Zawitkowska|first4=Joanna|last5=Niedźwiecki|first5=Maciej|last6=Lejman|first6=Monika|date=2023-05-15|title=Overview on Aneuploidy in Childhood B-Cell Acute Lymphoblastic Leukemia|url=https://pubmed.ncbi.nlm.nih.gov/37240110|journal=International Journal of Molecular Sciences|volume=24|issue=10|pages=8764|doi=10.3390/ijms24108764|issn=1422-0067|pmc=10218510|pmid=37240110}}</ref>.
|
 
|
|No (NCCN)
|It has been observed in the pediatric population with virtually no adult cases reported. Nonrandom retention of the X chromosome plus chromosomes 8, 14, 18, and 21 are frequently observed. The most common targets of aneuploidy are chromosomes 1–7, 9, 11–13, 15–17, 19–20 and 22<ref name=":2">{{Cite journal|last=Holmfeldt|first=Linda|last2=Wei|first2=Lei|last3=Diaz-Flores|first3=Ernesto|last4=Walsh|first4=Michael|last5=Zhang|first5=Jinghui|last6=Ding|first6=Li|last7=Payne-Turner|first7=Debbie|last8=Churchman|first8=Michelle|last9=Andersson|first9=Anna|date=2013|title=The genomic landscape of hypodiploid acute lymphoblastic leukemia|url=https://www.ncbi.nlm.nih.gov/pubmed/23334668|journal=Nature Genetics|volume=45|issue=3|pages=242–252|doi=10.1038/ng.2532|issn=1546-1718|pmc=3919793|pmid=23334668}}</ref><ref>{{Cite journal|last=Creasey|first=Thomas|last2=Enshaei|first2=Amir|last3=Nebral|first3=Karin|last4=Schwab|first4=Claire|last5=Watts|first5=Kathryn|last6=Cuthbert|first6=Gavin|last7=Vora|first7=Ajay|last8=Moppett|first8=John|last9=Harrison|first9=Christine J.|date=2021-09|title=Single nucleotide polymorphism array-based signature of low hypodiploidy in acute lymphoblastic leukemia|url=https://pubmed.ncbi.nlm.nih.gov/33938069|journal=Genes, Chromosomes & Cancer|volume=60|issue=9|pages=604–615|doi=10.1002/gcc.22956|issn=1098-2264|pmc=8600946|pmid=33938069}}</ref><ref name=":11">{{Cite journal|last=Harrison|first=Christine J.|last2=Moorman|first2=Anthony V.|last3=Broadfield|first3=Zoë J.|last4=Cheung|first4=Kan L.|last5=Harris|first5=Rachel L.|last6=Reza Jalali|first6=G.|last7=Robinson|first7=Hazel M.|last8=Barber|first8=Kerry E.|last9=Richards|first9=Sue M.|date=2004-06|title=Three distinct subgroups of hypodiploidy in acute lymphoblastic leukaemia|url=https://pubmed.ncbi.nlm.nih.gov/15147369|journal=British Journal of Haematology|volume=125|issue=5|pages=552–559|doi=10.1111/j.1365-2141.2004.04948.x|issn=0007-1048|pmid=15147369}}</ref><ref name=":6" /><ref name=":7">{{Cite journal|last=Holmfeldt|first=Linda|last2=Wei|first2=Lei|last3=Diaz-Flores|first3=Ernesto|last4=Walsh|first4=Michael|last5=Zhang|first5=Jinghui|last6=Ding|first6=Li|last7=Payne-Turner|first7=Debbie|last8=Churchman|first8=Michelle|last9=Andersson|first9=Anna|date=2013-03|title=The genomic landscape of hypodiploid acute lymphoblastic leukemia|url=https://pubmed.ncbi.nlm.nih.gov/23334668|journal=Nature Genetics|volume=45|issue=3|pages=242–252|doi=10.1038/ng.2532|issn=1546-1718|pmc=3919793|pmid=23334668}}</ref>.
Near-haploid and low-hypodiploid B-ALL/LBL may undergo doubling, resulting in a pseudohyperdiploid or near-triploid clone containing up to 78 chromosomes, and can present as a diagnostic challenge. If the original hypodiploid clone is not present, the hypodiploidy is regarded as masked, and the case may be mistaken for high-hyperdiploid B-ALL/LBL, resulting in an inappropriate prognostication<ref name=":1" /><ref>{{Cite journal|last=Carroll|first=Andrew J.|last2=Shago|first2=Mary|last3=Mikhail|first3=Fady M.|last4=Raimondi|first4=Susana C.|last5=Hirsch|first5=Betsy A.|last6=Loh|first6=Mignon L.|last7=Raetz|first7=Elizabeth A.|last8=Borowitz|first8=Michael J.|last9=Wood|first9=Brent L.|date=2019-10|title=Masked hypodiploidy: Hypodiploid acute lymphoblastic leukemia (ALL) mimicking hyperdiploid ALL in children: A report from the Children's Oncology Group|url=https://pubmed.ncbi.nlm.nih.gov/31425927|journal=Cancer Genetics|volume=238|pages=62–68|doi=10.1016/j.cancergen.2019.07.009|issn=2210-7762|pmc=6768693|pmid=31425927}}</ref><ref>{{Cite journal|last=Creasey|first=Thomas|last2=Enshaei|first2=Amir|last3=Nebral|first3=Karin|last4=Schwab|first4=Claire|last5=Watts|first5=Kathryn|last6=Cuthbert|first6=Gavin|last7=Vora|first7=Ajay|last8=Moppett|first8=John|last9=Harrison|first9=Christine J.|date=2021-09|title=Single nucleotide polymorphism array-based signature of low hypodiploidy in acute lymphoblastic leukemia|url=https://pubmed.ncbi.nlm.nih.gov/33938069|journal=Genes, Chromosomes & Cancer|volume=60|issue=9|pages=604–615|doi=10.1002/gcc.22956|issn=1098-2264|pmc=8600946|pmid=33938069}}</ref>. The two subtypes may be differentiated by SNP array analysis, demonstrating copy-neutral loss of heterozygosity for doubled monosomic chromosomes. The DNA index assessed by flow cytometry may also be helpful if distinct peaks representing the hypodiploid and doubled clones are both detectable<ref>{{Cite journal|last=Yu|first=Chih-Hsiang|last2=Lin|first2=Tze-Kang|last3=Jou|first3=Shiann-Tarng|last4=Lin|first4=Chien-Yu|last5=Lin|first5=Kai-Hsin|last6=Lu|first6=Meng-Yao|last7=Chen|first7=Shu-Huey|last8=Cheng|first8=Chao-Neng|last9=Wu|first9=Kang-Hsi|date=2020-07-13|title=MLPA and DNA index improve the molecular diagnosis of childhood B-cell acute lymphoblastic leukemia|url=https://pubmed.ncbi.nlm.nih.gov/32661308|journal=Scientific Reports|volume=10|issue=1|pages=11501|doi=10.1038/s41598-020-68311-9|issn=2045-2322|pmc=7359332|pmid=32661308}}</ref>.
|-
|-
|<span class="blue-text">EXAMPLE:</span>
|Low-hypodiploid B-ALL/LBL with hypodiploidy (32–39 chromosomes)
Microsatellite instability - hypermutated
|More than 90% of low-hypodiploid patients have been identified with ''TP53'' mutations, which occur in virtually all low-hypodiploid B-ALL cases due to the very recurrent loss of chromosome 17<ref name=":6" /><ref name=":9" /><ref name=":10">{{Cite journal|last=Stengel|first=Anna|last2=Schnittger|first2=Susanne|last3=Weissmann|first3=Sandra|last4=Kuznia|first4=Sabrina|last5=Kern|first5=Wolfgang|last6=Kohlmann|first6=Alexander|last7=Haferlach|first7=Torsten|last8=Haferlach|first8=Claudia|date=2014-07-10|title=TP53 mutations occur in 15.7% of ALL and are associated with MYC-rearrangement, low hypodiploidy, and a poor prognosis|url=https://pubmed.ncbi.nlm.nih.gov/24829203|journal=Blood|volume=124|issue=2|pages=251–258|doi=10.1182/blood-2014-02-558833|issn=1528-0020|pmid=24829203}}</ref>. p53 is one of the most prominent tumor suppressors. Its activation as a transcription factor stimulates downstream pathways leading to protective cellular processes, including cell-cycle arrest, apoptosis, and senescence, to prevent the propagation of genetically altered cells<ref>{{Cite journal|last=Vogelstein|first=B.|last2=Lane|first2=D.|last3=Levine|first3=A. J.|date=2000-11-16|title=Surfing the p53 network|url=https://pubmed.ncbi.nlm.nih.gov/11099028|journal=Nature|volume=408|issue=6810|pages=307–310|doi=10.1038/35042675|issn=0028-0836|pmid=11099028}}</ref>.
|
|Rare in children, recurrent in adolescents, young adults, and adults
|<span class="blue-text">EXAMPLE:</span> Common (Endometrial carcinoma)
|P: Associated with poor prognosis. EFS 30–50%<ref name=":8" /><ref name=":1" />.
|<span class="blue-text">EXAMPLE:</span> P, T
|No (NCCN)
|
|Low-hypodiploid B-ALL/LBL is rare in children (< 1%); however, the frequency increases with age, accounting for 5% of B-ALL/LBL cases in adolescents and young adults, and > 10% of cases in adults. Nonrandom retention of two copies of chromosomes from the following: the sex chromosomes plus chromosomes 1,6, 8, 10, 14, 18, and19.  Chromosome 21 is almost always retained in two copies.
|
The most common targets of aneuploidy are chromosomes 2–4, 7, 9, 12–13, 15–17 and 20<ref name=":7" />.
|-
|-
|
|High-hypodiploid B-ALL/LBL with hypodiploidy (40–43 chromosomes)
|
|Genetic alterations involve ''CDKN2A'' and ''TP53''<ref name=":9" />.
|
|Rare, occurring in approximately 4% of diagnosed cases of hypodiploidy in both children and adults, but with a predominance of the younger group<ref name=":11" /><ref name=":12" />.
|
|P: Associated with poor prognosis. EFS 75%<ref name=":14">{{Cite journal|last=Pui|first=Ching-Hon|last2=Rebora|first2=Paola|last3=Schrappe|first3=Martin|last4=Attarbaschi|first4=Andishe|last5=Baruchel|first5=Andre|last6=Basso|first6=Giuseppe|last7=Cavé|first7=Hélène|last8=Elitzur|first8=Sarah|last9=Koh|first9=Katsuyoshi|date=2019-04-01|title=Outcome of Children With Hypodiploid Acute Lymphoblastic Leukemia: A Retrospective Multinational Study|url=https://pubmed.ncbi.nlm.nih.gov/30657737|journal=Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology|volume=37|issue=10|pages=770–779|doi=10.1200/JCO.18.00822|issn=1527-7755|pmc=7051863|pmid=30657737}}</ref>.
|
|No (NCCN)
|
|Chromosome abnormalities include whole chromosome loss, specifically one sex chromosome and often chromosomes 7, 9, and/or 13.  Also detected are structural anomalies especially dicentric chromosomes involving chromosomes 7, 9 or 12.
|}
|}


<blockquote class="blockedit">{{Box-round|title=v4:Characteristic Chromosomal Aberrations / Patterns|The content below was from the old template. Please incorporate above.}}</blockquote>
<blockquote class="blockedit"><br />
'''Note: A slight variation in the range of chromosome number has been reported in the literature in the classification of NH, LH, HH and NH'''<ref name=":0" /><ref name=":2" /><ref name=":5" /><ref name=":3" /><ref name=":1">{{Cite journal|last=Safavi|first=Setareh|last2=Paulsson|first2=Kajsa|date=2017|title=Near-haploid and low-hypodiploid acute lymphoblastic leukemia: two distinct subtypes with consistently poor prognosis|url=https://www.ncbi.nlm.nih.gov/pubmed/27903530|journal=Blood|volume=129|issue=4|pages=420–423|doi=10.1182/blood-2016-10-743765|issn=1528-0020|pmid=27903530}}</ref><ref name=":18">{{Cite journal|last=Harrison|first=Christine J.|last2=Moorman|first2=Anthony V.|last3=Broadfield|first3=Zoë J.|last4=Cheung|first4=Kan L.|last5=Harris|first5=Rachel L.|last6=Reza Jalali|first6=G.|last7=Robinson|first7=Hazel M.|last8=Barber|first8=Kerry E.|last9=Richards|first9=Sue M.|date=2004|title=Three distinct subgroups of hypodiploidy in acute lymphoblastic leukaemia|url=https://www.ncbi.nlm.nih.gov/pubmed/15147369|journal=British Journal of Haematology|volume=125|issue=5|pages=552–559|doi=10.1111/j.1365-2141.2004.04948.x|issn=0007-1048|pmid=15147369}}</ref><ref name=":19">{{Cite journal|last=Wang|first=Yunhong|last2=Miller|first2=Sue|last3=Roulston|first3=Diane|last4=Bixby|first4=Dale|last5=Shao|first5=Lina|date=2016|title=Genome-Wide Single-Nucleotide Polymorphism Array Analysis Improves Prognostication of Acute Lymphoblastic Leukemia/Lymphoma|url=https://www.ncbi.nlm.nih.gov/pubmed/27161658|journal=The Journal of molecular diagnostics: JMD|volume=18|issue=4|pages=595–603|doi=10.1016/j.jmoldx.2016.03.004|issn=1943-7811|pmid=27161658}}</ref><ref name=":9">{{Cite journal|last=Safavi|first=Setareh|last2=Olsson|first2=Linda|last3=Biloglav|first3=Andrea|last4=Veerla|first4=Srinivas|last5=Blendberg|first5=Molly|last6=Tayebwa|first6=Johnbosco|last7=Behrendtz|first7=Mikael|last8=Castor|first8=Anders|last9=Hansson|first9=Markus|date=2015|title=Genetic and epigenetic characterization of hypodiploid acute lymphoblastic leukemia|url=https://www.ncbi.nlm.nih.gov/pubmed/26544893|journal=Oncotarget|volume=6|issue=40|pages=42793–42802|doi=10.18632/oncotarget.6000|issn=1949-2553|pmc=4767471|pmid=26544893}}</ref> <ref name=":12">{{Cite journal|last=Moorman|first=Anthony V.|date=2016|title=New and emerging prognostic and predictive genetic biomarkers in B-cell precursor acute lymphoblastic leukemia|url=https://www.ncbi.nlm.nih.gov/pubmed/27033238|journal=Haematologica|volume=101|issue=4|pages=407–416|doi=10.3324/haematol.2015.141101|issn=1592-8721|pmc=5004393|pmid=27033238}}</ref><ref>{{Cite journal|last=Fang|first=Min|last2=Becker|first2=Pamela S.|last3=Linenberger|first3=Michael|last4=Eaton|first4=Keith D.|last5=Appelbaum|first5=Frederick R.|last6=Dreyer|first6=ZoAnn|last7=Airewele|first7=Gladstone|last8=Redell|first8=Michele|last9=Lopez-Terrada|first9=Dolores|date=2015|title=Adult Low-Hypodiploid Acute B-Lymphoblastic Leukemia With IKZF3 Deletion and TP53 Mutation: Comparison With Pediatric Patients|url=https://www.ncbi.nlm.nih.gov/pubmed/26185311|journal=American Journal of Clinical Pathology|volume=144|issue=2|pages=263–270|doi=10.1309/AJCPW83OXPYKPEEN|issn=1943-7722|pmid=26185311}}</ref><ref name=":6">{{Cite journal|last=Mühlbacher|first=Verena|last2=Zenger|first2=Melanie|last3=Schnittger|first3=Susanne|last4=Weissmann|first4=Sandra|last5=Kunze|first5=Franziska|last6=Kohlmann|first6=Alexander|last7=Bellos|first7=Frauke|last8=Kern|first8=Wolfgang|last9=Haferlach|first9=Torsten|date=2014|title=Acute lymphoblastic leukemia with low hypodiploid/near triploid karyotype is a specific clinical entity and exhibits a very high TP53 mutation frequency of 93%|url=https://www.ncbi.nlm.nih.gov/pubmed/24619868|journal=Genes, Chromosomes & Cancer|volume=53|issue=6|pages=524–536|doi=10.1002/gcc.22163|issn=1098-2264|pmid=24619868}}</ref><ref>{{Cite journal|last=Woo|first=Jennifer S.|last2=Alberti|first2=Michael O.|last3=Tirado|first3=Carlos A.|date=2014|title=Childhood B-acute lymphoblastic leukemia: a genetic update|url=https://www.ncbi.nlm.nih.gov/pubmed/24949228|journal=Experimental Hematology & Oncology|volume=3|pages=16|doi=10.1186/2162-3619-3-16|issn=2162-3619|pmc=4063430|pmid=24949228}}</ref><ref>{{Cite journal|last=Collins-Underwood|first=J. R.|last2=Mullighan|first2=C. G.|date=2010|title=Genomic profiling of high-risk acute lymphoblastic leukemia|url=https://www.ncbi.nlm.nih.gov/pubmed/20739952|journal=Leukemia|volume=24|issue=10|pages=1676–1685|doi=10.1038/leu.2010.177|issn=1476-5551|pmid=20739952}}</ref><ref name=":4">Karen Seiter, MD; Chief Editor: Emmanuel C Besa, MD (2018). Acute lymphoblastic  leukemia (ALL). Medscape. emedicine, Medscape Article, Drugs & Diseases, Hematology.</ref>  '''[1-17].'''</blockquote>In addition, lymphoid transcription factor gene ''IKZF3'' (13%, encoding AIOLOS) and deletions of histone cluster at 6p22 (19%) were also reported<ref name=":2" />. In low hypodiploid (LH) ALL mutations involved ''TP53'' (91.2%) and ''IKZF2'' (53%, encoding HELIOS, 2q34), and ''RB1'' genes (41%) loci<ref name=":2" />. Both NH and LH had activation of RAS signaling and P13K signaling pathways and sensitive to P13K inhibitors indicating these drugs may offer a new therapeutic option<ref name=":2" />. Inn this group, several studies have not only identified a high percentage of pediatric patients with ''TP53'' mutations, but close to half displayed germline mutations, suggesting that LH ALL is a manifestation of Li-Fraumeni syndrome in children.  Adults also showed a high incidence of ''TP53'' (91%) in low hypodiploid ALL mutations, but these mutations appear to be somatic in origin. In NH, mutations appear in genes involving receptor tyrosine kinase (RTK) pathway, Ras signaling, ''IKZF3'' (17q21.1), and histone clusters, but rarely ''IZFK2'', ''RB1'', or ''TP53''<ref name=":2" />.


'''Based on WHO classification'''<ref name=":0" />''', hypodiploidy is divided into:'''


1. '''Near-haploidy (NH=23-29 chromosomes)'''
This is a very rare category, has been observed in the pediatric population with virtually no adult cases reported.  Nonrandom retention of the X chromosome plus chromosomes 8, 14, 18, and 21 are frequently observed.
2. '''Low Hypodiploidy (LH=33-39 chromosomes)'''
This category was reported in both children and adults.  Nonrandom retention of two copies of chromosomes from the following: the sex chromosomes plus chromosomes 1,6, 8, 10, 14, 18, and19.  Chromosome 21 is almost always retained in two copies.
3. '''High Hypodiploidy (HH=40-43 chromosomes)'''
This category was observed in both children and adults.  Chromosome abnormalities include whole chromosome loss, specifically one sex chromosome and often chromosomes 7, 9, and/or 13.  Also detected are structural anomalies especially dicentric chromosomes involving chromosomes 7, 9 or 12.
4. '''Near-diploid (ND=44-45 chromosomes)'''
This category is not often included in hypodiploid.
'''Note: A slight variation in the range of chromosome number has been reported in the literature in the classification of NH, LH, HH and NH'''<ref name=":0" /><ref name=":1">{{Cite journal|last=Terwilliger|first=T.|last2=Abdul-Hay|first2=M.|date=2017|title=Acute lymphoblastic leukemia: a comprehensive review and 2017 update|url=https://www.ncbi.nlm.nih.gov/pubmed/28665419|journal=Blood Cancer Journal|volume=7|issue=6|pages=e577|doi=10.1038/bcj.2017.53|issn=2044-5385|pmc=5520400|pmid=28665419}}</ref><ref name=":2" /><ref name=":5" /><ref name=":3" /><ref>{{Cite journal|last=Safavi|first=Setareh|last2=Paulsson|first2=Kajsa|date=2017|title=Near-haploid and low-hypodiploid acute lymphoblastic leukemia: two distinct subtypes with consistently poor prognosis|url=https://www.ncbi.nlm.nih.gov/pubmed/27903530|journal=Blood|volume=129|issue=4|pages=420–423|doi=10.1182/blood-2016-10-743765|issn=1528-0020|pmid=27903530}}</ref><ref>{{Cite journal|last=Mehta|first=Parinda A.|last2=Zhang|first2=Mei-Jie|last3=Eapen|first3=Mary|last4=He|first4=Wensheng|last5=Seber|first5=Adriana|last6=Gibson|first6=Brenda|last7=Camitta|first7=Bruce M.|last8=Kitko|first8=Carrie L.|last9=Dvorak|first9=Christopher C.|date=2015|title=Transplantation Outcomes for Children with Hypodiploid Acute Lymphoblastic Leukemia|url=https://www.ncbi.nlm.nih.gov/pubmed/25865650|journal=Biology of Blood and Marrow Transplantation: Journal of the American Society for Blood and Marrow Transplantation|volume=21|issue=7|pages=1273–1277|doi=10.1016/j.bbmt.2015.04.008|issn=1523-6536|pmc=4465998|pmid=25865650}}</ref><ref>{{Cite journal|last=Mullighan|first=Charles G.|date=2012|title=Molecular genetics of B-precursor acute lymphoblastic leukemia|url=https://www.ncbi.nlm.nih.gov/pubmed/23023711|journal=The Journal of Clinical Investigation|volume=122|issue=10|pages=3407–3415|doi=10.1172/JCI61203|issn=1558-8238|pmc=3461902|pmid=23023711}}</ref><ref>{{Cite journal|last=Harrison|first=Christine J.|last2=Moorman|first2=Anthony V.|last3=Broadfield|first3=Zoë J.|last4=Cheung|first4=Kan L.|last5=Harris|first5=Rachel L.|last6=Reza Jalali|first6=G.|last7=Robinson|first7=Hazel M.|last8=Barber|first8=Kerry E.|last9=Richards|first9=Sue M.|date=2004|title=Three distinct subgroups of hypodiploidy in acute lymphoblastic leukaemia|url=https://www.ncbi.nlm.nih.gov/pubmed/15147369|journal=British Journal of Haematology|volume=125|issue=5|pages=552–559|doi=10.1111/j.1365-2141.2004.04948.x|issn=0007-1048|pmid=15147369}}</ref><ref>{{Cite journal|last=Wang|first=Yunhong|last2=Miller|first2=Sue|last3=Roulston|first3=Diane|last4=Bixby|first4=Dale|last5=Shao|first5=Lina|date=2016|title=Genome-Wide Single-Nucleotide Polymorphism Array Analysis Improves Prognostication of Acute Lymphoblastic Leukemia/Lymphoma|url=https://www.ncbi.nlm.nih.gov/pubmed/27161658|journal=The Journal of molecular diagnostics: JMD|volume=18|issue=4|pages=595–603|doi=10.1016/j.jmoldx.2016.03.004|issn=1943-7811|pmid=27161658}}</ref><ref>{{Cite journal|last=Safavi|first=Setareh|last2=Olsson|first2=Linda|last3=Biloglav|first3=Andrea|last4=Veerla|first4=Srinivas|last5=Blendberg|first5=Molly|last6=Tayebwa|first6=Johnbosco|last7=Behrendtz|first7=Mikael|last8=Castor|first8=Anders|last9=Hansson|first9=Markus|date=2015|title=Genetic and epigenetic characterization of hypodiploid acute lymphoblastic leukemia|url=https://www.ncbi.nlm.nih.gov/pubmed/26544893|journal=Oncotarget|volume=6|issue=40|pages=42793–42802|doi=10.18632/oncotarget.6000|issn=1949-2553|pmc=4767471|pmid=26544893}}</ref> <ref>{{Cite journal|last=Moorman|first=Anthony V.|date=2016|title=New and emerging prognostic and predictive genetic biomarkers in B-cell precursor acute lymphoblastic leukemia|url=https://www.ncbi.nlm.nih.gov/pubmed/27033238|journal=Haematologica|volume=101|issue=4|pages=407–416|doi=10.3324/haematol.2015.141101|issn=1592-8721|pmc=5004393|pmid=27033238}}</ref><ref>{{Cite journal|last=Fang|first=Min|last2=Becker|first2=Pamela S.|last3=Linenberger|first3=Michael|last4=Eaton|first4=Keith D.|last5=Appelbaum|first5=Frederick R.|last6=Dreyer|first6=ZoAnn|last7=Airewele|first7=Gladstone|last8=Redell|first8=Michele|last9=Lopez-Terrada|first9=Dolores|date=2015|title=Adult Low-Hypodiploid Acute B-Lymphoblastic Leukemia With IKZF3 Deletion and TP53 Mutation: Comparison With Pediatric Patients|url=https://www.ncbi.nlm.nih.gov/pubmed/26185311|journal=American Journal of Clinical Pathology|volume=144|issue=2|pages=263–270|doi=10.1309/AJCPW83OXPYKPEEN|issn=1943-7722|pmid=26185311}}</ref><ref>{{Cite journal|last=Mühlbacher|first=Verena|last2=Zenger|first2=Melanie|last3=Schnittger|first3=Susanne|last4=Weissmann|first4=Sandra|last5=Kunze|first5=Franziska|last6=Kohlmann|first6=Alexander|last7=Bellos|first7=Frauke|last8=Kern|first8=Wolfgang|last9=Haferlach|first9=Torsten|date=2014|title=Acute lymphoblastic leukemia with low hypodiploid/near triploid karyotype is a specific clinical entity and exhibits a very high TP53 mutation frequency of 93%|url=https://www.ncbi.nlm.nih.gov/pubmed/24619868|journal=Genes, Chromosomes & Cancer|volume=53|issue=6|pages=524–536|doi=10.1002/gcc.22163|issn=1098-2264|pmid=24619868}}</ref><ref>{{Cite journal|last=Woo|first=Jennifer S.|last2=Alberti|first2=Michael O.|last3=Tirado|first3=Carlos A.|date=2014|title=Childhood B-acute lymphoblastic leukemia: a genetic update|url=https://www.ncbi.nlm.nih.gov/pubmed/24949228|journal=Experimental Hematology & Oncology|volume=3|pages=16|doi=10.1186/2162-3619-3-16|issn=2162-3619|pmc=4063430|pmid=24949228}}</ref><ref>{{Cite journal|last=Collins-Underwood|first=J. R.|last2=Mullighan|first2=C. G.|date=2010|title=Genomic profiling of high-risk acute lymphoblastic leukemia|url=https://www.ncbi.nlm.nih.gov/pubmed/20739952|journal=Leukemia|volume=24|issue=10|pages=1676–1685|doi=10.1038/leu.2010.177|issn=1476-5551|pmid=20739952}}</ref><ref name=":4">Karen Seiter, MD; Chief Editor: Emmanuel C Besa, MD (2018). Acute lymphoblastic  leukemia (ALL). Medscape. emedicine, Medscape Article, Drugs & Diseases, Hematology.</ref>  '''[1-17].'''
Sorting patients into these three rare groups is easy.  However, detecting the presence of a masked low-hypodiploid/masked near-hypodiploid group, which is endoreduplication of the low- and near-haploid groups and associated with a very poor prognosis, is difficult.  Often karyotypes in these two groups, usually ranging from 56-78 chromosomes, are mistaken for hyperdiploidy/near-triploidy, which in itself is associated with a good prognosis.  The key is to look for trisomies vs tetrasomies of the chromosomes.  Typically, hyperdiploidy/near-triploidy should have three copies of several chromosomes (usually the X, 4, 10, 17, and 18), and four copies of 14 and 21.  However, the masked low-hypodiploid/masked near-hypodiploid groups should show tetrasomies for the sex chromosomes and chromosomes 1, 14, 18, 21, and 22 while having only two copies of chromosomes 7 and 17.
When only a 56-78 chromosome count is detected, the above mentioned criteria is helpful, but SNP-array testing can also be informative. Masked near-haploidy appears to show LOH involving the chromosomes that are not gained and true hyperdiploidy will show heterozygosity. Dicentric chromosomes reportedly originated from chromosomes 9p, 12p or 20q in near diploid karyotypes<ref name=":2">{{Cite journal|last=Holmfeldt|first=Linda|last2=Wei|first2=Lei|last3=Diaz-Flores|first3=Ernesto|last4=Walsh|first4=Michael|last5=Zhang|first5=Jinghui|last6=Ding|first6=Li|last7=Payne-Turner|first7=Debbie|last8=Churchman|first8=Michelle|last9=Andersson|first9=Anna|date=2013|title=The genomic landscape of hypodiploid acute lymphoblastic leukemia|url=https://www.ncbi.nlm.nih.gov/pubmed/23334668|journal=Nature Genetics|volume=45|issue=3|pages=242–252|doi=10.1038/ng.2532|issn=1546-1718|pmc=3919793|pmid=23334668}}</ref>. In near haploid aneuploidy of chromosomes 1 through 7, 9, 11, 13, 15-17, 19,20, 22 while in low hypodiploid aneuploidy of chromosomes 2 through 4, 7, 9, 12, 13, 15 and 17 were reported<ref name=":2" />.
Near haploidy may be the primary event with loss of chromosomes, followed by a secondary event of doubling of chromosomes indicating uniparental isodisomy (UPID), microdeletions if any may occur after the secondary event<ref name=":5">{{Cite journal|last=Safavi|first=S.|last2=Forestier|first2=E.|last3=Golovleva|first3=I.|last4=Barbany|first4=G.|last5=Nord|first5=K. H.|last6=Moorman|first6=A. V.|last7=Harrison|first7=C. J.|last8=Johansson|first8=B.|last9=Paulsson|first9=K.|date=2013|title=Loss of chromosomes is the primary event in near-haploid and low-hypodiploid acute lymphoblastic leukemia|url=https://www.ncbi.nlm.nih.gov/pubmed/22889820|journal=Leukemia|volume=27|issue=1|pages=248–250|doi=10.1038/leu.2012.227|issn=1476-5551|pmid=22889820}}</ref>.
In hypodiploid ALL, molecular mutations are equally as important as chromosome number, or as a result of chromosome number, molecular mutations have a driving effect.  Both LH and NH have common mutations involved in the disease process. In near haploid ALL (NH) ''RTK'' and ''RAS'' (71%) signaling were a hallmark<ref name=":2" />. In addition, lymphoid transcription factor gene ''IKZF3'' (13%, encoding AIOLOS) and deletions of histone cluster at 6p22 (19%) were also reported<ref name=":2" />. In low hypodiploid (LH) ALL mutations involved ''TP53'' (91.2%) and ''IKZF2'' (53%, encoding HELIOS, 2q34), and ''RB1'' genes (41%) loci<ref name=":2" />. Both NH and LH had activation of RAS signaling and P13K signaling pathways and sensitive to P13K inhibitors indicating these drugs may offer a new therapeutic option<ref name=":2" />. Inn this group, several studies have not only identified a high percentage of pediatric patients with ''TP53'' mutations, but close to half displayed germline mutations, suggesting that LH ALL is a manifestation of Li-Fraumeni syndrome in children.  Adults also showed a high incidence of ''TP53'' (91%) in low hypodiploid ALL mutations, but these mutations appear to be somatic in origin. In NH, mutations appear in genes involving receptor tyrosine kinase (RTK) pathway, Ras signaling, ''IKZF3'' (17q21.1), and histone clusters, but rarely ''IZFK2'', ''RB1'', or ''TP53''<ref name=":2" />.
Copy number alterations and sequence mutations have been reported in ''FLT3'', ''NF1'', ''KRAS'', ''NRAS'', ''PTPN11'', ''RTK'', ''RAS'', ''IKZF1'', ''IKZF2'', ''IKZF3'', ''TP53'', ''RB1'', Histone, 6q22, ''CDKN2A'', ''CDKN2B'', ''PAX5'', and ''PAG1'' gene loci<ref name=":2" />.


The most significant observation by Holmfeldt et al.,<ref name=":2" /> is that a global difference in the gene expression profiles distinguishes subgroups of hypodiploid ALL. More than 600 genes had subtype specific enrichment on gene set enrichment analysis<ref name=":2" />. In addition, RAS pathway, ''RB1'' and ''TP53'' mutations mimic solid tumor pathways<ref name=":2" />.
The most significant observation by Holmfeldt et al.,<ref name=":2" /> is that a global difference in the gene expression profiles distinguishes subgroups of hypodiploid ALL. More than 600 genes had subtype specific enrichment on gene set enrichment analysis<ref name=":2" />. In addition, RAS pathway, ''RB1'' and ''TP53'' mutations mimic solid tumor pathways<ref name=":2" />.
Line 283: Line 147:
==Gene Mutations (SNV/INDEL)==
==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 or common as well either disease defining and/or clinically significant. If a gene has multiple mechanisms depending on the type or site of the alteration, add multiple entries 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. Details on clinical significance such as prognosis and other important information such as concomitant and mutually exclusive mutations can be provided in the notes section. Please include references throughout the table. Do not delete the table.'') </span>
{| class="wikitable sortable"
{| class="wikitable sortable"
|-
|-
Line 293: Line 155:
!Clinical Relevance Details/Other Notes
!Clinical Relevance Details/Other Notes
|-
|-
|<span class="blue-text">EXAMPLE:</span>''EGFR''
|''TP53''<br />
 
|The majority are missense mutations located in exon 7, exon 8, exon 6, and exon 5. Less frequent frameshift mutations in exon 4 and 7 have been described<ref name=":6" />. In general are predicted to be loss of function (LOF) mutations.
<br />
|Tumor supressor gene
|<span class="blue-text">EXAMPLE:</span> Exon 18-21 activating mutations
|Common  (>90%)
|<span class="blue-text">EXAMPLE:</span> Oncogene
|No established significance
|<span class="blue-text">EXAMPLE:</span> Common (lung cancer)
|No (NCCN)
|<span class="blue-text">EXAMPLE:</span> T
|These alterations correlate with low-hypodiploid ALL (32–39 chromosomes) and poorer clinical outcomes<ref name=":2" />. Approximately 50% of children with low-hypodiploid B-ALL/LBL carry germline ''TP53'' variants associated with Li–Fraumeni syndrome. Accordingly, genetic counseling is recommended for children with low-hypodiploid B-ALL carrying ''TP53'' mutations, and their relatives<ref name=":17" />. In contrast to childhood cases, ''TP53'' mutations in low-hypodiploid adult B-ALL are somatic, are not found in healthy hematopoietic cells, and not detectable in remission samples<ref name=":2" /><ref name=":6" />.
|<span class="blue-text">EXAMPLE:</span> Yes (NCCN)
|-
|<span class="blue-text">EXAMPLE:</span> Exons 18, 19, and 21 mutations are targetable for therapy. Exon 20 T790M variants cause resistance to first generation TKI therapy and are targetable by second and third generation TKIs (add references).
|''RB1''
|Focal deletion and mutation<ref name=":2" /><ref name=":16">{{Cite journal|last=Molina|first=Oscar|last2=Bataller|first2=Alex|last3=Thampi|first3=Namitha|last4=Ribera|first4=Jordi|last5=Granada|first5=Isabel|last6=Velasco|first6=Pablo|last7=Fuster|first7=José Luis|last8=Menéndez|first8=Pablo|date=2021-12-22|title=Near-Haploidy and Low-Hypodiploidy in B-Cell Acute Lymphoblastic Leukemia: When Less Is Too Much|url=https://pubmed.ncbi.nlm.nih.gov/35008193|journal=Cancers|volume=14|issue=1|pages=32|doi=10.3390/cancers14010032|issn=2072-6694|pmc=8750410|pmid=35008193}}</ref>
|Tumor supressor gene
|Common
|No established significance
|No (NCCN)
|Associated with low-hypodiploid B-ALL.
|-
|''NF1''
|Mutations and focal deletions. In 68% of the cases, the ''NF1'' deletions were intragenic involving exons 15 through 35<ref name=":2" />.
|Tumor supressor gene
|Mutations: Recurrent
Focal deletions: Common<ref name=":2" />
|No established significance
|No (NCCN)
| rowspan="6" |Involved in RTK/RAS cellular pathway, and associated primarily with near-haploid B-ALL<ref name=":2" /><ref name=":16" />.
|-
|''FLT3''
|Mutations<ref name=":2" />
|Oncogene
|Recurrent
|No established significance
|No (NCCN)
|-
|''NRAS''
|Mutations<ref name=":2" />
|Oncogene
|Recurrent 
|No established significance
|No (NCCN)
|-
|''KRAS''
|Mutation<ref name=":2" />
|Oncogene
|Rare
|No established significance
|No (NCCN)
|-
|''MAPK1''
|Mutation<ref name=":2" />
|Oncogene
|Rare
|No established significance
|No (NCCN)
|-
|-
|<span class="blue-text">EXAMPLE:</span> ''TP53''; Variable LOF mutations
|''PTPN11''
<br />
|Mutation<ref name=":2" />
|<span class="blue-text">EXAMPLE:</span> Variable LOF mutations
|Oncoogene
|<span class="blue-text">EXAMPLE:</span> Tumor Supressor Gene
|Rare
|<span class="blue-text">EXAMPLE:</span> Common (breast cancer)
|No established significance
|<span class="blue-text">EXAMPLE:</span> P
|No (NCCN)
|
|<span class="blue-text">EXAMPLE:</span> >90% are somatic; rare germline alterations associated with Li-Fraumeni syndrome (add reference). Denotes a poor prognosis in breast cancer.
|-
|-
|<span class="blue-text">EXAMPLE:</span> ''BRAF''; Activating mutations
|''CDKN2A/B''
|<span class="blue-text">EXAMPLE:</span> Activating mutations
|Focal deletion<ref name=":2" />
|<span class="blue-text">EXAMPLE:</span> Oncogene
|Tumor supressor
|<span class="blue-text">EXAMPLE:</span> Common (melanoma)
|Common
|<span class="blue-text">EXAMPLE:</span> T
|No established significance
|
|No (NCCN)
|
|Associated with near-haploid B-ALL and low-hypodiploid B-ALL.
|-
|-
|
|''IKZF2''
|
|Focal deletion<ref name=":16" />
|
|Tumor supressor
|
|Common
|
|No established significance
|
|No (NCCN)
|
|Associated with low-hypodiploid B-ALL.
|}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.
 
<blockquote class="blockedit">{{Box-round|title=v4:Gene Mutations (SNV/INDEL)|The content below was from the old template. Please incorporate above.}}</blockquote>
 
{| class="wikitable sortable"
|-
|-
!Gene!!Mutation!!Oncogene/Tumor Suppressor/Other!!Presumed Mechanism (LOF/GOF/Other; Driver/Passenger)!!Prevalence (COSMIC/TCGA/Other)
|''IKZF3''
<br />
|Focal deletion<ref name=":16" />
|Tumor supressor
|Recurrent
|No established significance
|No (NCCN)
|Associated with near-haploid B-ALL.
|-
|-
|TP53||R280S, Y220C and several other mutations, please see reference<ref name=":2" />.||Tumor Suppressor||Missense/Nonsense/Insertion/Splice||in Low Hypodiploid about 90%
|''PAG1''
|}
|Focal deletion<ref name=":2" />
|Tumor supressor
===Other Mutations===
|Recurrent
|No established significance
|No (NCCN)
|Associated with near-haploid B-ALL. It was identified as a putative RAS signaling inhibitor and have a negative regulatory function in proximal B-cell receptor signaling<ref name=":2" />.
|}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.


'''RTK-RAS signaling pathways''': About two-thirds of near haploid ALL (71%) had activation of RTK-RAS signaling pathways including deletion, amplification and sequence mutation of ''NF1'', ''NRAS'', ''KRAS'', ''MAPK1'', ''FLT3'' and ''PTPN11''<ref name=":2" />. ''NF1'' mutation was reported in 44% of near haploid cases with a biallelic mutation of ''NF1'' in 77% of the near haploid cases. In 68% of the cases, the ''NF1'' deletions were intragenic involving exons 15 through 35<ref name=":2" />. The focal deletion results in deletion of ''GAP''<ref name=":2" />.
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'''''PAG1'' mutations''': Recurrent alterations of ''PAG1'' was reported in 10.3% of near haploid ALL, ''PAG1'' mutations are rare in other hypodiploid cases<ref name=":2" />. ''PAG1'' was identified as a putative RAS signaling inhibitor and have a negative regulatory function in proximal B-cell receptor signaling<ref name=":2" />.


'''''TP53'' mutations''': High mutation rate was observed (91%) in low hypodiploid than in non-low hypodiploid (5%) B-ALL; In low hypodiploid ALL, 43% were observed in non-tumor hematopoietic cells, suggesting either an inherited or a germline ''de novo'' origin of the mutation<ref name=":2" />.
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<center><span style="color:Maroon">'''End of V4 Section'''</span>
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==Epigenomic Alterations==
==Epigenomic Alterations==


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==Genes and Main Pathways Involved==
==Genes and Main Pathways Involved==
Put your text here and fill in the table <span style="color:#0070C0">(''Instructions: Please include references throughout the table. Do not delete the table.)''</span>
{| class="wikitable sortable"
{| class="wikitable sortable"
|-
|-
!Gene; Genetic Alteration!!Pathway!!Pathophysiologic Outcome
!Gene; Genetic Alteration!!Pathway!!Pathophysiologic Outcome
|-
|-
|<span class="blue-text">EXAMPLE:</span> ''BRAF'' and ''MAP2K1''; Activating mutations
|''NF1, NRAS, KRAS, MAPK1, FLT3 or PTPN11''; Activating mutations<ref name=":2" />
|<span class="blue-text">EXAMPLE:</span> MAPK signaling
|RTK or Ras signaling
|<span class="blue-text">EXAMPLE:</span> Increased cell growth and proliferation
|Constitutive activation of mitogenic and anti-apoptotic pathways, driving uncontrolled cell proliferation, survival, and malignant transformation.
|-
|''IKZF1, IKZF2, IKZF3, PAX5, EBF1, VPREB1''
|B-cell development
|
|-
|''CDKN2A/B, TP53, RB1''
|Cell cycle and apoptosis
|
|-
|''ETV6''
|Hematopoiesis
|
|-
|''PAG1''
|BCR signaling  
|
|-
|''ARPP21''
|Calmodulin signaling
|
|-
|-
|<span class="blue-text">EXAMPLE:</span> ''CDKN2A''; Inactivating mutations
|''SLX4IP''
|<span class="blue-text">EXAMPLE:</span> Cell cycle regulation
|Telomere length maintenance
|<span class="blue-text">EXAMPLE:</span> Unregulated cell division
|
|-
|-
|<span class="blue-text">EXAMPLE:</span> ''KMT2C'' and ''ARID1A''; Inactivating mutations
|''CUL5''
|<span class="blue-text">EXAMPLE:</span> Histone modification, chromatin remodeling
|Ubiquitin pathway
|<span class="blue-text">EXAMPLE:</span> Abnormal gene expression program
|
|-
|-
|''FAM53B''
|Wnt signaling
|
|
|-
|''PDS5B''
|Cohesis complex
|
|
|-
|''ANKRD11, DMD''
|Cell adhesion
|
|
|}
|}
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RTK and RAS pathway alterations as ''de novo'' germline mutations or in primitive hematopoietic progenitor cells<ref name=":2" />.


<blockquote class="blockedit">
<blockquote class="blockedit">
<center><span style="color:Maroon">'''End of V4 Section'''</span>
<center>
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</blockquote>
</blockquote>
==Genetic Diagnostic Testing Methods==
==Genetic Diagnostic Testing Methods==


FLOW, Hematopathology, Cytogenetics, Fluorescence insitu Hybridization (FISH), Next Generation sequencing (NGS), Exome sequencing, Microarray.
Karyotype, flow cytometry DNA index, FISH, and SNP arrays are all useful in establishing the diagnosis<ref name=":13" />. When using FISH or karyotype, approximately 16% to 30% of the ALL cases yield no or inadequate cytogenetic results due to inadequate specimens and absent or few mitotic cells. Among those with a cytogenetic result, 15% to 25% have a normal karyotype<ref>{{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>. High-resolution SNP array can detect IKZF1 deletions and other cryptic copy number aberrations as well as CN-LOH that are not detectable by chromosome analysis<ref name=":19" />.


==Familial Forms==
==Familial Forms==


In Low hypodiploid (LH), several studies have not only identified a high percentage of pediatric patients with ''TP53'' mutations, but close to half displayed germline mutations, suggesting that LH ALL is a manifestation of Li-Fraumeni syndrome in children.  
In Low hypodiploid (LH), several studies have not only identified a high percentage of pediatric patients with ''TP53'' mutations, but close to half displayed germline mutations, suggesting that LH ALL is a manifestation of Li-Fraumeni syndrome in children<ref name=":2" /><ref name=":10" /><ref name=":17">{{Cite journal|last=Comeaux|first=Evan Q.|last2=Mullighan|first2=Charles G.|date=2017-03-01|title=TP53 Mutations in Hypodiploid Acute Lymphoblastic Leukemia|url=https://pubmed.ncbi.nlm.nih.gov/28003275|journal=Cold Spring Harbor Perspectives in Medicine|volume=7|issue=3|pages=a026286|doi=10.1101/cshperspect.a026286|issn=2157-1422|pmc=5334249|pmid=28003275}}</ref>.  


Adults also showed a high incidence of ''TP53'' mutations, but these mutations appear to be somatic in origin. In NH, mutations of genes of receptor tyrosine kinase (RTK) pathway, Ras signaling, ''IKZF3'' (17q21.1) and histone clusters, but mutations of ''IZFK2'', ''RB1'', or ''TP53'' were rare.
Adults also showed a high incidence of ''TP53'' mutations, but these mutations appear to be somatic in origin. In NH, mutations of genes of receptor tyrosine kinase (RTK) pathway, Ras signaling, ''IKZF3'' (17q21.1) and histone clusters, but mutations of ''IZFK2'', ''RB1'', or ''TP53'' were rare.
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==References==
==References==
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<references />


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