Compendium of Cancer Genome Aberrations

HAEM5:B-lymphoblastic leukaemia/lymphoma with iAMP21: Difference between revisions

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[[HAEM5:Table_of_Contents|Haematolymphoid Tumours (WHO Classification, 5th ed.)]]
[[HAEM5:Table_of_Contents|Haematolymphoid Tumours (WHO Classification, 5th ed.)]]
<br />


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


Holli M. Drendel, PhD, FACMGG, Carolinas Pathology Group, Charlotte
Holli M. Drendel, PhD, FACMGG, Carolinas Pathology Group, Charlotte
__TOC__
==WHO Classification of Disease==
==WHO Classification of Disease==


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|}
|}


<br />
==Related Terminology==


==Morphologic Features==
There are no unique morphological or cytochemical features that distinguish this entity from other types of ALL.<ref name=":02">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.</ref>
Cytogenetic morphology of the abnormal chromosome 21 can vary markedly between patients.<ref name=":1">{{Cite journal|last=Harewood|first=L.|last2=Robinson|first2=H.|last3=Harris|first3=R.|last4=Al-Obaidi|first4=M. Jabbar|last5=Jalali|first5=G. R.|last6=Martineau|first6=M.|last7=Moorman|first7=A. V.|last8=Sumption|first8=N.|last9=Richards|first9=S.|date=2003-03|title=Amplification of AML1 on a duplicated chromosome 21 in acute lymphoblastic leukemia: a study of 20 cases|url=https://pubmed.ncbi.nlm.nih.gov/12646943|journal=Leukemia|volume=17|issue=3|pages=547–553|doi=10.1038/sj.leu.2402849|issn=0887-6924|pmid=12646943}}</ref>
<br />
==Immunophenotype==
No detailed information is known, other than these cases occur exclusively in B-ALL.<ref name=":02" />
{| class="wikitable sortable"
|-
!Finding!!Marker
|-
|Positive (universal)||N/A
|-
|Positive (subset)||N/A
|-
|Negative (universal)||N/A
|-
|Negative (subset)||N/A
|}
==WHO Essential and Desirable Genetic Diagnostic Criteria==
<span style="color:#0070C0">(''Instructions: The table will have the diagnostic criteria from the WHO book <u>autocompleted</u>; remove any <u>non</u>-genetics related criteria. If applicable, add text about other classification'' ''systems that define this entity and specify how the genetics-related criteria differ.'')</span>
{| class="wikitable"
|+
|WHO Essential Criteria (Genetics)*
|
|-
|WHO Desirable Criteria (Genetics)*
|
|-
|Other Classification
|
|}
<nowiki>*</nowiki>Note: These are only the genetic/genomic criteria. Additional diagnostic criteria can be found in the [https://tumourclassification.iarc.who.int/home <u>WHO Classification of Tumours</u>].
==Related Terminology==
<span style="color:#0070C0">(''Instructions: The table will have the related terminology from the WHO <u>autocompleted</u>.)''</span>
{| class="wikitable"
{| class="wikitable"
|+
|+
|Acceptable
|Acceptable
|
|N/A
|-
|-
|Not Recommended
|Not Recommended
|
|N/A
|}
|}


==Gene Rearrangements==
==Gene Rearrangements==
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>
Some rearrangements have been seen as secondary abnormalities.
{| 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> ''ABL1''||<span class="blue-text">EXAMPLE:</span> ''BCR::ABL1''||<span class="blue-text">EXAMPLE:</span> The pathogenic derivative is the der(22) resulting in fusion of 5’ BCR and 3’ABL1.||<span class="blue-text">EXAMPLE:</span> t(9;22)(q34;q11.2)
|''CRLF2''
|<span class="blue-text">EXAMPLE:</span> Common (CML)
|''P2RY8::CRLF2''
|<span class="blue-text">EXAMPLE:</span> D, P, T
|<span class="blue-text">EXAMPLE:</span> Yes (WHO, NCCN)
|<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).
|-
|<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>
|del(X)(p22.33p22.33)/del(Y)(p11.32p11.32)
 
''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
|
|
|
|
| rowspan="3" |Because of the unique nature of the iAMP21 abnormality, cases that present with additional genomic lesions that may suggest another category, such as a ''CRLF2'' rearrangement, should still be classified as B-ALL with iAMP21.
|-
|-
|
|Chimeric transcription factor/fusion gene
|
|''ETV6::RUNX1''
|
|The driver gene is a result of the fusion of 5'<nowiki/>''ETV6'' and 3'''RUNX1,'' genes that regulate hematopoiesis, which creates a chimeric transcription factor.
|
|
|
|
|
|}
 
Some rearrangements have been seen as secondary abnormalities.
 
{| class="wikitable sortable"
|-
!Chromosomal Rearrangement!!Genes in Fusion (5’ or 3’ Segments)!!Pathogenic Derivative!!Prevalence
!Diagnostic Significance (Yes, No or Unknown)
!Prognostic Significance (Yes, No or Unknown)
!Therapeutic Significance (Yes, No or Unknown)
!Notes
|-
|del(X)(p22.33p22.33)/del(Y)(p11.32p11.32)||''P2RY8-CRLF2''||der(X)/der(Y)||
|
|
|
|Because of the unique nature of the iAMP21 abnormality, cases that present with additional genomic lesions that may suggest another category, such as a CRLF2 rearrangement, should still be classified as B-ALL with iAMP21.
|-
|t(12;21)(p13.2;q22.1)
|t(12;21)(p13.2;q22.1)
|''ETV6-RUNX1''
|der(21)
|
|
|
|
|
|
|
|
|-
|-
|''ABL''
|''BCR::ABL1''
|The pathogenic derivative is the der(22) resulting in fusion of 5’ ''BCR'' and 3’''ABL1''.
|t(9;22)(q34;q11.2)
|t(9;22)(q34;q11.2)
|''BCR-ABL1''
|der(22)
|
|
|
|
|
|
|
|
|}
|}
==Individual Region Genomic Gain/Loss/LOH==
==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 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"
{| class="wikitable sortable"
|-
|-
!Chr #!!'''Gain, Loss, Amp, LOH'''!!'''Minimal Region Cytoband and/or Genomic Coordinates [Genome Build; Size]'''!!'''Relevant Gene(s)'''
!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'''
!Diagnostic, Prognostic, and Therapeutic Significance - D, P, T
!'''Established Clinical Significance Per Guidelines - Yes or No (Source)'''
!Established Clinical Significance Per Guidelines - Yes or No (Source)
!'''Clinical Relevance Details/Other Notes'''
!Clinical Relevance Details/Other Notes
|-
|-
|<span class="blue-text">EXAMPLE:</span>
|<span class="blue-text">EXAMPLE:</span>7
7
|<span class="blue-text">EXAMPLE:</span> Loss
|<span class="blue-text">EXAMPLE:</span> Loss
|<span class="blue-text">EXAMPLE:</span>
|<span class="blue-text">EXAMPLE:</span>chr7
chr7
|<span class="blue-text">EXAMPLE:</span>Unknown
|<span class="blue-text">EXAMPLE:</span>
Unknown
|<span class="blue-text">EXAMPLE:</span> D, P
|<span class="blue-text">EXAMPLE:</span> D, P
|<span class="blue-text">EXAMPLE:</span> No
|<span class="blue-text">EXAMPLE:</span> No
|<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>
|<span class="blue-text">EXAMPLE:</span>8
8
|<span class="blue-text">EXAMPLE:</span> Gain
|<span class="blue-text">EXAMPLE:</span> Gain
|<span class="blue-text">EXAMPLE:</span>
|<span class="blue-text">EXAMPLE:</span>chr8
chr8
|<span class="blue-text">EXAMPLE:</span>Unknown
|<span class="blue-text">EXAMPLE:</span>
Unknown
|<span class="blue-text">EXAMPLE:</span> D, P
|<span class="blue-text">EXAMPLE:</span> D, P
|
|
|<span class="blue-text">EXAMPLE:</span>
|<span class="blue-text">EXAMPLE:</span>Common recurrent secondary finding for t(8;21) (add references).
Common recurrent secondary finding for t(8;21) (add references).
|-
|-
|<span class="blue-text">EXAMPLE:</span>
|<span class="blue-text">EXAMPLE:</span>17
17
|<span class="blue-text">EXAMPLE:</span> Amp
|<span class="blue-text">EXAMPLE:</span> Amp
|<span class="blue-text">EXAMPLE:</span>
|<span class="blue-text">EXAMPLE:</span>17q12; chr17:39,700,064-39,728,658 [hg38; 28.6 kb]
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>
''ERBB2''
|<span class="blue-text">EXAMPLE:</span> D, P, T
|<span class="blue-text">EXAMPLE:</span> D, P, T
|
|
|<span class="blue-text">EXAMPLE:</span>
|<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.
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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|
|
|
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|}Cytogenetic morphology of the abnormal chromosome 21 can vary markedly between patients.<ref name=":3">{{Cite journal|last=Harewood|first=L.|last2=Robinson|first2=H.|last3=Harris|first3=R.|last4=Al-Obaidi|first4=M. Jabbar|last5=Jalali|first5=G. R.|last6=Martineau|first6=M.|last7=Moorman|first7=A. V.|last8=Sumption|first8=N.|last9=Richards|first9=S.|date=2003-03|title=Amplification of AML1 on a duplicated chromosome 21 in acute lymphoblastic leukemia: a study of 20 cases|url=https://pubmed.ncbi.nlm.nih.gov/12646943|journal=Leukemia|volume=17|issue=3|pages=547–553|doi=10.1038/sj.leu.2402849|issn=0887-6924|pmid=12646943}}</ref> In ~80% of iAMP21 B-ALL cases, recurrent secondary abnormalities, both chromosomal and molecular, have been documented. Deletions involving particular genes such as; ''IKZF1, CDKN2A/B, PAX5, SH2B3, ETV6'' and ''RB1'' have also been observed.[[File:IAMP21 met.jpg|center|thumb|875x875px|iAMP21 in a ring formation; Courtesy of Fullerton Genetics Lab|link=Special:FilePath/IAMP21_met.jpg]]


Cytogenetic morphology of the abnormal chromosome 21 can vary markedly between patients.<ref name=":1" />[[File:IAMP21 met.jpg|center|thumb|778.994x778.994px|iAMP21 in a ring formation; Courtesy of Fullerton Genetics Lab]]
==Characteristic Chromosomal or Other Global Mutational Patterns==
 
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>
 
 
 
In ~80% of iAMP21 B-ALL cases, recurrent secondary abnormalities, both chromosomal and molecular, have been documented. Deletions involving particular genes such as; ''IKZF1, CDKN2A/B, PAX5, SH2B3, ETV6'' and ''RB1'' have also been observed.


iAMP21 cases have a characteristic pattern that is both complex and variable. This pattern comprises multiple regions of gain, amplification and deletion. Interestingly, ''RUNX1'' amplification is not always intrachromosomal.<ref>{{Cite journal|last=Arber|first=Daniel A.|date=04 2019|title=The 2016 WHO classification of acute myeloid leukemia: What the practicing clinician needs to know|url=https://pubmed.ncbi.nlm.nih.gov/30926096|journal=Seminars in Hematology|volume=56|issue=2|pages=90–95|doi=10.1053/j.seminhematol.2018.08.002|issn=1532-8686|pmid=30926096}}</ref><ref>{{Cite journal|last=Johnson|first=Ryan C.|last2=Weinberg|first2=Olga K.|last3=Cascio|first3=Michael J.|last4=Dahl|first4=Gary V.|last5=Mitton|first5=Bryan A.|last6=Silverman|first6=Lewis B.|last7=Cherry|first7=Athena M.|last8=Arber|first8=Daniel A.|last9=Ohgami|first9=Robert S.|date=2015-07|title=Cytogenetic Variation of B-Lymphoblastic Leukemia With Intrachromosomal Amplification of Chromosome 21 (iAMP21): A Multi-Institutional Series Review|url=https://pubmed.ncbi.nlm.nih.gov/26071468|journal=American Journal of Clinical Pathology|volume=144|issue=1|pages=103–112|doi=10.1309/AJCPLUYF11HQBYRB|issn=1943-7722|pmid=26071468}}</ref> The formation of iAMP21 is considered to be due to breakage-fusion-bridge cycles followed by chromothripsis and other complex structural rearrangements of chromosome 21. Studies, molecular and cytogenetic, have elucidated a common 5.1 Mb region that includes the ''RUNX1'' gene. However, even though ''RUNX1'' is included in the amplified region, there has not yet been any conclusive evidence that ''RUNX1'' is critical in the pathogenesis of disease given that it is not overexpressed in some individuals with this abnormality.<ref name=":0">{{Cite journal|last=Akkari|first=Yassmine M. N.|last2=Bruyere|first2=Helene|last3=Hagelstrom|first3=R. Tanner|last4=Kanagal-Shamanna|first4=Rashmi|last5=Liu|first5=Jie|last6=Luo|first6=Minjie|last7=Mikhail|first7=Fady M.|last8=Pitel|first8=Beth A.|last9=Raca|first9=Gordana|date=2020-05|title=Evidence-based review of genomic aberrations in B-lymphoblastic leukemia/lymphoma: Report from the cancer genomics consortium working group for lymphoblastic leukemia|url=https://pubmed.ncbi.nlm.nih.gov/32302940|journal=Cancer Genetics|volume=243|pages=52–72|doi=10.1016/j.cancergen.2020.03.001|issn=2210-7762|pmid=32302940}}</ref><ref>{{Cite journal|last=Rand|first=Vikki|last2=Parker|first2=Helen|last3=Russell|first3=Lisa J.|last4=Schwab|first4=Claire|last5=Ensor|first5=Hannah|last6=Irving|first6=Julie|last7=Jones|first7=Lisa|last8=Masic|first8=Dino|last9=Minto|first9=Lynne|date=2011-06-23|title=Genomic characterization implicates iAMP21 as a likely primary genetic event in childhood B-cell precursor acute lymphoblastic leukemia|url=https://pubmed.ncbi.nlm.nih.gov/21527530|journal=Blood|volume=117|issue=25|pages=6848–6855|doi=10.1182/blood-2011-01-329961|issn=1528-0020|pmid=21527530}}</ref><ref>{{Cite journal|last=Hunger|first=Stephen P.|last2=Lu|first2=Xiaomin|last3=Devidas|first3=Meenakshi|last4=Camitta|first4=Bruce M.|last5=Gaynon|first5=Paul S.|last6=Winick|first6=Naomi J.|last7=Reaman|first7=Gregory H.|last8=Carroll|first8=William L.|date=2012-05-10|title=Improved survival for children and adolescents with acute lymphoblastic leukemia between 1990 and 2005: a report from the children's oncology group|url=https://pubmed.ncbi.nlm.nih.gov/22412151|journal=Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology|volume=30|issue=14|pages=1663–1669|doi=10.1200/JCO.2011.37.8018|issn=1527-7755|pmc=3383113|pmid=22412151}}</ref>
{| class="wikitable sortable"
{| class="wikitable sortable"
|-
|-
!Chr #!!Gain / Loss / Amp / LOH!!Minimal Region Genomic Coordinates [Genome Build]!!Minimal Region Cytoband
!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
|-
|-
|X
|<span class="blue-text">EXAMPLE:</span>Co-deletion of 1p and 18q
|Gain
|<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).
|<span class="blue-text">EXAMPLE:</span>
|<span class="blue-text">EXAMPLE:</span> Common (Oligodendroglioma)
 
|<span class="blue-text">EXAMPLE:</span> D, P
chr7:1- 159,335,973 [hg38]
|<span class="blue-text">EXAMPLE:</span>
 
chr7
|Yes
|Yes
|No
|<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 reference).
|-
|10
|Gain
|<span class="blue-text">EXAMPLE:</span>
 
chr8:1-145,138,636 [hg38]
|<span class="blue-text">EXAMPLE:</span>
 
chr8
|No
|No
|No
|<span class="blue-text">EXAMPLE:</span>
 
Common recurrent secondary finding for t(8;21) (add reference).
|-
|14
|Gain
|
|
|
|
|
|-
|<span class="blue-text">EXAMPLE:</span>Microsatellite instability - hypermutated
|
|
|<span class="blue-text">EXAMPLE:</span> Common (Endometrial carcinoma)
|<span class="blue-text">EXAMPLE:</span> P, T
|
|
|
|
|-
|-
|7/7q
|Amplification of ''RUNX1''
|Loss
|
|
|
|
|
|
|
|D
|
|
|See CMA image displaying the amplification of RUNX1. This is part of the critical region consistently amplified: chr21:32.8-37.9 Mb (hg19).
|-
|-
|11q
|Terminal deletion of 21q
|Loss
|
|
|
|
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|
|
|
|
|
|}
==Characteristic Chromosomal or Other Global Mutational Patterns==
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"
|-
|-
!Chromosomal Pattern
|Gain of X chromosome
!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'''
|-
|<span class="blue-text">EXAMPLE:</span>
Co-deletion of 1p and 18q
|<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).
|<span class="blue-text">EXAMPLE:</span> Common (Oligodendroglioma)
|<span class="blue-text">EXAMPLE:</span> D, P
|
|
|
|
|-
|<span class="blue-text">EXAMPLE:</span>
Microsatellite instability - hypermutated
|
|
|<span class="blue-text">EXAMPLE:</span> Common (Endometrial carcinoma)
|<span class="blue-text">EXAMPLE:</span> P, T
|
|
|
|
|-
|-
|Abnormalities of chromosomes 7 and 11
|
|
|
|
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|
|}
iAMP21 cases have a characteristic pattern that is both complex and variable. This pattern comprises multiple regions of gain, amplification and deletion. Interestingly, ''RUNX1'' amplification is not always intrachromosomal.<ref>{{Cite journal|last=Arber|first=Daniel A.|date=04 2019|title=The 2016 WHO classification of acute myeloid leukemia: What the practicing clinician needs to know|url=https://pubmed.ncbi.nlm.nih.gov/30926096|journal=Seminars in Hematology|volume=56|issue=2|pages=90–95|doi=10.1053/j.seminhematol.2018.08.002|issn=1532-8686|pmid=30926096}}</ref><ref>{{Cite journal|last=Johnson|first=Ryan C.|last2=Weinberg|first2=Olga K.|last3=Cascio|first3=Michael J.|last4=Dahl|first4=Gary V.|last5=Mitton|first5=Bryan A.|last6=Silverman|first6=Lewis B.|last7=Cherry|first7=Athena M.|last8=Arber|first8=Daniel A.|last9=Ohgami|first9=Robert S.|date=2015-07|title=Cytogenetic Variation of B-Lymphoblastic Leukemia With Intrachromosomal Amplification of Chromosome 21 (iAMP21): A Multi-Institutional Series Review|url=https://pubmed.ncbi.nlm.nih.gov/26071468|journal=American Journal of Clinical Pathology|volume=144|issue=1|pages=103–112|doi=10.1309/AJCPLUYF11HQBYRB|issn=1943-7722|pmid=26071468}}</ref> The formation of iAMP21 is considered to be due to breakage-fusion-bridge cycles followed by chromothripsis and other complex structural rearrangements of chromosome 21. Studies, molecular and cytogenetic, have elucidated a common 5.1 Mb region that includes the ''RUNX1'' gene. However, even though ''RUNX1'' is included in the amplified region, there has not yet been any conclusive evidence that ''RUNX1'' is critical in the pathogenesis of disease given that it is not overexpressed in some individuals with this abnormality.<ref name=":0">{{Cite journal|last=Akkari|first=Yassmine M. N.|last2=Bruyere|first2=Helene|last3=Hagelstrom|first3=R. Tanner|last4=Kanagal-Shamanna|first4=Rashmi|last5=Liu|first5=Jie|last6=Luo|first6=Minjie|last7=Mikhail|first7=Fady M.|last8=Pitel|first8=Beth A.|last9=Raca|first9=Gordana|date=2020-05|title=Evidence-based review of genomic aberrations in B-lymphoblastic leukemia/lymphoma: Report from the cancer genomics consortium working group for lymphoblastic leukemia|url=https://pubmed.ncbi.nlm.nih.gov/32302940|journal=Cancer Genetics|volume=243|pages=52–72|doi=10.1016/j.cancergen.2020.03.001|issn=2210-7762|pmid=32302940}}</ref><ref>{{Cite journal|last=Rand|first=Vikki|last2=Parker|first2=Helen|last3=Russell|first3=Lisa J.|last4=Schwab|first4=Claire|last5=Ensor|first5=Hannah|last6=Irving|first6=Julie|last7=Jones|first7=Lisa|last8=Masic|first8=Dino|last9=Minto|first9=Lynne|date=2011-06-23|title=Genomic characterization implicates iAMP21 as a likely primary genetic event in childhood B-cell precursor acute lymphoblastic leukemia|url=https://pubmed.ncbi.nlm.nih.gov/21527530|journal=Blood|volume=117|issue=25|pages=6848–6855|doi=10.1182/blood-2011-01-329961|issn=1528-0020|pmid=21527530}}</ref><ref>{{Cite journal|last=Hunger|first=Stephen P.|last2=Lu|first2=Xiaomin|last3=Devidas|first3=Meenakshi|last4=Camitta|first4=Bruce M.|last5=Gaynon|first5=Paul S.|last6=Winick|first6=Naomi J.|last7=Reaman|first7=Gregory H.|last8=Carroll|first8=William L.|date=2012-05-10|title=Improved survival for children and adolescents with acute lymphoblastic leukemia between 1990 and 2005: a report from the children's oncology group|url=https://pubmed.ncbi.nlm.nih.gov/22412151|journal=Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology|volume=30|issue=14|pages=1663–1669|doi=10.1200/JCO.2011.37.8018|issn=1527-7755|pmc=3383113|pmid=22412151}}</ref>
{| class="wikitable sortable"
|-
|-
!Chromosomal Pattern
|Deletions of ''RB1'' and ''ETV6''
!Diagnostic Significance (Yes, No or Unknown)
!Prognostic Significance (Yes, No or Unknown)
!Therapeutic Significance (Yes, No or Unknown)
!Notes
|-
|Amplification of RUNX1
|
|
|
|
|See CMA image displaying the amplification of RUNX1. This is part of the critical region consistently amplified: chr21:32.8-37.9 Mb (hg19).
|-
|Terminal deletion of 21q
|
|
|
|
|
|
|
|
|}
|}[[File:IAMP21 CMA .png|center|thumb|1028x1028px|Characteristic iAMP21 CMA; Courtesy of Fullerton Genetics Lab]]
[[File:IAMP21 CMA .png|center|thumb|1028x1028px|Characteristic iAMP21 CMA; Courtesy of Fullerton Genetics Lab]]
<br />
<br />


==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>
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>
In a 2016 paper, it was shown that in the iAMP21-ALL exome, the mutations were more commonly transitions (for example: C>T) than transversions or indels.<ref name=":0" /><ref name=":2">{{Cite journal|last=Ryan|first=S. L.|last2=Matheson|first2=E.|last3=Grossmann|first3=V.|last4=Sinclair|first4=P.|last5=Bashton|first5=M.|last6=Schwab|first6=C.|last7=Towers|first7=W.|last8=Partington|first8=M.|last9=Elliott|first9=A.|date=09 2016|title=The role of the RAS pathway in iAMP21-ALL|url=https://pubmed.ncbi.nlm.nih.gov/27168466|journal=Leukemia|volume=30|issue=9|pages=1824–1831|doi=10.1038/leu.2016.80|issn=1476-5551|pmc=5017527|pmid=27168466}}</ref> Frequently, mutations in the RAS signaling pathway have been observed. Interestingly, these mutations were observed to coexist in patterns ranging from 2-3 mutated genes to 2-4 mutations in the same gene in one sample. Further, the ''FLT3''-ITD was more prevalent in iAMP21-ALL.<ref name=":2" />
{| class="wikitable sortable"
{| class="wikitable sortable"
|-
|-
!Gene!!'''Genetic Alteration'''!!'''Tumor Suppressor Gene, Oncogene, Other'''!!'''Prevalence -'''
!Gene!!Genetic Alteration!!Tumor Suppressor Gene, Oncogene, Other!!Prevalence -
'''Common >20%, Recurrent 5-20% or Rare <5% (Disease)'''
Common >20%, Recurrent 5-20% or Rare <5% (Disease)
!'''Diagnostic, Prognostic, and Therapeutic Significance - D, P, T  '''
!Diagnostic, Prognostic, and Therapeutic Significance - D, P, T  
!'''Established Clinical Significance Per Guidelines - Yes or No (Source)'''
!Established Clinical Significance Per Guidelines - Yes or No (Source)
!'''Clinical Relevance Details/Other Notes'''
!Clinical Relevance Details/Other Notes
|-
|-
|<span class="blue-text">EXAMPLE:</span>''EGFR''
|<span class="blue-text">EXAMPLE:</span>''EGFR''<br />
 
<br />
|<span class="blue-text">EXAMPLE:</span> Exon 18-21 activating mutations
|<span class="blue-text">EXAMPLE:</span> Exon 18-21 activating mutations
|<span class="blue-text">EXAMPLE:</span> Oncogene
|<span class="blue-text">EXAMPLE:</span> Oncogene
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|<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).
|<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).
|-
|-
|<span class="blue-text">EXAMPLE:</span> ''TP53''; Variable LOF mutations
|<span class="blue-text">EXAMPLE:</span> ''TP53''; Variable LOF mutations<br />
<br />
|<span class="blue-text">EXAMPLE:</span> Variable LOF mutations
|<span class="blue-text">EXAMPLE:</span> Variable LOF mutations
|<span class="blue-text">EXAMPLE:</span> Tumor Supressor Gene
|<span class="blue-text">EXAMPLE:</span> Tumor Supressor Gene
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|
|
|
|
|}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.
|}
 
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.
In a 2016 paper, it was shown that in the iAMP21-ALL exome, the mutations were more commonly transitions (for example: C>T) than transversions or indels.<ref name=":0" /><ref name=":2">{{Cite journal|last=Ryan|first=S. L.|last2=Matheson|first2=E.|last3=Grossmann|first3=V.|last4=Sinclair|first4=P.|last5=Bashton|first5=M.|last6=Schwab|first6=C.|last7=Towers|first7=W.|last8=Partington|first8=M.|last9=Elliott|first9=A.|date=09 2016|title=The role of the RAS pathway in iAMP21-ALL|url=https://pubmed.ncbi.nlm.nih.gov/27168466|journal=Leukemia|volume=30|issue=9|pages=1824–1831|doi=10.1038/leu.2016.80|issn=1476-5551|pmc=5017527|pmid=27168466}}</ref> Frequently, mutations in the RAS signaling pathway have been observed. Interestingly, these mutations were observed to coexist in patterns ranging from 2-3 mutated genes to 2-4 mutations in the same gene in one sample. Further, the ''FLT3''-ITD was more prevalent in iAMP21-ALL.<ref name=":2" />
<br />
 
{| class="wikitable sortable"
{| class="wikitable sortable"
|-
|-
!Gene; Genetic Alteration!!'''Presumed Mechanism (Tumor Suppressor Gene [TSG] / Oncogene / Other)'''!!'''Prevalence (COSMIC /  TCGA / Other)'''!!'''Concomitant Mutations'''!!'''Mutually Exclusive Mutations'''
!Gene; Genetic Alteration!!Presumed Mechanism (Tumor Suppressor Gene [TSG] / Oncogene / Other)!!Prevalence (COSMIC /  TCGA / Other)!!Concomitant Mutations!!Mutually Exclusive Mutations
!'''Diagnostic Significance (Yes, No or Unknown)'''
!Diagnostic Significance (Yes, No or Unknown)
!Prognostic Significance (Yes, No or Unknown)
!Prognostic Significance (Yes, No or Unknown)
!Therapeutic Significance (Yes, No or Unknown)
!Therapeutic Significance (Yes, No or Unknown)
Line 483: Line 294:
|
|
|}
|}
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.
<br />


==Epigenomic Alterations==
==Epigenomic Alterations==
Line 499: Line 310:
|RAS pathway<ref name=":2" />
|RAS pathway<ref name=":2" />
|<span class="blue-text">EXAMPLE:</span> Increased cell growth and proliferation
|<span class="blue-text">EXAMPLE:</span> Increased cell growth and proliferation
|-
|<span class="blue-text">EXAMPLE:</span> CDKN2A; Inactivating mutations
|<span class="blue-text">EXAMPLE:</span> Cell cycle regulation
|<span class="blue-text">EXAMPLE:</span> Unregulated cell division
|-
|<span class="blue-text">EXAMPLE:</span>  KMT2C and ARID1A; Inactivating mutations
|<span class="blue-text">EXAMPLE:</span>  Histone modification, chromatin remodeling
|<span class="blue-text">EXAMPLE:</span>  Abnormal gene expression program
|}
|}
==Genetic Diagnostic Testing Methods==
==Genetic Diagnostic Testing Methods==
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This disease is <u>defined/characterized</u> as detailed below:
This disease is <u>defined/characterized</u> as detailed below:


*Intrachromosomal amplification of chromosome 21 (iAMP21) is a neoplasm of lymphoblasts that are of the B-cell lineage. It is characterized by amplification of the ''RUNX1'' gene at 21q22.3 on a structurally abnormal chromosome 21. Amplification is defined as ≥5 copies of ''RUNX1'' detected by FISH or ≥3 copies of ''RUNX1'' on a single abnormal chromosome 21.<ref name=":02" />
*Intrachromosomal amplification of chromosome 21 (iAMP21) is a neoplasm of lymphoblasts that are of the B-cell lineage. It is characterized by amplification of the ''RUNX1'' gene at 21q22.3 on a structurally abnormal chromosome 21. Amplification is defined as ≥5 copies of ''RUNX1'' detected by FISH or ≥3 copies of ''RUNX1'' on a single abnormal chromosome 21.<ref name=":02">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.</ref>


The <u>epidemiology/prevalence</u> of this disease is detailed below:
The <u>epidemiology/prevalence</u> of this disease is detailed below:
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The <u>clinical features</u> of this disease are detailed below:
The <u>clinical features</u> of this disease are detailed below:


*Signs and symptoms - ~50% of cases are classified as high-risk based on an age of ≥10 years.<ref>{{Cite journal|last=Harrison|first=Christine J.|date=2015-02-26|title=Blood Spotlight on iAMP21 acute lymphoblastic leukemia (ALL), a high-risk pediatric disease|url=https://pubmed.ncbi.nlm.nih.gov/25608562|journal=Blood|volume=125|issue=9|pages=1383–1386|doi=10.1182/blood-2014-08-569228|issn=1528-0020|pmid=25608562}}</ref> Pediatric iAMP21 has been associated with a poor outcome. It displays an increased rate of relapse when treated on standard protocols. Further, the event-free survival and overall survival were significantly worse for individuals with the iAMP21 and standard-risk B-ALL, but not significant in individuals with iAMP21 and high-risk B-ALL.
*~50% of cases are classified as high-risk based on an age of ≥10 years.<ref name=":1">{{Cite journal|last=Harrison|first=Christine J.|date=2015-02-26|title=Blood Spotlight on iAMP21 acute lymphoblastic leukemia (ALL), a high-risk pediatric disease|url=https://pubmed.ncbi.nlm.nih.gov/25608562|journal=Blood|volume=125|issue=9|pages=1383–1386|doi=10.1182/blood-2014-08-569228|issn=1528-0020|pmid=25608562}}</ref> Pediatric iAMP21 has been associated with a poor outcome. It displays an increased rate of relapse when treated on standard protocols. Further, the event-free survival and overall survival were significantly worse for individuals with the iAMP21 and standard-risk B-ALL, but not significant in individuals with iAMP21 and high-risk B-ALL.
*Laboratory findings - Low platelet count; Low WBC count (<50,000/μl)
 
The <u>sites of involvement</u> of this disease are detailed below:
 
*Bone Marrow and peripheral blood
 
The <u>morphologic features</u> of this disease are detailed below:
 
*There are no unique morphological or cytochemical features that distinguish this entity from other types of ALL.<ref name=":02" />
 
The <u>immunophenotype</u> of this disease is detailed below:
 
*No detailed information is known, other than these cases occur exclusively in B-ALL.<ref name=":02" />


==Links==
==Links==
Retrieved from "https://test.ccga.io/index.php/HAEM5:B-lymphoblastic_leukaemia/lymphoma_with_iAMP21"