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==Primary Author(s)*== Holli M. Drendel, PhD, FACMGG, Carolinas Pathology Group, Charlotte TOC ==Cancer Category/Type== B-lymphoblastic leukemia/lymphoma ==Ca..."

2023-11-03T17:38:50Z

Created page with "<br /> ==Primary Author(s)*== Holli M. Drendel, PhD, FACMGG, Carolinas Pathology Group, Charlotte __TOC__ ==Cancer Category/Type== B-lymphoblastic leukemia/lymphoma ==Ca..."

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==Primary Author(s)*==

Holli M. Drendel, PhD, FACMGG, Carolinas Pathology Group, Charlotte

__TOC__

==Cancer Category/Type==

B-lymphoblastic leukemia/lymphoma

==Cancer Sub-Classification / Subtype==

B-lymphoblastic leukemia/lymphoma with iAMP21

==Definition / Description of Disease==

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=":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.</ref>

==Synonyms / Terminology==

Put your text here

==Epidemiology / Prevalence==

iAMP21 is observed most often in the older pediatric group (median age of 9 years, with a range of 2-30 years). It accounts for ~2% of B-ALL cases including ~2% of standard-risk and 3% of high-risk patients. The incidence in adult B-ALL has not been established; however, it appears to be less prevalent than in the pediatric population.<ref name=":1">{{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=05 2020|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>

Further, patients carrying a rob(15;21)(q10;q10) have an ~2700-fold increased risk of developing iAMP21 ALL compared to the general population. Additionally, patients with a constitutional ring chromosome 21, r(21), may potentially be predisposed to iAMP21 ALL.<ref name=":1" />

==Clinical Features==

Patients tend to present with a low platelet count and low WBC count (<50,000/µl). ~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>

==Sites of Involvement==

Bone Marrow and peripheral blood

==Morphologic Features==

There are no unique morphological or cytochemical features that distinguish this entity from other types of ALL.<ref name=":0" />

Cytogenetic morphology of the abnormal chromosome 21 can vary markedly between patients.<ref>{{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>
[[File:IAMP21 met.jpg|thumb|515x515px|iAMP21 in a ring formation; Courtesy of Fullerton Genetics Lab|alt=|center]]
<br />

==Immunophenotype==

No detailed information is known, other than these cases occur exclusively in B-ALL.<ref name=":0" />

{| class="wikitable sortable"
|-
!Finding!!Marker
|-
|Positive (universal)||EXAMPLE CD1
|-
|Positive (subset)||EXAMPLE CD2
|-
|Negative (universal)||EXAMPLE CD3
|-
|Negative (subset)||EXAMPLE CD4
|}

==Chromosomal Rearrangements (Gene Fusions)==

Some rearrangements have been seen as secondary abnormalities.

{| class="wikitable sortable"
|-
!Chromosomal Rearrangement!!Genes in Fusion (5’ or 3’ Segments)!!Pathogenic Derivative!!Prevalence
|-
|del(X)(p22.33p22.33)/del(Y)(p11.32p11.32)||''P2RY8-CRLF2''||der(X)/der(Y)||
|-
|t(12;21)(p13.2;q22.1)||''ETV6-RUNX1''||der(21)||
|-
|t(9;22)(q34;q11.2)
|''BCR-ABL1''
|der(22)
|
|}

==Characteristic Chromosomal Aberrations / Patterns==
[[File:IAMP21 CMA .png|center|thumb|861x861px|Characteristic iAMP21 CMA; Courtesy of Fullerton Genetics Lab]]
iAMP21 cases have a characteristic pattern that is both complex and variable. This pattern comprises multiple regions of gain, amplification and deletion. Further, it often is accompanied by a terminal deletion of 21q. 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. This is part of the critical region consistently amplified (chr21:32.8-37.9 Mb, GRCh37/hg19). 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=":1" /><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>

==Genomic Gain/Loss/LOH==
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.
{| class="wikitable sortable"
|-
!Chromosome Number!!Gain/Loss/Amp/LOH
|-
|X
|Gain
|-
|10
|Gain
|-
|14
|Gain
|-
|7/7q
|Loss
|-
|11q
|Loss
|}

==Gene Mutations (SNV/INDEL)==

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=":1" /><ref name=":2" /> 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"
|-
!Gene!!Mutation!!Oncogene/Tumor Suppressor/Other!!Presumed Mechanism (LOF/GOF/Other; Driver/Passenger)!!Prevalence (COSMIC/TCGA/Other)
|-
|''NRAS''|| || || ||45%
|-
|''KRAS''
|
|
|
|18%
|-
|''FLT3''
|
|
|
|20%
|-
|''PTPN11''
|
|
|
|11%
|-
|''BRAF''
|
|
|
|2%
|-
|''NF1''
|
|
|
|2%
|}

===Other Mutations===
{| class="wikitable sortable"
|-
!Type!!Gene/Region/Other
|-
|Concomitant Mutations||EXAMPLE IDH1 R123H
|-
|Secondary Mutations||EXAMPLE Trisomy 7
|-
|Mutually Exclusive||EXAMPLE EGFR Amplification
|}

==Epigenomics (Methylation)==

Put your text here

==Genes and Main Pathways Involved==

''[[RUNX1]]''

RAS pathway<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>

==Diagnostic Testing Methods==

Different methodologies are able to detect the iAMP21, such as:

*Fluorescence in situ hybridization (FISH) utilizing the probe set for the t(12;21)

*Conventional chromosome analysis

*Multiplex ligation-dependent probe amplification (MLPA)

*Chromosomal microarray (CMA)

*Next generation sequencing (NGS).

==Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications)==

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.

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.

==Familial Forms==

Put your text here

==Other Information==

Put your text here

==Links==

[[RUNX1]]

Put your links here (use "Link" icon at top of page)

==References==
(use "Cite" icon at top of page)
<references />
===EXAMPLE Book===

#Arber DA, et al., (2008). Acute myeloid leukaemia with recurrent genetic abnormalities, in World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, 4th edition. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Vardiman JW, Editors. IARC Press: Lyon, France, p117-118.

==Notes==
<nowiki>*</nowiki>Primary authors will typically be those that initially create and complete the content of a page. If a subsequent user modifies the content and feels the effort put forth is of high enough significance to warrant listing in the authorship section, please contact the CCGA coordinators (contact information provided on the homepage). Additional global feedback or concerns are also welcome.

[[Category:Amplification Chromosome 21]]
[[Category:Structural Chromosome Abnormalities]]
[[Category:Structural Chromosome Abnormalities in ALL]]
[[Category:Structural Abnormalities Chromosome 21]]
[[Category:Oncogenes R]]
[[Category:Recently Added Pages]]

HAEM4Backup:B-Lymphoblastic Leukemia/Lymphoma with iAMP21 - Revision history

Bailey.Glen: Created page with " ==Primary Author(s)*== Holli M. Drendel, PhD, FACMGG, Carolinas Pathology Group, Charlotte __TOC__ ==Cancer Category/Type== B-lymphoblastic leukemia/lymphoma ==Ca..."

Bailey.Glen: Created page with "
==Primary Author(s)*== Holli M. Drendel, PhD, FACMGG, Carolinas Pathology Group, Charlotte TOC ==Cancer Category/Type== B-lymphoblastic leukemia/lymphoma ==Ca..."