Compendium of Cancer Genome Aberrations

HAEM5:Acute myeloid leukaemia with BCR::ABL1 fusion: Difference between revisions

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|Rare (BCR-ABL1 AML)
|Rare (BCR-ABL1 AML)
|D,P
|D,P
|No
|No<!-- Here, is it for Inv(16) in BCR-ABL1 patient or in all AML patients? -->
|The rarity of Philadelphia-positive subclones in AML patients with specific genetic lesions requires more cases for conclusive prognosis and therapeutic insights<ref name=":12" />.
|The rarity of Philadelphia-positive subclones in AML patients with specific genetic lesions requires more cases for conclusive prognosis and therapeutic insights<ref name=":12" />.
|-
|-
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Coinciding molecular events such as ''NPM1'' mutations have been reported<ref name=":12" />. ''RUNX1'' mutation is common in AML with ''BCR::ABL1'' and occurs in ~40% of cases<ref name=":13" />.
''RUNX1'' mutation is common in AML with ''BCR::ABL1'' and occurs in ~40% of cases<ref name=":13" />. Other mutated genes include ''ASXL1, BCOR, IDH1 / IDH2'' and ''SRSF2''; each of these occur in 10 - 15% of cases<ref name=":14">{{Cite journal|last=Konoplev|first=Sergej|last2=Yin|first2=C. Cameron|last3=Kornblau|first3=Steven M.|last4=Kantarjian|first4=Hagop M.|last5=Konopleva|first5=Marina|last6=Andreeff|first6=Michael|last7=Lu|first7=Gary|last8=Zuo|first8=Zhuang|last9=Luthra|first9=Rajyalakshmi|date=2013-01|title=Molecular characterization of de novo Philadelphia chromosome-positive acute myeloid leukemia|url=https://pubmed.ncbi.nlm.nih.gov/22691121|journal=Leukemia & Lymphoma|volume=54|issue=1|pages=138–144|doi=10.3109/10428194.2012.701739|issn=1029-2403|pmc=3925981|pmid=22691121}}</ref><ref name=":15">{{Cite journal|last=Eisfeld|first=A.-K.|last2=Mrózek|first2=K.|last3=Kohlschmidt|first3=J.|last4=Nicolet|first4=D.|last5=Orwick|first5=S.|last6=Walker|first6=C. J.|last7=Kroll|first7=K. W.|last8=Blachly|first8=J. S.|last9=Carroll|first9=A. J.|date=2017-10|title=The mutational oncoprint of recurrent cytogenetic abnormalities in adult patients with de novo acute myeloid leukemia|url=https://pubmed.ncbi.nlm.nih.gov/28321123|journal=Leukemia|volume=31|issue=10|pages=2211–2218|doi=10.1038/leu.2017.86|issn=1476-5551|pmc=5628133|pmid=28321123}}</ref><ref name=":13" />.Coinciding molecular events such as ''NPM1'' mutations have been reported<ref name=":12" />. Mutations of ''FLT3'' or ''DNMT3A'' are not commonly detected<ref name=":13" />.  
 
Mutations of ''NPM1, FLT3'' or ''DNMT3A'' are not commonly detected<ref name=":13" />. Other mutated genes include ''ASXL1, BCOR, IDH1 / IDH2'' and ''SRSF2''; each of these occur in 10 - 15% of cases<ref>{{Cite journal|last=Konoplev|first=Sergej|last2=Yin|first2=C. Cameron|last3=Kornblau|first3=Steven M.|last4=Kantarjian|first4=Hagop M.|last5=Konopleva|first5=Marina|last6=Andreeff|first6=Michael|last7=Lu|first7=Gary|last8=Zuo|first8=Zhuang|last9=Luthra|first9=Rajyalakshmi|date=2013-01|title=Molecular characterization of de novo Philadelphia chromosome-positive acute myeloid leukemia|url=https://pubmed.ncbi.nlm.nih.gov/22691121|journal=Leukemia & Lymphoma|volume=54|issue=1|pages=138–144|doi=10.3109/10428194.2012.701739|issn=1029-2403|pmc=3925981|pmid=22691121}}</ref><ref>{{Cite journal|last=Eisfeld|first=A.-K.|last2=Mrózek|first2=K.|last3=Kohlschmidt|first3=J.|last4=Nicolet|first4=D.|last5=Orwick|first5=S.|last6=Walker|first6=C. J.|last7=Kroll|first7=K. W.|last8=Blachly|first8=J. S.|last9=Carroll|first9=A. J.|date=2017-10|title=The mutational oncoprint of recurrent cytogenetic abnormalities in adult patients with de novo acute myeloid leukemia|url=https://pubmed.ncbi.nlm.nih.gov/28321123|journal=Leukemia|volume=31|issue=10|pages=2211–2218|doi=10.1038/leu.2017.86|issn=1476-5551|pmc=5628133|pmid=28321123}}</ref><ref name=":13" />.
{| 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>''EGFR''
| ''RUNX1''


<br />
<br />
|<span class="blue-text">EXAMPLE:</span> Exon 18-21 activating mutations
|Variable LOF and missense mutations
|<span class="blue-text">EXAMPLE:</span> Oncogene
|Tumor Suppressor Gene
|<span class="blue-text">EXAMPLE:</span> Common (lung cancer)
|Common (BCR-ABL1 AML)
|<span class="blue-text">EXAMPLE:</span> T
|D,P
|<span class="blue-text">EXAMPLE:</span> Yes (NCCN)
|Yes (NCCN, WHO)
|<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).
|AML with ''RUNX1'' mutation is associated with a poorer prognosis<ref name=":6" />. ''RUNX1'' was the most commonly mutated gene, altered in eight of 21 BCR-ABL1 AML cases (38%)<ref name=":13" />.
Mutations in five genes (''BCOR, BCORL1, SF3B1, SRSF2,'' and ''STAG2''), along with ''ASXL1'' and ''RUNX1'' mutations, are linked to the proposed high-risk AML chromatin-spliceosome group<ref name=":13" />.
|-
|-
|<span class="blue-text">EXAMPLE:</span> ''TP53''; Variable LOF mutations
|''ASXL1''
<br />
|Variable LOF and missense mutations
|<span class="blue-text">EXAMPLE:</span> Variable LOF mutations
|Tumor Suppressor Gene
|<span class="blue-text">EXAMPLE:</span> Tumor Supressor Gene
|Recurrent (BCR-ABL1 AML)
|<span class="blue-text">EXAMPLE:</span> Common (breast cancer)
|D,P
|<span class="blue-text">EXAMPLE:</span> P
|No
|
|Mutations in five genes (''BCOR, BCORL1, SF3B1, SRSF2,'' and ''STAG2''), along with ''ASXL1'' and ''RUNX1'' mutations, are linked to the proposed high-risk AML chromatin-spliceosome group<ref name=":13" />.
|<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.
|-
|''BCOR''
|Variable LOF and missense mutations
|Tumor Suppressor Gene
|Recurrent (BCR-ABL1 AML)
|D,P
|No
|Mutations in five genes (''BCOR, BCORL1, SF3B1, SRSF2,'' and ''STAG2''), along with ''ASXL1'' and ''RUNX1'' mutations, are linked to the proposed high-risk AML chromatin-spliceosome group<ref name=":13" />.
|-
|-
|<span class="blue-text">EXAMPLE:</span> ''BRAF''; Activating mutations
|''IDH1 / IDH2''
|<span class="blue-text">EXAMPLE:</span> Activating mutations
|Missense
|<span class="blue-text">EXAMPLE:</span> Oncogene
|Oncogene
|<span class="blue-text">EXAMPLE:</span> Common (melanoma)
|Recurrent (BCR-ABL1 AML)
|<span class="blue-text">EXAMPLE:</span> T
|D,P
|
|No
|
|Other mutated genes include ''ASXL1, BCOR, IDH1 / IDH2'' and ''SRSF2''; each of these occur in 10 - 15% of cases<ref name=":14" /><ref name=":15" /><ref name=":13" />.
|-
|-
|
|''SRSF2''
|
|Missense and in frame del
|
|Tumor Suppressor Gene
|
|Recurrent (BCR-ABL1 AML)
|
|D,P
|
|No
|
|Mutations in five genes (''BCOR, BCORL1, SF3B1, SRSF2,'' and ''STAG2''), along with ''ASXL1'' and ''RUNX1'' mutations, are linked to the proposed high-risk AML chromatin-spliceosome group<ref name=":13" />.
|-
|''NPM1''
|Variable LOF
|Tumor Suppressor Gene and Oncogene
|Rare (BCR-ABL1 AML)
|D,P
|No
|Philadelphia-positive subclones can emerge in ''NPM1''-mutated AML at diagnosis or during follow-up, and may cooperate with the ''NPM1'' mutation like other class I mutations, such as ''FLT3-''ITD or ''MLL-''PTD<ref name=":12" />.
|}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 [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.
==Epigenomic Alterations==
==Epigenomic Alterations==
Line 232: Line 246:




The ''BCR'' gene product has serine/threonine kinase activity and is a GTPase-activating protein for p21rac<ref name=":7" />. The ''ABL1'' gene is a proto-oncogene that encodes a protein tyrosine kinase involved in a variety of cellular processes, including cell division, adhesion, differentiation, and response to stress. The activity of this protein is negatively regulated by its SH3 domain, whereby deletion of the region encoding this domain results in an oncogene<ref name=":8" />. The t(9,22)(q34;q11) leads to the formation of a Philadelphia chromosome and generates an active chimeric BCR-ABL1 tyrosine kinase. The fusion gene is created by juxtaposing the ''ABL1'' gene on chromosome 9 (region q34) to a part of ''BCR'' (breakpoint cluster region) gene on chromosome 22 (region q11). This is a reciprocal translocation, creating an elongated chromosome 9 (der 9), and a truncated chromosome 22 (the Philadelphia chromosome, 22q-), the oncogenic BCR-ABL1 being found on the shorter derivative 22 chromosome<ref name=":9" /><ref name=":10" />. This gene encodes for a BCR-ABL1 fusion protein, a tyrosine kinase. Tyrosine kinase activities are typically regulated in an auto-inhibitory manner, but the BCR-ABL1 fusion gene codes for a protein that is continuously activated, causing unregulated cell division. This is a result of the replacement of the myristoylated cap region which causes a conformational change rendering the kinase domain inactive, with a truncated portion of the BCR protein<ref name=":11" />. The enzyme is responsible for the uncontrolled growth of leukemic cells which survive better than normal blood cells. As a result of BCR/ABL1 variable splicing (fusion RNA and hybrid proteins), two transcripts p190 and p210 are found for BCR-ABL1 positive AML.
The ''BCR'' gene product has serine/threonine kinase activity and is a GTPase-activating protein for p21rac<ref name=":7">{{Cite journal|last=Maru|first=Y.|last2=Witte|first2=O. N.|date=1991|title=The BCR gene encodes a novel serine/threonine kinase activity within a single exon|url=https://www.ncbi.nlm.nih.gov/pubmed/1657398|journal=Cell|volume=67|issue=3|pages=459–468|doi=10.1016/0092-8674(91)90521-y|issn=0092-8674|pmid=1657398}}</ref>. The ''ABL1'' gene is a proto-oncogene that encodes a protein tyrosine kinase involved in a variety of cellular processes, including cell division, adhesion, differentiation, and response to stress. The activity of this protein is negatively regulated by its SH3 domain, whereby deletion of the region encoding this domain results in an oncogene<ref name=":8">{{Cite journal|last=Wang|first=Jean Y. J.|date=2014|title=The capable ABL: what is its biological function?|url=https://www.ncbi.nlm.nih.gov/pubmed/24421390|journal=Molecular and Cellular Biology|volume=34|issue=7|pages=1188–1197|doi=10.1128/MCB.01454-13|issn=1098-5549|pmc=3993570|pmid=24421390}}</ref>. The t(9,22)(q34;q11) leads to the formation of a Philadelphia chromosome and generates an active chimeric BCR-ABL1 tyrosine kinase. The fusion gene is created by juxtaposing the ''ABL1'' gene on chromosome 9 (region q34) to a part of ''BCR'' (breakpoint cluster region) gene on chromosome 22 (region q11). This is a reciprocal translocation, creating an elongated chromosome 9 (der 9), and a truncated chromosome 22 (the Philadelphia chromosome, 22q-), the oncogenic BCR-ABL1 being found on the shorter derivative 22 chromosome<ref name=":9">{{Cite journal|last=Kurzrock|first=Razelle|last2=Kantarjian|first2=Hagop M.|last3=Druker|first3=Brian J.|last4=Talpaz|first4=Moshe|date=2003|title=Philadelphia chromosome-positive leukemias: from basic mechanisms to molecular therapeutics|url=https://www.ncbi.nlm.nih.gov/pubmed/12755554|journal=Annals of Internal Medicine|volume=138|issue=10|pages=819–830|doi=10.7326/0003-4819-138-10-200305200-00010|issn=1539-3704|pmid=12755554}}</ref><ref name=":10">{{Cite journal|last=Melo|first=J. V.|date=1996|title=The diversity of BCR-ABL fusion proteins and their relationship to leukemia phenotype|url=https://www.ncbi.nlm.nih.gov/pubmed/8839828|journal=Blood|volume=88|issue=7|pages=2375–2384|issn=0006-4971|pmid=8839828}}</ref>. This gene encodes for a BCR-ABL1 fusion protein, a tyrosine kinase. Tyrosine kinase activities are typically regulated in an auto-inhibitory manner, but the BCR-ABL1 fusion gene codes for a protein that is continuously activated, causing unregulated cell division. This is a result of the replacement of the myristoylated cap region which causes a conformational change rendering the kinase domain inactive, with a truncated portion of the BCR protein<ref name=":11">{{Cite journal|last=Nagar|first=Bhushan|last2=Hantschel|first2=Oliver|last3=Young|first3=Matthew A.|last4=Scheffzek|first4=Klaus|last5=Veach|first5=Darren|last6=Bornmann|first6=William|last7=Clarkson|first7=Bayard|last8=Superti-Furga|first8=Giulio|last9=Kuriyan|first9=John|date=2003|title=Structural basis for the autoinhibition of c-Abl tyrosine kinase|url=https://www.ncbi.nlm.nih.gov/pubmed/12654251|journal=Cell|volume=112|issue=6|pages=859–871|doi=10.1016/s0092-8674(03)00194-6|issn=0092-8674|pmid=12654251}}</ref>. The enzyme is responsible for the uncontrolled growth of leukemic cells which survive better than normal blood cells. As a result of BCR/ABL1 variable splicing (fusion RNA and hybrid proteins), two transcripts p190 and p210 are found for BCR-ABL1 positive AML.
{| 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
|''BCR'' and ''ABL1''; Activating mutations
|<span class="blue-text">EXAMPLE:</span> MAPK signaling
|Ras/MAPK, PI3K/AKT, JAK/STAT and NF-kappaB pathways
|<span class="blue-text">EXAMPLE:</span> Increased cell growth and proliferation
|The BCR-ABL fusion protein is an constitutively active tyrosine kinase that triggers multiple pathways,  promoting unchecked cell proliferation and survival.
|-
|<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
|-
|
|
|
|}
|}


<blockquote class="blockedit">{{Box-round|title=v4:Genes and Main Pathways Involved|The content below was from the old template. Please incorporate above.}}</blockquote>
<br />
 
The ''BCR'' gene product has serine/threonine kinase activity and is a GTPase-activating protein for p21rac<ref name=":7">{{Cite journal|last=Maru|first=Y.|last2=Witte|first2=O. N.|date=1991|title=The BCR gene encodes a novel serine/threonine kinase activity within a single exon|url=https://www.ncbi.nlm.nih.gov/pubmed/1657398|journal=Cell|volume=67|issue=3|pages=459–468|doi=10.1016/0092-8674(91)90521-y|issn=0092-8674|pmid=1657398}}</ref>. The ''ABL1'' gene is a proto-oncogene that encodes a protein tyrosine kinase involved in a variety of cellular processes, including cell division, adhesion, differentiation, and response to stress. The activity of this protein is negatively regulated by its SH3 domain, whereby deletion of the region encoding this domain results in an oncogene<ref name=":8">{{Cite journal|last=Wang|first=Jean Y. J.|date=2014|title=The capable ABL: what is its biological function?|url=https://www.ncbi.nlm.nih.gov/pubmed/24421390|journal=Molecular and Cellular Biology|volume=34|issue=7|pages=1188–1197|doi=10.1128/MCB.01454-13|issn=1098-5549|pmc=3993570|pmid=24421390}}</ref>. The t(9,22)(q34;q11) leads to the formation of a Philadelphia chromosome and generates an active chimeric BCR-ABL1 tyrosine kinase. The fusion gene is created by juxtaposing the ''ABL1'' gene on chromosome 9 (region q34) to a part of ''BCR'' (breakpoint cluster region) gene on chromosome 22 (region q11). This is a reciprocal translocation, creating an elongated chromosome 9 (der 9), and a truncated chromosome 22 (the Philadelphia chromosome, 22q-), the oncogenic BCR-ABL1 being found on the shorter derivative 22 chromosome<ref name=":9">{{Cite journal|last=Kurzrock|first=Razelle|last2=Kantarjian|first2=Hagop M.|last3=Druker|first3=Brian J.|last4=Talpaz|first4=Moshe|date=2003|title=Philadelphia chromosome-positive leukemias: from basic mechanisms to molecular therapeutics|url=https://www.ncbi.nlm.nih.gov/pubmed/12755554|journal=Annals of Internal Medicine|volume=138|issue=10|pages=819–830|doi=10.7326/0003-4819-138-10-200305200-00010|issn=1539-3704|pmid=12755554}}</ref><ref name=":10">{{Cite journal|last=Melo|first=J. V.|date=1996|title=The diversity of BCR-ABL fusion proteins and their relationship to leukemia phenotype|url=https://www.ncbi.nlm.nih.gov/pubmed/8839828|journal=Blood|volume=88|issue=7|pages=2375–2384|issn=0006-4971|pmid=8839828}}</ref>. This gene encodes for a BCR-ABL1 fusion protein, a tyrosine kinase. Tyrosine kinase activities are typically regulated in an auto-inhibitory manner, but the BCR-ABL1 fusion gene codes for a protein that is continuously activated, causing unregulated cell division. This is a result of the replacement of the myristoylated cap region which causes a conformational change rendering the kinase domain inactive, with a truncated portion of the BCR protein<ref name=":11">{{Cite journal|last=Nagar|first=Bhushan|last2=Hantschel|first2=Oliver|last3=Young|first3=Matthew A.|last4=Scheffzek|first4=Klaus|last5=Veach|first5=Darren|last6=Bornmann|first6=William|last7=Clarkson|first7=Bayard|last8=Superti-Furga|first8=Giulio|last9=Kuriyan|first9=John|date=2003|title=Structural basis for the autoinhibition of c-Abl tyrosine kinase|url=https://www.ncbi.nlm.nih.gov/pubmed/12654251|journal=Cell|volume=112|issue=6|pages=859–871|doi=10.1016/s0092-8674(03)00194-6|issn=0092-8674|pmid=12654251}}</ref>. The enzyme is responsible for the uncontrolled growth of leukemic cells which survive better than normal blood cells. As a result of BCR/ABL1 variable splicing (fusion RNA and hybrid proteins), two transcripts p190 and p210 are found for BCR-ABL1 positive AML.
 
[[File:BCR-ABL1 translocation image.jpg|Figure 1. Philadelphia chromosome. A piece of chromosome 9 and a piece of chrosomome 22 break off and trade places. The BCR-ABL1 gene is formed on chromosome 22 where the piece of chromosome 9 attaches. The changed chromosome 22 is called Philadelphia chromosome. Image from National Cancer Institute website https://www.cancer.gov/publications/dictionaries/cancer-terms/def/bcr-abl-fusion-gene|frame|center]]


<blockquote class="blockedit">
[[File:BCR-ABL1 translocation image.jpg|Figure 1. Philadelphia chromosome. A piece of chromosome 9 and a piece of chrosomome 22 break off and trade places. The BCR-ABL1 gene is formed on chromosome 22 where the piece of chromosome 9 attaches. The changed chromosome 22 is called Philadelphia chromosome. Image from National Cancer Institute website https://www.cancer.gov/publications/dictionaries/cancer-terms/def/bcr-abl-fusion-gene|frame|center]]<br />
<center><span style="color:Maroon">'''End of V4 Section'''</span>
----
</blockquote>
==Genetic Diagnostic Testing Methods==
==Genetic Diagnostic Testing Methods==


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