Compendium of Cancer Genome Aberrations

HAEM5:Acute myeloid leukaemia with DEK::NUP214 fusion: Difference between revisions

[checked revision][checked revision]
← Older editNewer edit →
VisualWikitext
No edit summary
No edit summary
Line 67: Line 67:
This AML subtype is classified based on the presence of a t(6;9)(p23;q34.1), which results in fusion of the 5’ portion of ''DEK'' at “6p23” (specifically 6p22.3[hg38]) and the 3’ portion of ''NUP214''(''CAN'') at “9q34.1” (specifically 9q34.13[hg38]).  The breakpoints are intronic, producing an in-frame fusion<ref>{{Cite journal|last=von Lindern|first=M.|last2=Fornerod|first2=M.|last3=van Baal|first3=S.|last4=Jaegle|first4=M.|last5=de Wit|first5=T.|last6=Buijs|first6=A.|last7=Grosveld|first7=G.|date=1992|title=The translocation (6;9), associated with a specific subtype of acute myeloid leukemia, results in the fusion of two genes, dek and can, and the expression of a chimeric, leukemia-specific dek-can mRNA|url=https://www.ncbi.nlm.nih.gov/pubmed/1549122|journal=Molecular and Cellular Biology|volume=12|issue=4|pages=1687–1697|doi=10.1128/mcb.12.4.1687|issn=0270-7306|pmc=PMC369612|pmid=1549122}}</ref>.  The ''DEK''-''NUP214'' fusion present on the derivative chromosome 6 is considered the pathogenic entity as the reciprocal ''NUP214''-''DEK'' fusion on chromosome 9 does not appear to be transcribed<ref>{{Cite journal|last=von Lindern|first=M.|last2=Fornerod|first2=M.|last3=Soekarman|first3=N.|last4=van Baal|first4=S.|last5=Jaegle|first5=M.|last6=Hagemeijer|first6=A.|last7=Bootsma|first7=D.|last8=Grosveld|first8=G.|date=1992|title=Translocation t(6;9) in acute non-lymphocytic leukaemia results in the formation of a DEK-CAN fusion gene|url=https://www.ncbi.nlm.nih.gov/pubmed/1308167|journal=Bailliere's Clinical Haematology|volume=5|issue=4|pages=857–879|doi=10.1016/s0950-3536(11)80049-1|issn=0950-3536|pmid=1308167}}</ref>.  Typically the ''DEK''-''NUP214'' fusion presents as the sole abnormality but can be part of a complex karyotype<ref name=":0">Arber DA, et al., (2017). Acute myeloid leukaemia 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, p137-138.</ref>.
This AML subtype is classified based on the presence of a t(6;9)(p23;q34.1), which results in fusion of the 5’ portion of ''DEK'' at “6p23” (specifically 6p22.3[hg38]) and the 3’ portion of ''NUP214''(''CAN'') at “9q34.1” (specifically 9q34.13[hg38]).  The breakpoints are intronic, producing an in-frame fusion<ref>{{Cite journal|last=von Lindern|first=M.|last2=Fornerod|first2=M.|last3=van Baal|first3=S.|last4=Jaegle|first4=M.|last5=de Wit|first5=T.|last6=Buijs|first6=A.|last7=Grosveld|first7=G.|date=1992|title=The translocation (6;9), associated with a specific subtype of acute myeloid leukemia, results in the fusion of two genes, dek and can, and the expression of a chimeric, leukemia-specific dek-can mRNA|url=https://www.ncbi.nlm.nih.gov/pubmed/1549122|journal=Molecular and Cellular Biology|volume=12|issue=4|pages=1687–1697|doi=10.1128/mcb.12.4.1687|issn=0270-7306|pmc=PMC369612|pmid=1549122}}</ref>.  The ''DEK''-''NUP214'' fusion present on the derivative chromosome 6 is considered the pathogenic entity as the reciprocal ''NUP214''-''DEK'' fusion on chromosome 9 does not appear to be transcribed<ref>{{Cite journal|last=von Lindern|first=M.|last2=Fornerod|first2=M.|last3=Soekarman|first3=N.|last4=van Baal|first4=S.|last5=Jaegle|first5=M.|last6=Hagemeijer|first6=A.|last7=Bootsma|first7=D.|last8=Grosveld|first8=G.|date=1992|title=Translocation t(6;9) in acute non-lymphocytic leukaemia results in the formation of a DEK-CAN fusion gene|url=https://www.ncbi.nlm.nih.gov/pubmed/1308167|journal=Bailliere's Clinical Haematology|volume=5|issue=4|pages=857–879|doi=10.1016/s0950-3536(11)80049-1|issn=0950-3536|pmid=1308167}}</ref>.  Typically the ''DEK''-''NUP214'' fusion presents as the sole abnormality but can be part of a complex karyotype<ref name=":0">Arber DA, et al., (2017). Acute myeloid leukaemia 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, p137-138.</ref>.


This translocation has traditionally been associated with a poor prognosis in both adult and pediatric cases<ref name=":0" />.  Of note, a 2014 retrospective analysis suggests a better outcome for pediatric patients with this translocation than previously reported<ref>{{Cite journal|last=Sandahl|first=Julie Damgaard|last2=Coenen|first2=Eva A.|last3=Forestier|first3=Erik|last4=Harbott|first4=Jochen|last5=Johansson|first5=Bertil|last6=Kerndrup|first6=Gitte|last7=Adachi|first7=Souichi|last8=Auvrignon|first8=Anne|last9=Beverloo|first9=H. Berna|date=2014|title=t(6;9)(p22;q34)/DEK-NUP214-rearranged pediatric myeloid leukemia: an international study of 62 patients|url=https://www.ncbi.nlm.nih.gov/pubmed/24441146|journal=Haematologica|volume=99|issue=5|pages=865–872|doi=10.3324/haematol.2013.098517|issn=1592-8721|pmc=4008104|pmid=24441146}}</ref>.  Elevated white blood cell counts and higher bone marrow blast percentages are associated with shorter periods of overall survival and disease-free survival, respectively<ref name=":0" />.
Limited data suggests early allogeneic stem cell transplantation may be associated with better overall survival compared to patients without transplantation, suggesting accurate diagnosis for these patients is crucial<ref name=":0" /><ref>{{Cite journal|last=Slovak|first=M. L.|last2=Gundacker|first2=H.|last3=Bloomfield|first3=C. D.|last4=Dewald|first4=G.|last5=Appelbaum|first5=F. R.|last6=Larson|first6=R. A.|last7=Tallman|first7=M. S.|last8=Bennett|first8=J. M.|last9=Stirewalt|first9=D. L.|date=2006|title=A retrospective study of 69 patients with t(6;9)(p23;q34) AML emphasizes the need for a prospective, multicenter initiative for rare 'poor prognosis' myeloid malignancies|url=https://www.ncbi.nlm.nih.gov/pubmed/16628187|journal=Leukemia|volume=20|issue=7|pages=1295–1297|doi=10.1038/sj.leu.2404233|issn=0887-6924|pmid=16628187}}</ref><ref>{{Cite journal|last=Ishiyama|first=K.|last2=Takami|first2=A.|last3=Kanda|first3=Y.|last4=Nakao|first4=S.|last5=Hidaka|first5=M.|last6=Maeda|first6=T.|last7=Naoe|first7=T.|last8=Taniguchi|first8=S.|last9=Kawa|first9=K.|date=2012|title=Allogeneic hematopoietic stem cell transplantation for acute myeloid leukemia with t(6;9)(p23;q34) dramatically improves the patient prognosis: a matched-pair analysis|url=https://www.ncbi.nlm.nih.gov/pubmed/21869835|journal=Leukemia|volume=26|issue=3|pages=461–464|doi=10.1038/leu.2011.229|issn=1476-5551|pmid=21869835}}</ref>.


The concurrent presence of FLT3-ITD does not appear to negatively impact survival in the pediatric population<ref name=":0" />.
The concurrent presence of FLT3-ITD does not appear to negatively impact survival in the pediatric population<ref name=":0" />.
Line 86: Line 83:
|D, P
|D, P
|Yes (WHO)
|Yes (WHO)
|<span class="blue-text">EXAMPLE:</span>
|The t(6;9) is diagnostic of AML in the appropriate morphology and clinical context (add reference). ''DEK''::''NUP214'' has traditionally been associated with a poor prognosis in both adult and pediatric AML cases<ref name=":0" />.  Of note, a 2014 retrospective analysis suggests a better outcome for pediatric patients with this translocation than previously reported<ref>{{Cite journal|last=Sandahl|first=Julie Damgaard|last2=Coenen|first2=Eva A.|last3=Forestier|first3=Erik|last4=Harbott|first4=Jochen|last5=Johansson|first5=Bertil|last6=Kerndrup|first6=Gitte|last7=Adachi|first7=Souichi|last8=Auvrignon|first8=Anne|last9=Beverloo|first9=H. Berna|date=2014|title=t(6;9)(p22;q34)/DEK-NUP214-rearranged pediatric myeloid leukemia: an international study of 62 patients|url=https://www.ncbi.nlm.nih.gov/pubmed/24441146|journal=Haematologica|volume=99|issue=5|pages=865–872|doi=10.3324/haematol.2013.098517|issn=1592-8721|pmc=4008104|pmid=24441146}}</ref>.  Elevated white blood cell counts and higher bone marrow blast percentages are associated with shorter periods of overall survival and disease-free survival, respectively<ref name=":0" />. Limited data suggests early allogeneic stem cell transplantation may be associated with better overall survival compared to patients without transplantation, suggesting accurate diagnosis for these patients is crucial<ref name=":0" /><ref>{{Cite journal|last=Slovak|first=M. L.|last2=Gundacker|first2=H.|last3=Bloomfield|first3=C. D.|last4=Dewald|first4=G.|last5=Appelbaum|first5=F. R.|last6=Larson|first6=R. A.|last7=Tallman|first7=M. S.|last8=Bennett|first8=J. M.|last9=Stirewalt|first9=D. L.|date=2006|title=A retrospective study of 69 patients with t(6;9)(p23;q34) AML emphasizes the need for a prospective, multicenter initiative for rare 'poor prognosis' myeloid malignancies|url=https://www.ncbi.nlm.nih.gov/pubmed/16628187|journal=Leukemia|volume=20|issue=7|pages=1295–1297|doi=10.1038/sj.leu.2404233|issn=0887-6924|pmid=16628187}}</ref><ref>{{Cite journal|last=Ishiyama|first=K.|last2=Takami|first2=A.|last3=Kanda|first3=Y.|last4=Nakao|first4=S.|last5=Hidaka|first5=M.|last6=Maeda|first6=T.|last7=Naoe|first7=T.|last8=Taniguchi|first8=S.|last9=Kawa|first9=K.|date=2012|title=Allogeneic hematopoietic stem cell transplantation for acute myeloid leukemia with t(6;9)(p23;q34) dramatically improves the patient prognosis: a matched-pair analysis|url=https://www.ncbi.nlm.nih.gov/pubmed/21869835|journal=Leukemia|volume=26|issue=3|pages=461–464|doi=10.1038/leu.2011.229|issn=1476-5551|pmid=21869835}}</ref>.
The t(6;9) is diagnostic of AML in the appropriate morphology and clinical context (add reference). This fusion is responsive to targeted therapy such as Imatinib (Gleevec) (add reference). ''DEK''::''NUP214'' is generally unfavorable in CML
|}
|}
==Individual Region Genomic Gain/Loss/LOH==
==Individual Region Genomic Gain/Loss/LOH==
Line 128: Line 124:


COSMIC does not have specific information on mutations related to this subtype of AML.
COSMIC does not have specific information on mutations related to this subtype of AML.
Concomitant mutations - FLT3-ITD (69% of children and 78% of adults)
Mutually exclusive - FLT3-TKD is very uncommon
{| class="wikitable sortable"
{| class="wikitable sortable"
|-
|-
Line 140: Line 132:
!'''Clinical Relevance Details/Other Notes'''
!'''Clinical Relevance Details/Other Notes'''
|-
|-
|<span class="blue-text">EXAMPLE:</span>''EGFR''
|''FLT3''


<br />
<br />
|<span class="blue-text">EXAMPLE:</span> Exon 18-21 activating mutations
|ITD mutations
|<span class="blue-text">EXAMPLE:</span> Oncogene
|Oncogene
|<span class="blue-text">EXAMPLE:</span> Common (lung cancer)
|Common (AML with DEK::NUP214 fusion)
|<span class="blue-text">EXAMPLE:</span> T
|<span class="blue-text">EXAMPLE:</span> T
|<span class="blue-text">EXAMPLE:</span> Yes (NCCN)
|<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).
|FLT3-ITD occurs in 69% of children and 78% of adults. In contrast to FLT3-ITD mutations, FLT3-TKD is very uncommon.
|-
|<span class="blue-text">EXAMPLE:</span> ''TP53''; Variable LOF mutations
<br />
|<span class="blue-text">EXAMPLE:</span> Variable LOF mutations
|<span class="blue-text">EXAMPLE:</span> Tumor Supressor Gene
|<span class="blue-text">EXAMPLE:</span> Common (breast cancer)
|<span class="blue-text">EXAMPLE:</span> P
|
|<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
|<span class="blue-text">EXAMPLE:</span> Activating mutations
|<span class="blue-text">EXAMPLE:</span> Oncogene
|<span class="blue-text">EXAMPLE:</span> Common (melanoma)
|<span class="blue-text">EXAMPLE:</span> T
|
|
|-
|
|
|
|
|
|
|
|}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==
Retrieved from "https://test.ccga.io/index.php/HAEM5:Acute_myeloid_leukaemia_with_DEK::NUP214_fusion"