Compendium of Cancer Genome Aberrations

HAEM5:T-prolymphocytic leukaemia: Difference between revisions

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|Major diagnostic criteria <ref name=":6" />
|Major diagnostic criteria <ref name=":6" />
|-
|-
|ATM loss / mutation; del(11)(q22–q23), loss of heterozygosity, or biallelic mutation
|ATM loss/mutation; del(11)(q22–q23)
|Impaired DNA damage response → genomic instability, accumulation of secondary lesions
|Impaired DNA damage response → genomic instability, accumulation of secondary lesions
|Common
|Common
|D,P
|D,P
|No
|No
|Major diagnostic criteria, the most frequent cooperating lesion <ref name=":6" />
|Minor diagnostic criteria, the most frequent cooperating lesion <ref name=":6" />
|}<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>
Although gene mutations beyond ''TCL1'' family alterations are not yet recognized as diagnostic criteria and remain under investigation for T-PLL, the mutational landscape of T-PLL provides valuable insights. These discoveries open up potential avenues for novel targeted therapies in treating this aggressive form of leukemia.
{| class="wikitable sortable"
{| class="wikitable sortable"
|-
|-
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<br />
<br />
|Mutation/deletion
|Mutation/deletion, loss of heterozygosity, or biallelic mutation
|Tumor suppressor
|Tumor Suppressor Gene
|<span class="blue-text">EXAMPLE:</span> Common (lung cancer)
|Common  
|<span class="blue-text">EXAMPLE:</span> T
|D, P, T
|<span class="blue-text">EXAMPLE:</span> Yes (NCCN)
|No
|<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).
|Since alterations at the ''ATM'' locus are found in up to 80% to 90% of T-PLL cases, it can serve as a minor diagnostic criterion.<ref name=":6" /><ref name=":8">{{Cite journal|last=Schrader|first=A.|last2=Crispatzu|first2=G.|last3=Oberbeck|first3=S.|last4=Mayer|first4=P.|last5=Pützer|first5=S.|last6=von Jan|first6=J.|last7=Vasyutina|first7=E.|last8=Warner|first8=K.|last9=Weit|first9=N.|date=2018-02-15|title=Actionable perturbations of damage responses by TCL1/ATM and epigenetic lesions form the basis of T-PLL|url=https://pubmed.ncbi.nlm.nih.gov/29449575|journal=Nature Communications|volume=9|issue=1|pages=697|doi=10.1038/s41467-017-02688-6|issn=2041-1723|pmc=5814445|pmid=29449575}}</ref>
|-
|<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.


Although gene mutations beyond ''TCL1'' family alterations are not yet recognized as diagnostic criteria and remain under investigation for T-PLL, the mutational landscape of T-PLL provides valuable insights. These discoveries open up potential avenues for novel targeted therapies in treating this aggressive form of leukemia.


Deletions and mutations of the ATM gene (present in up to 90% of T-PLL cases but typically absent in other mature T-cell malignancies) are considered highly indicative for a diagnosis of suspected TCL1 family-negative T-PLL.<ref name=":8">{{Cite journal|last=Schrader|first=A.|last2=Crispatzu|first2=G.|last3=Oberbeck|first3=S.|last4=Mayer|first4=P.|last5=Pützer|first5=S.|last6=von Jan|first6=J.|last7=Vasyutina|first7=E.|last8=Warner|first8=K.|last9=Weit|first9=N.|date=2018-02-15|title=Actionable perturbations of damage responses by TCL1/ATM and epigenetic lesions form the basis of T-PLL|url=https://pubmed.ncbi.nlm.nih.gov/29449575|journal=Nature Communications|volume=9|issue=1|pages=697|doi=10.1038/s41467-017-02688-6|issn=2041-1723|pmc=5814445|pmid=29449575}}</ref><ref name=":3" />
Deletions and mutations of the ATM gene (present in up to 90% of T-PLL cases but typically absent in other mature T-cell malignancies) are considered highly indicative for a diagnosis of suspected TCL1 family-negative T-PLL.<ref name=":8" /><ref name=":3">{{Cite journal|last=Kiel|first=Mark J.|last2=Velusamy|first2=Thirunavukkarasu|last3=Rolland|first3=Delphine|last4=Sahasrabuddhe|first4=Anagh A.|last5=Chung|first5=Fuzon|last6=Bailey|first6=Nathanael G.|last7=Schrader|first7=Alexandra|last8=Li|first8=Bo|last9=Li|first9=Jun Z.|date=2014-08-28|title=Integrated genomic sequencing reveals mutational landscape of T-cell prolymphocytic leukemia|url=https://pubmed.ncbi.nlm.nih.gov/24825865|journal=Blood|volume=124|issue=9|pages=1460–1472|doi=10.1182/blood-2014-03-559542|issn=1528-0020|pmc=4148768|pmid=24825865}}</ref>
{| class="wikitable sortable"
|-
!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)
!Prognostic Significance (Yes, No or Unknown)
!Therapeutic Significance (Yes, No or Unknown)
!Notes
|-
|''ATM''
|TSG
|53% (COSMIC)
|''ATM'' mutation/deletion
|None specified
|Yes
|Yes
|Yes (PARP inhibitors, NCT03263637)
|Since deletions of or missense mutations at the ''ATM'' locus are found in up to 80% to 90% of T-PLL cases, ''ATM'' alterations can serve as a minor diagnostic criterion.<ref name=":6" /><ref name=":8" />
|-
|-
|''FBXW10''
|''FBXW10''
|TSG
<br />
|72% (COSMIC)
|<span class="blue-text">EXAMPLE:</span> Variable LOF mutations
|''JAK/STAT'' pathway
|Tumor Supressor Gene
|None specified
|Common
|Unknown
|Unknown
|Unknown
|Unknown
|No
|
|
|-
|-
|''IL2RG,'' ''JAK1, JAK3, STAT5B''
|''IL2RG,'' ''JAK1, JAK3, STAT5B''
|Activating mutations
|Oncogene
|Oncogene
|8% ''JAK1''
|Variable based on gene; Recurrent to Common
 
|D, P, T
34% ''JAK3''
|No
 
|Targeting this pathway with specific ''JAK/STAT'' pathway inhibitors, has shown promise in preclinical studies and early clinical trials. Combining JAK/STAT inhibitors with other treatments, like BCL-2 inhibitors, may enhance therapeutic efficacy and improve outcomes for T-PLL patients <ref>{{Cite journal|last=Gomez-Arteaga|first=Alexandra|last2=Margolskee|first2=Elizabeth|last3=Wei|first3=Mike T.|last4=van Besien|first4=Koen|last5=Inghirami|first5=Giorgio|last6=Horwitz|first6=Steven|date=2019-07|title=Combined use of tofacitinib (pan-JAK inhibitor) and ruxolitinib (a JAK1/2 inhibitor) for refractory T-cell prolymphocytic leukemia (T-PLL) with a JAK3 mutation|url=https://pubmed.ncbi.nlm.nih.gov/30997845|journal=Leukemia & Lymphoma|volume=60|issue=7|pages=1626–1631|doi=10.1080/10428194.2019.1594220|issn=1029-2403|pmc=8162842|pmid=30997845}}</ref><ref>{{Cite journal|url=https://ashpublications.org/blood/article/126/23/5486/134544/Refractory-TCell-Prolymphocytic-Leukemia-with-JAK3|doi=10.1182/blood.v126.23.5486.5486}}</ref>
16% ''STAT5B''
 
2% ''IL2RG''
 
(COSMIC)
 
(cumulative prevalence of ~ 60%)<ref>{{Cite journal|last=Wahnschaffe|first=Linus|last2=Braun|first2=Till|last3=Timonen|first3=Sanna|last4=Giri|first4=Anil K.|last5=Schrader|first5=Alexandra|last6=Wagle|first6=Prerana|last7=Almusa|first7=Henrikki|last8=Johansson|first8=Patricia|last9=Bellanger|first9=Dorine|date=2019-11-21|title=JAK/STAT-Activating Genomic Alterations Are a Hallmark of T-PLL|url=https://pubmed.ncbi.nlm.nih.gov/31766351|journal=Cancers|volume=11|issue=12|pages=1833|doi=10.3390/cancers11121833|issn=2072-6694|pmc=6966610|pmid=31766351}}</ref>
|''ATM, TP53'', Epigenetic modifiers <ref name=":1">{{Cite journal|last=Andersson|first=E. I.|last2=Pützer|first2=S.|last3=Yadav|first3=B.|last4=Dufva|first4=O.|last5=Khan|first5=S.|last6=He|first6=L.|last7=Sellner|first7=L.|last8=Schrader|first8=A.|last9=Crispatzu|first9=G.|date=2018-03|title=Discovery of novel drug sensitivities in T-PLL by high-throughput ex vivo drug testing and mutation profiling|url=https://pubmed.ncbi.nlm.nih.gov/28804127|journal=Leukemia|volume=32|issue=3|pages=774–787|doi=10.1038/leu.2017.252|issn=1476-5551|pmid=28804127}}</ref><ref name=":2">{{Cite journal|last=Pinter-Brown|first=Lauren C.|date=2021-12-30|title=JAK/STAT: a pathway through the maze of PTCL?|url=https://doi.org/10.1182/blood.2021014238|journal=Blood|volume=138|issue=26|pages=2747–2748|doi=10.1182/blood.2021014238|issn=0006-4971}}</ref>
|Typically, mutations within this pathway occur in a mutually exclusive manner.<ref name=":3">{{Cite journal|last=Kiel|first=Mark J.|last2=Velusamy|first2=Thirunavukkarasu|last3=Rolland|first3=Delphine|last4=Sahasrabuddhe|first4=Anagh A.|last5=Chung|first5=Fuzon|last6=Bailey|first6=Nathanael G.|last7=Schrader|first7=Alexandra|last8=Li|first8=Bo|last9=Li|first9=Jun Z.|date=2014-08-28|title=Integrated genomic sequencing reveals mutational landscape of T-cell prolymphocytic leukemia|url=https://pubmed.ncbi.nlm.nih.gov/24825865|journal=Blood|volume=124|issue=9|pages=1460–1472|doi=10.1182/blood-2014-03-559542|issn=1528-0020|pmc=4148768|pmid=24825865}}</ref>
|Yes
|Yes
|Yes
|Targeting this pathway with specific ''JAK/STAT'' pathway inhibitors, such as tofacitinib, has shown promise in preclinical studies and early clinical trials. Combining JAK/STAT inhibitors with other treatments, like BCL-2 inhibitors, may enhance therapeutic efficacy and improve outcomes for T-PLL patients<ref>{{Cite journal|last=Gomez-Arteaga|first=Alexandra|last2=Margolskee|first2=Elizabeth|last3=Wei|first3=Mike T.|last4=van Besien|first4=Koen|last5=Inghirami|first5=Giorgio|last6=Horwitz|first6=Steven|date=2019-07|title=Combined use of tofacitinib (pan-JAK inhibitor) and ruxolitinib (a JAK1/2 inhibitor) for refractory T-cell prolymphocytic leukemia (T-PLL) with a JAK3 mutation|url=https://pubmed.ncbi.nlm.nih.gov/30997845|journal=Leukemia & Lymphoma|volume=60|issue=7|pages=1626–1631|doi=10.1080/10428194.2019.1594220|issn=1029-2403|pmc=8162842|pmid=30997845}}</ref><ref>{{Cite journal|url=https://ashpublications.org/blood/article/126/23/5486/134544/Refractory-TCell-Prolymphocytic-Leukemia-with-JAK3|doi=10.1182/blood.v126.23.5486.5486}}</ref>
|-
|-
|''EZH2''
|''EZH2''
|Both oncogene and TSG
|Loss-of-function
|16% (COSMIC)
|Both oncogene and Tumor Suppressor Gene
|''JAK/STAT'' pathway<ref name=":1" /><ref name=":2" />
|Recurrent
|None specified
|Unknown
|No
|No
|No (see note)
|''EZH2'' inhibitors like tazemetostat have shown efficacy in other hematologic malignancies, providing a rationale for off-label use in T-PLL
|See note
|''EZH2'' inhibitors like tazemetostat have shown efficacy in other hematologic malignancies, providing a rationale for their potential use in T-PLL
|-
|-
|''BCOR''
|''BCOR''
|TSG
|
|8% (COSMIC)
|Tumor Supressor Gene
|''JAK/STAT'' pathway<ref name=":1" /><ref name=":2" />
|Rare
|None specified
|Unknown
|No
|No (see note)
|No
|No
|A negative impact on overall survival (OS) was not observed for T-PLL patients in the study. However, this might be attributable to the relatively low number of cases compared to studies on AML and MDS.<ref name=":9">{{Cite journal|last=Stengel|first=Anna|last2=Kern|first2=Wolfgang|last3=Zenger|first3=Melanie|last4=Perglerová|first4=Karolína|last5=Schnittger|first5=Susanne|last6=Haferlach|first6=Torsten|last7=Haferlach|first7=Claudia|date=2016-01|title=Genetic characterization of T-PLL reveals two major biologic subgroups and JAK3 mutations as prognostic marker|url=https://pubmed.ncbi.nlm.nih.gov/26493028|journal=Genes, Chromosomes & Cancer|volume=55|issue=1|pages=82–94|doi=10.1002/gcc.22313|issn=1098-2264|pmid=26493028}}</ref>
|A negative impact on overall survival (OS) was not observed for T-PLL patients in the study. However, this might be attributable to the relatively low number of cases compared to studies on AML and MDS.<ref name=":9">{{Cite journal|last=Stengel|first=Anna|last2=Kern|first2=Wolfgang|last3=Zenger|first3=Melanie|last4=Perglerová|first4=Karolína|last5=Schnittger|first5=Susanne|last6=Haferlach|first6=Torsten|last7=Haferlach|first7=Claudia|date=2016-01|title=Genetic characterization of T-PLL reveals two major biologic subgroups and JAK3 mutations as prognostic marker|url=https://pubmed.ncbi.nlm.nih.gov/26493028|journal=Genes, Chromosomes & Cancer|volume=55|issue=1|pages=82–94|doi=10.1002/gcc.22313|issn=1098-2264|pmid=26493028}}</ref>
|-
|-
|''SAMHD1''
|''SAMHD1''
|TSG
|
|~7-20%<ref name=":8" /><ref name=":4">{{Cite journal|last=Johansson|first=Patricia|last2=Klein-Hitpass|first2=Ludger|last3=Choidas|first3=Axel|last4=Habenberger|first4=Peter|last5=Mahboubi|first5=Bijan|last6=Kim|first6=Baek|last7=Bergmann|first7=Anke|last8=Scholtysik|first8=René|last9=Brauser|first9=Martina|date=2018-01-19|title=SAMHD1 is recurrently mutated in T-cell prolymphocytic leukemia|url=https://pubmed.ncbi.nlm.nih.gov/29352181|journal=Blood Cancer Journal|volume=8|issue=1|pages=11|doi=10.1038/s41408-017-0036-5|issn=2044-5385|pmc=5802577|pmid=29352181}}</ref>
|Tumor Supressor Gene
|None specified
|Recurrent
|None specified
|D, P
|Yes
|Yes
|No
|No
|''SAMHD1'' mutations may indicate a defective DNA damage response and aggressive disease <ref name=":4" />
|''SAMHD1'' mutations may indicate a defective DNA damage response and aggressive disease <ref name=":4">{{Cite journal|last=Johansson|first=Patricia|last2=Klein-Hitpass|first2=Ludger|last3=Choidas|first3=Axel|last4=Habenberger|first4=Peter|last5=Mahboubi|first5=Bijan|last6=Kim|first6=Baek|last7=Bergmann|first7=Anke|last8=Scholtysik|first8=René|last9=Brauser|first9=Martina|date=2018-01-19|title=SAMHD1 is recurrently mutated in T-cell prolymphocytic leukemia|url=https://pubmed.ncbi.nlm.nih.gov/29352181|journal=Blood Cancer Journal|volume=8|issue=1|pages=11|doi=10.1038/s41408-017-0036-5|issn=2044-5385|pmc=5802577|pmid=29352181}}</ref>
|-
|-
|''CHEK2''
|''CHEK2''
|TSG
|
|5% (COSMIC)
|Tumor Supressor Gene
|''ATM, TP53, JAK/STA''T pathway, Epigenetic modifiers
|Rare
|None specified
|Unknown
|No
|No  
|Yes
|No
|''CHEK2'' mutations may indicate a defective DNA damage response and aggressive disease <ref name=":3" /><ref>{{Cite journal|last=Braun|first=Till|last2=Dechow|first2=Annika|last3=Friedrich|first3=Gregor|last4=Seifert|first4=Michael|last5=Stachelscheid|first5=Johanna|last6=Herling|first6=Marco|date=2021|title=Advanced Pathogenetic Concepts in T-Cell Prolymphocytic Leukemia and Their Translational Impact|url=https://pubmed.ncbi.nlm.nih.gov/34869023|journal=Frontiers in Oncology|volume=11|pages=775363|doi=10.3389/fonc.2021.775363|issn=2234-943X|pmc=8639578|pmid=34869023}}</ref>
|''CHEK2'' mutations may indicate a defective DNA damage response and aggressive disease <ref name=":3" /><ref>{{Cite journal|last=Braun|first=Till|last2=Dechow|first2=Annika|last3=Friedrich|first3=Gregor|last4=Seifert|first4=Michael|last5=Stachelscheid|first5=Johanna|last6=Herling|first6=Marco|date=2021|title=Advanced Pathogenetic Concepts in T-Cell Prolymphocytic Leukemia and Their Translational Impact|url=https://pubmed.ncbi.nlm.nih.gov/34869023|journal=Frontiers in Oncology|volume=11|pages=775363|doi=10.3389/fonc.2021.775363|issn=2234-943X|pmc=8639578|pmid=34869023}}</ref>
|-
|-
|''TP53''
|''TP53''
|TSG
|
|2% (COSMIC)
|Tumor Supressor Gene
|''ATM, JAK/STA''T pathway, Epigenetic modifiers
|Rare
|None specified-In a study of T-PLL case, TP53 mutations were predominantly found in patients lacking TCRA/D rearrangements.<ref name=":9" />
|P (may portend resistance to therapy)
|No
|No
|Yes
|Associated with resistance to therapy
|Mutations in TP53 are less frequent than deletions.<ref name=":9" />May show overexpression of p53 in some cases.<ref name=":7" />
|Mutations in TP53 are less frequent than deletions.<ref name=":9" />May show overexpression of p53 in some cases.<ref name=":7" />
|}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.
|}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==
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