Compendium of Cancer Genome Aberrations

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{{DISPLAYTITLE:NTRK-rearranged spindle cell neoplasm (emerging)}}
{{DISPLAYTITLE:NTRK-rearranged spindle cell neoplasm (emerging)}}
[[STBT5:Table_of_Contents|Soft Tissue and Bone Tumours (Who Classification, 5th ed.)]]
[[STBT5:Table_of_Contents|Soft Tissue and Bone Tumours (Who Classification, 5th ed.)]]


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<span style="color:#0070C0">(''General Instructions – The focus of these pages is the clinically significant genetic alterations in each disease type. This is based on up-to-date knowledge from multiple resources such as PubMed and the WHO classification books. The CCGA is meant to be a supplemental resource to the WHO classification books; the CCGA captures in a continually updated wiki-stye manner the current genetics/genomics knowledge of each disease, which evolves more rapidly than books can be revised and published. If the same disease is described in multiple WHO classification books, the genetics-related information for that disease will be consolidated into a single main page that has this template (other pages would only contain a link to this main page). Use [https://www.genenames.org/ <u>HUGO-approved gene names and symbols</u>] (italicized when appropriate), [https://varnomen.hgvs.org/ <u>HGVS-based nomenclature for variants</u>], as well as generic names of drugs and testing platforms or assays if applicable. Please complete tables whenever possible and do not delete them (add N/A if not applicable in the table and delete the examples); to add (or move) a row or column in a table, click nearby within the table and select the > symbol that appears. Please do not delete or alter the section headings. The use of bullet points alongside short blocks of text rather than only large paragraphs is encouraged. Additional instructions below in italicized blue text should not be included in the final page content. Please also see'' </span><u>''[[Author_Instructions]]''</u><span style="color:#0070C0"> ''and [[Frequently Asked Questions (FAQs)|<u>FAQs</u>]] as well as contact your [[Leadership|<u>Associate Editor</u>]] or [mailto:CCGA@cancergenomics.org <u>Technical Support</u>].)''</span>
<span style="color:#0070C0">(''General Instructions – The focus of these pages is the clinically significant genetic alterations in each disease type. This is based on up-to-date knowledge from multiple resources such as PubMed and the WHO classification books. The CCGA is meant to be a supplemental resource to the WHO classification books; the CCGA captures in a continually updated wiki-stye manner the current genetics/genomics knowledge of each disease, which evolves more rapidly than books can be revised and published. If the same disease is described in multiple WHO classification books, the genetics-related information for that disease will be consolidated into a single main page that has this template (other pages would only contain a link to this main page). Use [https://www.genenames.org/ <u>HUGO-approved gene names and symbols</u>] (italicized when appropriate), [https://varnomen.hgvs.org/ <u>HGVS-based nomenclature for variants</u>], as well as generic names of drugs and testing platforms or assays if applicable. Please complete tables whenever possible and do not delete them (add N/A if not applicable in the table and delete the examples); to add (or move) a row or column in a table, click nearby within the table and select the > symbol that appears. Please do not delete or alter the section headings. The use of bullet points alongside short blocks of text rather than only large paragraphs is encouraged. Additional instructions below in italicized blue text should not be included in the final page content. Please also see'' </span><u>''[[Author_Instructions]]''</u><span style="color:#0070C0"> ''and [[Frequently Asked Questions (FAQs)|<u>FAQs</u>]] as well as contact your [[Leadership|<u>Associate Editor</u>]] or [mailto:CCGA@cancergenomics.org <u>Technical Support</u>].)''</span>
==Primary Author(s)*==
==Primary Author(s)*==
Put your text here<span style="color:#0070C0"> (''<span class="blue-text">EXAMPLE:</span>'' Jane Smith, PhD) </span>
James P. Solomon, M.D., Ph.D.
 
Weill Cornell Medicine
==WHO Classification of Disease==
==WHO Classification of Disease==


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==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>
Fusions involving ''NTRK1'' are the most common oncogenic driver in ''NTRK-''rearranged spindle cell neoplasm, but ''NTRK2'' or ''NTRK3'' fusions are also occasionally seen (PMID: 30276917, 30520818). In-frame fusions that include the kinase domain of any of ''NTRK1'', ''NTRK2'', or ''NTRK3'' could represent the oncogenic driver, and there are over 80 partners that have been reported for ''NTRK'' fusions (PMID: 31075511).  As this is an emerging entity, prevalence of specific pairings is unknown.  RNA sequencing-based fusion detection methods provide the most information about the identity of both gene partners (see Genetic Testing Diagnostic Methods section below).
{| 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)
|''NTRK1''||''TPM3::NTRK1''
|<span class="blue-text">EXAMPLE:</span> Common (CML)
''TPR::NTRK1''
|<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>


''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).
''LMNA::NTRK1''
|-
|<span class="blue-text">EXAMPLE:</span> ''ALK''
|<span class="blue-text">EXAMPLE:</span> ''ELM4::ALK''


Many other fusion partners also possible
|In-frame fusions that include the tyrosine kinase domain result in constitutive activation of the neurotrophic tyrosine receptor kinase and downstream pathways including the MAP-kinase and PI3-kinase pathways.||t(1;1)(q21.3;q23.1)
t(1;1)(q31.1;q23.1)


Other fusion partners include ''KIF5B, NPM1, STRN, TFG, TPM3, CLTC, KLC1''
t(1;1)(q22;q23.1)
|<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.
|Common
|<span class="blue-text">EXAMPLE:</span> N/A
|D, T
|<span class="blue-text">EXAMPLE:</span> Rare (Lung adenocarcinoma)
|Yes (WHO, NCCN)
|<span class="blue-text">EXAMPLE:</span> T
|Larotrectinib, entrectinib, and repotrectinib are FDA approved for the treatment of solid tumors harboring an NTRK fusion.
|
|<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
|
|
|-
|
|
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|
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|
|
|}
|}
==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>
''CDKN2A'' homozygous deletion is recurrently reported in ''NTRK-''rearranged spindle cell neoplasms (PMID: 30877273, 35149769).
 
<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"
|-
|-
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!Clinical Relevance Details/Other Notes
!Clinical Relevance Details/Other Notes
|-
|-
|<span class="blue-text">EXAMPLE:</span>
|9
7
|Loss
|<span class="blue-text">EXAMPLE:</span> Loss
|chr9p21
|<span class="blue-text">EXAMPLE:</span>
|''CDKN2A''
chr7
|<span class="blue-text">EXAMPLE:</span>
Unknown
|<span class="blue-text">EXAMPLE:</span> D, P
|<span class="blue-text">EXAMPLE:</span> 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 references).
|-
|<span class="blue-text">EXAMPLE:</span>
8
|<span class="blue-text">EXAMPLE:</span> Gain
|<span class="blue-text">EXAMPLE:</span>
chr8
|<span class="blue-text">EXAMPLE:</span>
Unknown
|<span class="blue-text">EXAMPLE:</span> D, P
|
|<span class="blue-text">EXAMPLE:</span>
Common recurrent secondary finding for t(8;21) (add references).
|-
|<span class="blue-text">EXAMPLE:</span>
17
|<span class="blue-text">EXAMPLE:</span> Amp
|<span class="blue-text">EXAMPLE:</span>
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> D, P, T
|
|<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.
|-
|
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|No
|
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|}
|}
==Characteristic Chromosomal or Other Global Mutational Patterns==
==Characteristic Chromosomal or Other Global Mutational Patterns==
N/A -
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>
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"
{| class="wikitable sortable"
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|}
|}
==Gene Mutations (SNV/INDEL)==
==Gene Mutations (SNV/INDEL)==
N/A -
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>
{| class="wikitable sortable"
{| class="wikitable sortable"
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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 [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==
Put your text here
N/A
==Genes and Main Pathways Involved==
==Genes and Main Pathways Involved==
Put your text here and fill in the table <span style="color:#0070C0">(''Instructions: 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: Please include references throughout the table. Do not delete the table.)''</span>
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!Gene; Genetic Alteration!!Pathway!!Pathophysiologic Outcome
!Gene; Genetic Alteration!!Pathway!!Pathophysiologic Outcome
|-
|-
|<span class="blue-text">EXAMPLE:</span> ''BRAF'' and ''MAP2K1''; Activating mutations
|''NTRK1/2/3'' fusion
|<span class="blue-text">EXAMPLE:</span> MAPK signaling
|NTRK signaling
|<span class="blue-text">EXAMPLE:</span> Increased cell growth and proliferation
|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==
Put your text here <span style="color:#0070C0">(''Instructions: Include recommended testing type(s) to identify the clinically significant genetic alterations.'')</span>
''Immunohistochemistry:''  Antibodies have been developed for detection of ''NTRK'' fusions and are being used in clinical laboratories.  Immunohistochemistry has a fast turnaround time, but sensitivity and specificity for detection of ''NTRK'' fusions are lower than other methods listed here.  In sarcomas in particular, false positives can be seen in neural-derived tumors and in tumors harboring ''BCOR'' alterations (PMID: 31375766, 29863809, 32034283, 35149769).  Confirmatory testing with other molecular-based methods is recommended.
 
 
''Fluorescent in situ hybridization (FISH)'':  Breakapart probes for ''NTRK1, NTRK2,'' and ''NTRK3'' can identify breaks in these genes, although the probes not widely available in clinical laboratories.  Benefits of this approach include high sensitivity, particularly in samples with low tumor content, fast turnaround time, and only require a few unstained slides.  This approach does not allow for identification of the fusion partner nor for a detailed evaluation of oncogenicity.
 
''Reverse transcriptase polymerase chain reaction (RT-PCR)'' can only identify specific fusion pairs (e.g. ''ETV6::NTRK3''), such that alternate pairings will be missed. '' ''With the availability of RNA-based sequencing, this technique is now rarely used clinically.
 
 
''RNA-based sequencing'' is becoming widely used for comprehensive fusion detection.  It is often performed as a comprehensive panel, so ''NTRK'' fusions can be assessed at the same time as many other sarcoma-associated fusions.  A platform that supports fusion detection in a partner agnostic manner such as anchored multiplex PCR or hybridization capture methods is preferred (PMID: 31738428).  A systematic approach should be used to assess oncogenicity of ''NTRK'' fusions including stranding and directionality, inclusion of the kinase domain, and review of the literature (PMID: 35366592).
 
==Familial Forms==
==Familial Forms==
Put your text here <span style="color:#0070C0">(''Instructions: Include associated hereditary conditions/syndromes that cause this entity or are caused by this entity.'') </span>
N/A <span style="color:#0070C0">(''Instructions: Include associated hereditary conditions/syndromes that cause this entity or are caused by this entity.'') </span>
==Additional Information==
==Additional Information==
Put your text here
'''Definition/Description of Disease'''
 
This “emerging entity” is defined by the molecular identification of an oncogenic fusion involving ''NTRK1, NTRK2,'' or ''NTRK3. '' This provisional category excludes tumors with distinct classifications like infantile fibrosarcoma, congenital mesoblastic nephroma and inflammatory myofibroblastic tumor.  Because of the availability and efficacy of the FDA-approved ''NTRK'' inhibitors, the identification of ''NTRK'' fusions and accurate characterization of these tumors is paramount (PMID: 33179614).
 
'''Epidemiology/Prevalence'''
 
According to current evidence, these tumors are very rare.  As an emerging entity, more data is needed to accurately determine the true prevalence.  With increasing awareness of this entity, use of immunohistochemical and molecular techniques to screen for ''NTRK'' fusions, this diagnosis may become more frequent.
 
'''Clinical Features'''
 
The clinical presentation and behavior of these entities is variable (PMID: 32891793).  While most often seen in the pediatric and young adult population, it can also present in adulthood.  Clinical course is variable, with aggressiveness and propensity to metastasize correlated with clinical and morphological features.  All tumors with ''NTRK'' fusions are eligible for NTRK-targeted therapies (PMID: 29466156, 32891793). Case reports have demonstrated the efficacy of these treatments for ''NTRK­-''rearranged spindle cell neoplasms (PMID: 35070960).
 
'''Sites of Involvement'''
 
Most often reported in the superficial or deep soft tissue of the extremities and trunk, also reported in other sites, including in the viscera (PMID: 35149769), especially the uterine cervix (PMID: 29553955).
 
'''Morphologic Features'''
 
''NTRK''­-rearranged spindle cell neoplasms exhibit a histologic spectrum from a lipofibromatosis-like neural tumor to a peripheral nerve sheath tumor-like morphology.  The lipofibromatosis-like tumor has an infiltrative growth pattern, with monomorphic spindle cells with cytologic atypia infiltrating into subcutaneous fat.  Mitotic count is low and there is a lack of necrosis (PMID: 27259011).  Peripheral nerve sheath tumor-like morphology is more cellular with streaming monomorphic spindle cells and a background of prominent stromal bands and keloid-like collagen (PMID:  30276917).  Some tumors exhibit a mixture of features or may be spatially heterogeneous with areas closer to one end of the spectrum.  Some reports have also identified tumors with other morphologic features, including abundant myxoid stroma (PMID: 32050835).
 
'''Immunophenotype'''
 
Many ''NTRK''-rearranged spindle cell neoplasms exhibit co-expression of S100 and CD34 (PMID: 30276917, 32891793), while others have a nonspecific immunophenotype.
 
==Links==
==Links==
Put a link here or anywhere appropriate in this page <span style="color:#0070C0">(''Instructions: Highlight the text to which you want to add a link in this section or elsewhere, select the "Link" icon at the top of the wiki page, and search the name of the internal page to which you want to link this text, or enter an external internet address by including the "<nowiki>http://www</nowiki>." portion.'')</span>
Put a link here or anywhere appropriate in this page <span style="color:#0070C0">(''Instructions: Highlight the text to which you want to add a link in this section or elsewhere, select the "Link" icon at the top of the wiki page, and search the name of the internal page to which you want to link this text, or enter an external internet address by including the "<nowiki>http://www</nowiki>." portion.'')</span>
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Prior Author(s):
Prior Author(s):
<nowiki>*</nowiki>''Citation of this Page'': “NTRK-rearranged spindle cell neoplasm (emerging)”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated {{REVISIONMONTH}}/{{REVISIONDAY}}/{{REVISIONYEAR}}, <nowiki>https://ccga.io/index.php/STBT5:NTRK-rearranged spindle cell neoplasm (emerging)</nowiki>.
<nowiki>*</nowiki>''Citation of this Page'': “NTRK-rearranged spindle cell neoplasm (emerging)”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated {{REVISIONMONTH}}/{{REVISIONDAY}}/{{REVISIONYEAR}}, <nowiki>https://ccga.io/index.php/STBT5:NTRK-rearranged spindle cell neoplasm (emerging)</nowiki>.
[[Category:STBT5]][[Category:DISEASE]][[Category:Diseases N]]
[[Category:STBT5]]
[[Category:DISEASE]]
[[Category:Diseases N]]
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