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| ==Gene Rearrangements== | | ==Gene Rearrangements== |
| 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). <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 |
| |- | | |- |
| |''NTRK1''||''TPM3::NTRK1''||<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
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| |<span class="blue-text">EXAMPLE:</span> Yes (WHO, NCCN)
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| |<span class="blue-text">EXAMPLE:</span>
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| 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).
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| |-
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| |''NTRK1''
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| |<span class="blue-text">EXAMPLE:</span> ''TPR::NTRK1''
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| |<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''.
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| |<span class="blue-text">EXAMPLE:</span> t(4;19)(q25;q13)
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| |<span class="blue-text">EXAMPLE:</span> Common (CIC-rearranged sarcoma)
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| |<span class="blue-text">EXAMPLE:</span> D
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| |<span class="blue-text">EXAMPLE:</span>
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| ''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).
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| |-
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| |''NTRK1''
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| |<span class="blue-text">EXAMPLE:</span> ''TPM3::ALK''
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| | ''LMNA::NTRK1'' |
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| Other fusion partners include ''KIF5B, NPM1, STRN, TFG, TPM3, CLTC, KLC1''
| | Many other fusion partners also possible |
| |<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. | | |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) |
| |<span class="blue-text">EXAMPLE:</span> N/A
| | t(1;1)(q31.1;q23.1) |
| |<span class="blue-text">EXAMPLE:</span> Rare (Lung adenocarcinoma)
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| |<span class="blue-text">EXAMPLE:</span> T
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| |<span class="blue-text">EXAMPLE:</span>
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| Both balanced and unbalanced forms are observed by FISH (add references).
| | t(1;1)(q22;q23.1) |
| | |Common |
| | |D, T |
| | |Yes (WHO, NCCN) |
| | |Larotrectinib, entrectinib, and repotrectinib are FDA approved for the treatment of solid tumors harboring an NTRK fusion. |
| |} | | |} |
| ==Individual Region Genomic Gain/Loss/LOH== | | ==Individual Region Genomic Gain/Loss/LOH== |
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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
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| |<span class="blue-text">EXAMPLE:</span>
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| Unknown
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| |<span class="blue-text">EXAMPLE:</span> D, P
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| |<span class="blue-text">EXAMPLE:</span> No
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| |<span class="blue-text">EXAMPLE:</span>
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| 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).
| |
| |-
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| |<span class="blue-text">EXAMPLE:</span>
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| 8
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| |<span class="blue-text">EXAMPLE:</span> Gain
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| |<span class="blue-text">EXAMPLE:</span>
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| chr8
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| |<span class="blue-text">EXAMPLE:</span>
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| Unknown
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| |<span class="blue-text">EXAMPLE:</span> D, P
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| |<span class="blue-text">EXAMPLE:</span>
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| Common recurrent secondary finding for t(8;21) (add references).
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| |-
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| |<span class="blue-text">EXAMPLE:</span> | |
| 17
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| |<span class="blue-text">EXAMPLE:</span> Amp
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| |<span class="blue-text">EXAMPLE:</span>
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| 17q12; chr17:39,700,064-39,728,658 [hg38; 28.6 kb]
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| |<span class="blue-text">EXAMPLE:</span>
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| ''ERBB2'' | |
| |<span class="blue-text">EXAMPLE:</span> D, P, T
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| |<span class="blue-text">EXAMPLE:</span>
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| 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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| |-
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| | |No |
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| |} | | |} |
