Clinical impact of genomic testing in T-cell neoplasms
| Entity . | Genetic alteration: test . | Diagnostic use . | Clinical impact . | Future assays . |
|---|---|---|---|---|
| T-cell neoplasms | TRG and/or TRB gene rearrangements∗,†: PCR-based assays with fragment analysis or HTS | Demonstration of monoclonal TCR gene rearrangement is (1) recommended to support a diagnosis of T-cell lymphoma, especially when morphology and immunophenotyping are not fully conclusive for T-cell lymphoma/leukemia, and to diagnose clonal T-LPD; (2) useful in the assessment of atypical T-cell populations and establishing lineage in phenotypically ambiguous malignancies; and (3) helping in the distinction between T and NK origin | Accurate diagnosis of a neoplastic T-cell proliferation | WTS or targeted gene expression assays to determine T-cell repertoire and disease classification and detect driver fusions282,469 WGS to detect CNAs and SVs ctDNA assays for disease monitoring |
| Mutations and small indels in genes recurrently altered: HTS Various gene fusions: HTS or FISH | Useful in certain circumstances to establish clonality or to support the diagnosis of a specific entity | Mechanism of actionable alterations and how they could be targeted clinically is displayed in Figure 5 | ||
| ALCL, ALK-positive | ALK gene fusions†: IHC, FISH, or transcript detection | Mandatory to establish the diagnosis of ALK-positive ALCL | Use of ALK inhibitors | HTS to guide second-/third-generation ALK inhibitors in cases of resistance to ALK inhibitors470 |
| ALCL, ALK-negative | DUSP22-IRF4 (6p25.3) rearrangement†: FISH; TP63 (3q28) rearrangement†: FISH | DUSP22-R defines a subtype of ALK- ALCL2; see scenario 4E in Table 3 | Treatment may be adapted according to genomic configuration with (possibly) less aggressive therapy in patients with DUSP22-R ALCL‡ | |
| TFHL angioimmunoblastic type; follicular type; NOS | TET2, DNMT3A, IDH2, RHOA mutations†: HTS (or PCR-based for RHOAG17V and IDH2R172) | Useful in certain circumstances to support the diagnosis; see scenario 4B in Table 3 | DNMT3A hotspot mutation may be predictive of nonresponse to standard chemotherapy and associated with adverse prognosis471 | |
| PTCL, NOS | Mutations and small indels in genes recurrently altered: HTS | Demonstration of genomic alterations useful in certain circumstances to establish clonality and support the diagnosis | Adverse prognostic impact of higher mutation load, complex genomic imbalances, TP53 mutations, and Th2 molecular subgroup280,281,284 | WGS, cytogenetics or array-based determination of SVs Gene expression–based subtyping469 (or IHC surrogate472) for risk stratification and patient selection |
| HSTCL | I(7q), trisomy 8†: FISH or cytogenetics INO80, PIK3CD, SETD2, STAT5B, STAT3, TET3, SMARCA2 mutations†: HTS | Useful in certain circumstances to support the diagnosis; see scenario 4C in Table 3 | ||
| ENKTCL, nasal type | CD274 SVs and amplifications: HTS | Useful in certain circumstances for prediction of response to PD1 inhibitors329-332 | Integrated HTS and TME analysis for disease stratification and guiding treatment decisions326,333 | |
| Adult T-cell leukemia/lymphoma | Clonal HTLV-1 integration: HTS | Useful in certain circumstances to support the diagnosis in HTLV-1 carriers | Disease follow-up and clonal evolution340,473 | HTS to assess risk of transformation in HTLV-1 carriers and guide treatment decisions340 |
| Mutations in genes related to immune function, signaling, cell cycle: HTS | Useful in certain circumstances for prognostic or predictive value. CCR4 mutations predictive of response to mogamulizumab.344,345, Some alterations indicative of unfavorable prognosis (TP53 or PRKBC mutations; TcR/NF-κB pathway alterations in the indolent subtype)340,346,474 | |||
| T-LGLL and NK-LGLL | STAT3 and STAT5B mutations†: HTS | Useful in certain circumstances to support the diagnosis; see scenario 4C in Table 3 | STAT3 mutations relate with neutropenia | |
| T-cell prolymphocytic leukemia | inv(14)(q11q32), t(14;14)(q11;q32), t(X;14)(q28;q11), trisomy 8: FISH (TCL1A or MCTP1) or cytogenetics∗ | Strongly recommended for establishing the diagnosis; see scenario 4C in Table 3 | Prognosis: complex karyotype (≥3 aberrations) indicative of less favorable prognosis366 |
| Entity . | Genetic alteration: test . | Diagnostic use . | Clinical impact . | Future assays . |
|---|---|---|---|---|
| T-cell neoplasms | TRG and/or TRB gene rearrangements∗,†: PCR-based assays with fragment analysis or HTS | Demonstration of monoclonal TCR gene rearrangement is (1) recommended to support a diagnosis of T-cell lymphoma, especially when morphology and immunophenotyping are not fully conclusive for T-cell lymphoma/leukemia, and to diagnose clonal T-LPD; (2) useful in the assessment of atypical T-cell populations and establishing lineage in phenotypically ambiguous malignancies; and (3) helping in the distinction between T and NK origin | Accurate diagnosis of a neoplastic T-cell proliferation | WTS or targeted gene expression assays to determine T-cell repertoire and disease classification and detect driver fusions282,469 WGS to detect CNAs and SVs ctDNA assays for disease monitoring |
| Mutations and small indels in genes recurrently altered: HTS Various gene fusions: HTS or FISH | Useful in certain circumstances to establish clonality or to support the diagnosis of a specific entity | Mechanism of actionable alterations and how they could be targeted clinically is displayed in Figure 5 | ||
| ALCL, ALK-positive | ALK gene fusions†: IHC, FISH, or transcript detection | Mandatory to establish the diagnosis of ALK-positive ALCL | Use of ALK inhibitors | HTS to guide second-/third-generation ALK inhibitors in cases of resistance to ALK inhibitors470 |
| ALCL, ALK-negative | DUSP22-IRF4 (6p25.3) rearrangement†: FISH; TP63 (3q28) rearrangement†: FISH | DUSP22-R defines a subtype of ALK- ALCL2; see scenario 4E in Table 3 | Treatment may be adapted according to genomic configuration with (possibly) less aggressive therapy in patients with DUSP22-R ALCL‡ | |
| TFHL angioimmunoblastic type; follicular type; NOS | TET2, DNMT3A, IDH2, RHOA mutations†: HTS (or PCR-based for RHOAG17V and IDH2R172) | Useful in certain circumstances to support the diagnosis; see scenario 4B in Table 3 | DNMT3A hotspot mutation may be predictive of nonresponse to standard chemotherapy and associated with adverse prognosis471 | |
| PTCL, NOS | Mutations and small indels in genes recurrently altered: HTS | Demonstration of genomic alterations useful in certain circumstances to establish clonality and support the diagnosis | Adverse prognostic impact of higher mutation load, complex genomic imbalances, TP53 mutations, and Th2 molecular subgroup280,281,284 | WGS, cytogenetics or array-based determination of SVs Gene expression–based subtyping469 (or IHC surrogate472) for risk stratification and patient selection |
| HSTCL | I(7q), trisomy 8†: FISH or cytogenetics INO80, PIK3CD, SETD2, STAT5B, STAT3, TET3, SMARCA2 mutations†: HTS | Useful in certain circumstances to support the diagnosis; see scenario 4C in Table 3 | ||
| ENKTCL, nasal type | CD274 SVs and amplifications: HTS | Useful in certain circumstances for prediction of response to PD1 inhibitors329-332 | Integrated HTS and TME analysis for disease stratification and guiding treatment decisions326,333 | |
| Adult T-cell leukemia/lymphoma | Clonal HTLV-1 integration: HTS | Useful in certain circumstances to support the diagnosis in HTLV-1 carriers | Disease follow-up and clonal evolution340,473 | HTS to assess risk of transformation in HTLV-1 carriers and guide treatment decisions340 |
| Mutations in genes related to immune function, signaling, cell cycle: HTS | Useful in certain circumstances for prognostic or predictive value. CCR4 mutations predictive of response to mogamulizumab.344,345, Some alterations indicative of unfavorable prognosis (TP53 or PRKBC mutations; TcR/NF-κB pathway alterations in the indolent subtype)340,346,474 | |||
| T-LGLL and NK-LGLL | STAT3 and STAT5B mutations†: HTS | Useful in certain circumstances to support the diagnosis; see scenario 4C in Table 3 | STAT3 mutations relate with neutropenia | |
| T-cell prolymphocytic leukemia | inv(14)(q11q32), t(14;14)(q11;q32), t(X;14)(q28;q11), trisomy 8: FISH (TCL1A or MCTP1) or cytogenetics∗ | Strongly recommended for establishing the diagnosis; see scenario 4C in Table 3 | Prognosis: complex karyotype (≥3 aberrations) indicative of less favorable prognosis366 |
Figure 5 shows the potential therapeutic targeting of specific genetic alterations that may be common to several T/NK-cell neoplastic entities.
ALCL, anaplastic large-cell lymphoma; ALK, anaplastic lymphoma kinase; ENKTCL, extranodal NK/T-cell lymphoma; HSTCL, hepatosplenic T-cell lymphoma; HTLV, human T-lymphotropic virus; LPD, lymphoproliferative disorder; NK-LGLL, chronic lymphoproliferative disorder of natural killer cells; TFHL, follicular helper T-cell lymphoma; T-LGLL, T-cell large granular lymphocytic leukemia.
Required/strongly recommended in the National Comprehensive Cancer Network 2022 guidelines.
Useful in certain circumstances in the National Comprehensive Cancer Network 2022 guidelines.
National Comprehensive Cancer Network 2022 treatment guidelines.