Edit

Contact Us


    Human Verification

    What Test Should I Order?

    Based on the Clinical Indications for Molecular Testing

    Molecular Profiling Indications

    Molecular Profiling Indications

    Solid Tumors

    Suggestion

    The following tables can be viewed better in big screens. Please turn your device horizontally for optimal viewing experience.

    Recommended Test:

    1)Solid Tumor Profile PLUS™ (FFPE block or unstained slides)

    2)Liquid Biopsy Solid Tumor™ (Peripheral blood/cfDNA)

    Clinical Indication
    Genes/Molecular Abnormality
    Remarks
    Aiding in establishing diagnosis/stratification

    EGFR, ALK, ROS1, BRAF, MET exon 14 skipping, RET, PD-L1, (category 1)

    -KRAS (especially G12C), NTRK 1/2/3, ERBB2 mut/amplification, MET amplification, TMB, RET, TP53, KEAP1, STK11, NF1, SETD2, RBM10, ARID1A, PIK3CA, SMARCA4, RB1, CDKN2A, PTEN, AKT1

    Fusions: CD74–NRG1, SLC3A2–NRG1, EZR–ERBB4, TRIM24–BRAF, and KIAA1468–RET

    NCCN Recommendation: EGFR, ALK, ROS1, BRAF, MET exon 14 skipping, RET, PD-L1, (category 1)

    -KRAS (especially G12C), NTRK 1/2/3, ERBB2 mut/amplification, MET amplification, TMB, RET

    Prognosis

    EGFR, ALK, ROS1, BRAF, MET exon 14 skipping, RET, PD-L1, (category 1)

    -KRAS (especially G12C), NTRK 1/2/3, ERBB2 mut/amplification, MET amplification, TMB, RET, TP53, KEAP1, STK11, NF1, SETD2, RBM10, ARID1A, PIK3CA, SMARCA4, RB1, CDKN2A, PTEN, AKT1

    Fusions: CD74–NRG1, SLC3A2–NRG1, EZR–ERBB4, TRIM24–BRAF, and KIAA1468–RET

    Prognosis is based on predicting response to specific therapy
    Selecting therapy

    EGFR, ALK, ROS1, BRAF, MET exon 14 skipping, RET, PD-L1, (category 1)

    -KRAS (especially G12C), NTRK 1/2/3, ERBB2 mut/amplification, MET amplification, TMB, RET, TP53, KEAP1, STK11, NF1, SETD2, RBM10, ARID1A, PIK3CA, SMARCA4, RB1, CDKN2A, PTEN, AKT1

    Fusions: CD74–NRG1, SLC3A2–NRG1, EZR–ERBB4, TRIM24–BRAF, and KIAA1468–RET

    Targeted mutations: EGFR, BRAF, KRAS(G12C), TMB, PIK3CA, PTEN, AKT1

    Targetable fusions: ALK, RET, ROS1, NTRK1, NRG1, ERBB4, BRAF, FGFR

    Follow-up and minimal residual disease (MRD)Mutations: EGFR, TP53, KEAP1, STK11, NF1, SETD2, RBM10, ARID1A, PIK3CA, SMARCA4, RB1, CDKN2A, PTEN, AKT1

    Plasma-based testing should be considered at progression on EGFR TKIs for the T790M mutation.

    -Minimal residual disease and relapse

    Recommended Test:

    1)Solid Tumor Profile PLUS™ (FFPE block or unstained slides)

    2)Liquid Biopsy Solid Tumor™ (Liquid Biopsy) (Peripheral blood/cfDNA)

    Clinical Indication
    Genes/Molecular Abnormality
    Remarks
    Aiding in establishing diagnosis/stratification

    MSI, BRAF, KRAS, NRNA, PD-L1, (category 1)

    -HRAS, EGFR amplification, NTRK 1/2/3, ERBB2 mut/amplification, MET amplification, TMB, TP53, KEAP1, STK11, NF1, SETD2, RBM10, ARID1A, PIK3CA, SMARCA4, RB1, CDKN2A, PTEN, AKT1

    Lynch: MSH6, PMS2, MLH1, EPCAM and MSH2.

    FAP: APC and MUTYH

    Cowden/PTEN

    Peutz-Jeghers syndrome: STK11

    Juvenile polyposis syndrome: SMAD4, BMPR1A

    NCCN Recommendation:

    MSI, BRAF, KRAS, NRNA, PD-L1, (category 1)

    -HRAS, EGFR amplification, NTRK 1/2/3, ERBB2 mut/amplification,

    Lynch: MSH6, PMS2, MLH1, EPCAM and MSH2

    FAP: APC and MUTYH

    Cowden/PTEN

    Peutz-Jeghers syndrome: STK11

    Juvenile polyposis syndrome: SMAD4, BMPR1A

    Prognosis

    MSI, BRAF, KRAS, NRNA, PD-L1, (category 1)

    -HRAS, EGFR amplification, NTRK 1/2/3, ERBB2 mut/amplification, MET amplification, TMB, TP53, KEAP1, STK11, NF1, SETD2, RBM10, ARID1A, PIK3CA, SMARCA4, RB1, CDKN2A, PTEN, AKT1

    Lynch: MSH6, PMS2, MLH1, EPCAM and MSH2.

    FAP: APC and MUTYH

    Cowden/PTEN

    Peutz-Jeghers syndrome: STK11

    Juvenile polyposis syndrome: SMAD4, BMPR1A

    Prognosis is based on predicting response to specific therapy
    Selecting therapy

    MSI, BRAF, KRAS, NRNA, PD-L1, (category 1)

    -HRAS, EGFR amplification, NTRK 1/2/3, ERBB2 mut/amplification, MET amplification, TMB, TP53, KEAP1, STK11, NF1, SETD2, RBM10, ARID1A, PIK3CA, SMARCA4, RB1, CDKN2A, PTEN, AKT1

    Lynch: MSH6, PMS2, MLH1, EPCAM and MSH2.

    FAP: APC and MUTYH

    Cowden/PTEN

    Peutz-Jeghers Syndrome: STK11

    Juvenile polyposis syndrome: SMAD4, BMPR1A

    Targeted mutations: KRAS (G12C), lack of RAS/REAF mutations

    BRAF mutation

    TMB, MSI

    PIK3CA, PTEN, AKT1

    Follow-up and Minimal Residual Disease (MRD)

    MSI, BRAF, KRAS, NRNA, PD-L1, (category 1)

    -HRAS, EGFR amplification, NTRK 1/2/3, ERBB2 mut/amplification, MET amplification, TMB, TP53, KEAP1, STK11, NF1, SETD2, RBM10, ARID1A, PIK3CA, SMARCA4, RB1, CDKN2A, PTEN, AKT1

    Lynch: MSH6, PMS2, MLH1, EPCAM and MSH2.

    FAP: APC and MUTYH

    Cowden/PTEN

    Peutz-Jeghers syndrome: STK11

    Juvenile polyposis syndrome: SMAD4, BMPR1A

    Detecting mutations

    Recommended Test:

    1)Solid Tumor Profile PLUS™ (FFPE block or slides)

    2)Liquid Biopsy Solid Tumor™ (Liquid Biopsy) (Peripheral blood/cfDNA)

    Clinical Indication
    Genes/Molecular Abnormality
    Remarks
    Aiding in establishing diagnosis/stratification

    ERBB2 (HER2) amplification, Mutation, overexpression

    MSI, BRCA1, BRCA2, ATM, TP53, PIK3CA,

    BRAF, KRAS, NRNA, PD-L1,

    EGFR amplification, NTRK 1/2/3, FGFR1/2/3/4, ERBB3, MET amplification, TMB, KEAP1, STK11, NF1, SETD2, RBM10, ARID1A, SMARCA4, RB1, CDKN2A, PTEN, AKT1, TMB, MSI

    Copy number change: CCND1, TOP2A, PPM1D, MYC, AKT1, CDK9, KRAS, MDM2, CDKN2A, RB1, PTEN, and TP53

    NCCN guideline:

    TMB, HER2, BRCA1/2, ATM, MSI, PIK3CA, NTRK1/2/3

    Prognosis

    ERBB2 (HER2) amplification, mutation, overexpression

    MSI, BRCA1, BRCA2, ATM, TP53, PIK3CA,

    BRAF, KRAS, NRNA, PD-L1,

    EGFR amplification, NTRK 1/2/3, FGFR1/2/3/4, ERBB3, MET amplification, TMB, KEAP1, STK11, NF1, SETD2, RBM10, ARID1A, SMARCA4, RB1, CDKN2A, PTEN, AKT1

    Copy number change: CCND1, TOP2A, PPM1D, MYC, AKT1, CDK9, KRAS, MDM2, CDKN2A, RB1, PTEN, and TP53

     
    Selecting therapy

    ERBB2 (HER2) amplification, Mutation, overexpression

    MSI, BRCA1, BRCA2, ATM, TP53, PIK3CA,

    BRAF, KRAS, NRNA, PD-L1,

    EGFR amplification, NTRK 1/2/3, FGFR1/2/3/4, ERBB3, MET amplification, TMB, KEAP1, STK11, NF1, SETD2, RBM10, ARID1A, SMARCA4, RB1, CDKN2A, PTEN, AKT1

    Copy number change: CCND1, TOP2A, PPM1D, MYC, AKT1, CDK9, KRAS, MDM2, CDKN2A, RB1, PTEN, and TP53

    NCCN guideline:

    TMB, HER2, BRCA1/2, ATM, MSI, PIK3CA, NTRK1/2/3

    ESR1 resistant to both AIs and tamoxifen.

    Follow-up and minimal residual disease (MRD)

    ERBB2 (HER2) amplification, mutation, overexpression

    MSI, BRCA1, BRCA2, ATM, TP53, PIK3CA,

    BRAF, KRAS, NRNA, PD-L1,

    EGFR amplification, NTRK 1/2/3, FGFR1/2/3/4, ERBB3, MET amplification, TMB, KEAP1, STK11, NF1, SETD2, RBM10, ARID1A, SMARCA4, RB1, CDKN2A, PTEN, AKT1

    Copy number change: CCND1, TOP2A, PPM1D, MYC, AKT1, CDK9, KRAS, MDM2, CDKN2A, RB1, PTEN, and TP53

    Detecting mutations

    Recommended Test:

    1)Solid Tumor Profile PLUS™ (FFPE block or slides)

    2)Liquid Biopsy Solid Tumor™ (Liquid Biopsy) (Peripheral blood/cfDNA)

    Clinical Indication
    Genes/Molecular Abnormality
    Remarks
    Aiding in establishing diagnosis/stratification  PAX3, FOXO1, PAX 7, PAX3, AFX, NCOA1, NCOA2, INO80D, MYOD1,  EWSR1, WT1, FLI1, ERG, FEV, ETV1, E1AF, ZSG, FUS, CIC, DUX4, BCOR, CCNB, MYOD1, PIK3CA, RAS, TSC1, TSC2, TFE3, MDM2, CDK4, HMGA2, SAS, GLI, DDIT3, ASPL, TFE3, ATF1, CREB1, ATF1, CREB1, ETV6, NTRK3, COL1A1, PDGFB, CTNNB1, APC, YWHAE, NUTM2,  ZC3H7B, WWTR1, CAMTA1, YAP1, TFE3, ALK, ROS1, NTRK3, TPM3, TPM4, CLTC, RANBP2, CARS, ATIC, SMARCB (INI1), NR4A3, TAF2N, NR4A3, TCF12, NR4A3, TFG-NR4A3, KIT, PDGFRA, SDH, FUS, CREB3L2, FUS-CREB3L1, NF1, CDKN2A, EED, SUZ12, HEY1, NCOA2, NAB2, STAT6, SS18, SSX1, SSX2, SSX4, CSF1, TP53, PTEN, IDH1/2

    NCCN guideline:

    Alveolar RMS:  PAX3-FOXO1, PAX 7-FOXO1, PAX3-AFX, PAX3-NCOA1, PAX3-NCOA2, PAX3-INO80D, MYOD1 mutations

    Desmoplastic small round cell: EWSR1-WT1

    Ewing Sarcoma: EWSR1-FLI1, EWSR1-ERG, EWSR1-FEV, EWSR1-ETV1, EWSR1-E1AF, EWSR1-ZSG, FUS-ERG

    Undifferentiated round cell: CIC-DUX4, BCOR-CCNB

    Embryonal RMS:  MYOD1, PIK3CA, RAS mutations

    PEComa: Loss of TSC1, TSC2, or TFE3 fusion

    Atypical lipomatous tumor/well-differentiated liposarcoma (ALT/WDLS)/ Dedifferentiated liposarcoma: Amplification of region 12q14-15, including MDM2, CDK4, HMGA2, SAS, GLI

    Myxoid/round cell liposarcoma: FUS-DDIT3EWSR1-DDIT3

    Alveolar soft part sarcoma: ASPL-TFE3

    Angiomatoid fibrous histiocytoma: EWSR1-ATF1EWSR1-CREB1FUS-ATF1

    Clear cell sarcoma: EWSR1-ATF1EWSR1-CREB1

    Congenital/infantile fibrosarcoma: ETV6-NTRK3

    Dermatofibrosarcoma protuberans: COL1A1-PDGFB

    Desmoid fibromatosis: CTNNB1 or APC mutations

    High-grade endometrial stromal sarcoma: YWHAE-NUTM2 ZC3H7B-BCOR

    Epithelioid hemangioendothelioma: WWTR1-CAMTA1YAP1 - TFE3

    Inflammatory myofibroblastic tumors: ALK, ROS1 and NTRK3, TPM3-ALK5TPM4-ALK5CLTC-ALK5RANBP2-ALK5CARS-ALK5ATIC-ALK5

    Epithelioid sarcoma/Extrarenal rhabdoid tumor: SMARCB (INI1) deletion

    Extraskeletal myxoid chondrosarcoma: EWSR1-NR4A3 TAF2N-NR4A3 TCF12-NR4A3 TFG-NR4A3

    GIST/CARmey-Sratakis syndrome: KIT or PDGFRA Germline SDH subunit mutations

    Low-grade fibromyxoid sarcoma: FUS-CREB3L2FUS-CREB3L1

    Malignant peripheral nerve sheath tumor:  NF1, CDKN2A, EED, SUZ12

    Mesenchymal chondrosarcoma: HEY1 - NCOA2

    Solitary fibrous tumor: NAB2 - STAT6

    Synovial sarcoma: SS18-SSX1SS18-SSX2SS18-SSX4

    Tenosynovial giant cell tumor/pigmented villonodular synovitis (TGCT/PVNS): CSF1

    Prognosis  PAX3, FOXO1, PAX 7, PAX3, AFX, NCOA1, NCOA2, INO80D, MYOD1,  EWSR1, WT1, FLI1, ERG, FEV, ETV1, E1AF, ZSG, FUS, CIC, DUX4, BCOR, CCNB, MYOD1, PIK3CA, RAS, TSC1, TSC2, TFE3, MDM2, CDK4, HMGA2, SAS, GLI, DDIT3, ASPL, TFE3, ATF1, CREB1, ATF1, CREB1, ETV6, NTRK3, COL1A1, PDGFB, CTNNB1, APC, YWHAE, NUTM2, ZC3H7B, WWTR1, CAMTA1, YAP1, TFE3, ALK, ROS1, NTRK3, TPM3, TPM4, CLTC, RANBP2, CARS, ATIC, SMARCB (INI1), NR4A3, TAF2N, NR4A3, TCF12, NR4A3, TFG-NR4A3, KIT, PDGFRA, SDH, FUS, CREB3L2, FUS-CREB3L1, NF1, CDKN2A, EED, SUZ12, HEY1, NCOA2, NAB2, STAT6, SS18, SSX1, SSX2, SSX4, CSF1, IDH1/2See diagnostics
    Selecting therapy  PAX3, FOXO1, PAX 7, PAX3, AFX, , NCOA1, NCOA2, INO80D, MYOD1,  EWSR1, WT1, FLI1, ERG, FEV, , ETV1, E1AF, ZSG, FUS, CIC, DUX4, BCOR, CCNB, MYOD1, PIK3CA, RAS, TSC1, TSC2, TFE3, MDM2, CDK4, HMGA2, SAS, GLI, DDIT3, ASPL, TFE3, , ATF1, CREB1, ATF1, CREB1, ETV6, NTRK3, COL1A1, PDGFB, CTNNB1, APC, YWHAE, NUTM2, ZC3H7B, WWTR1, CAMTA1, YAP1, TFE3, ALK, ROS1, NTRK3, TPM3, TPM4, CLTC, RANBP2, CARS, ATIC, SMARCB (INI1), NR4A3, TAF2N, NR4A3, TCF12, NR4A3, TFG-NR4A3, KIT, PDGFRA, SDH, FUS, CREB3L2, FUS-CREB3L1, NF1, CDKN2A, EED, SUZ12, HEY1, NCOA2, NAB2, STAT6, SS18, SSX1, SSX2, SSX4, CSF1, IDH1/2

    IDH1/2 in chondrosarcoma

    NCCN guideline:

    See diagnostics.

    Follow-up and minimal residual disease (MRD)  PAX3, FOXO1, PAX 7, PAX3, AFX, NCOA1, NCOA2, INO80D, MYOD1,  EWSR1, WT1, FLI1, ERG, FEV, ETV1, E1AF, ZSG, FUS, CIC, DUX4, BCOR, CCNB, MYOD1, PIK3CA, RAS, TSC1, TSC2, TFE3, MDM2, CDK4, HMGA2, SAS, GLI, DDIT3, ASPL, TFE3, ATF1, CREB1, ATF1, CREB1, ETV6, NTRK3, COL1A1, PDGFB, CTNNB1, APC, YWHAE, NUTM2, ZC3H7B, WWTR1, CAMTA1, YAP1, TFE3, ALK, ROS1, NTRK3, TPM3, TPM4, CLTC, RANBP2, CARS, ATIC, SMARCB (INI1), NR4A3, TAF2N, NR4A3, TCF12, NR4A3, TFG-NR4A3, KIT, PDGFRA, SDH, FUS, CREB3L2, FUS-CREB3L1, NF1, CDKN2A, EED, SUZ12, HEY1, NCOA2, NAB2, STAT6, SS18, SSX1, SSX2, SSX4, CSF1, IDH1/2Detecting mutations

    Recommended Test:

    1)Solid Tumor Profile PLUS™ (FFPE block or unstained slides)

    2)Liquid Biopsy Solid Tumor™ (Liquid Biopsy) (Peripheral blood/cfDNA)

    Clinical Indication
    Genes/Molecular Abnormality
    Remarks
    Aiding in establishing diagnosis/stratificationIDH1/2 (grade II & IIIastrocytoma), MGMT methylation, Codeletion of 1p, 19q/t(1;19), ATRX deletion/Mutation (tumor should not be diagnosed as Oligodendroma if IDH+ and 1p/19q+), TERT mutation/Expression, H3F3A mutation (Midline glioma), BRAF/ BRAF-KIAA1549 (fusion/mutation), RELA-C11orf95 fusion (ependydoma), WNT, TP53, CTNNB1, APC (Medulloblastoma classification, 6q-, EGFR amplification/mutation

    NCCN guidelines:

    With the use of genetic and molecular testing, histologically similar CNS neoplasms can be differentiated more accurately in terms of prognosis and, in some instances, response to different therapies

    PrognosisIDH1/2 (grade II & IIIastrocytoma), MGMT methylation, Codeletion of 1p, 19q/t(1;19), ATRX deletion/Mutation (tumor should not be diagnosed as Oligodendroma if IDH+ and 1p/19q+), TERT mutation/Expression, H3F3A mutation (Midline glioma), BRAF/ BRAF-KIAA1549 (fusion/mutation), RELA-C11orf95 fusion (ependydoma), WNT, TP53, CTNNB1, APC (Medulloblastoma classification, 6q-, EGFR amplification/mutationSee diagnostics
    Selecting therapyIDH1/2 (grade II & IIIastrocytoma), MGMT methylation, codeletion of 1p, 19q/t(1;19), ATRX deletion/mutation (tumor should not be diagnosed as Oligodendroma if IDH+ and 1p/19q+), TERT mutation/Expression, H3F3A mutation (Midline glioma), BRAF/ BRAF-KIAA1549 (fusion/mutation), RELA-C11orf95 fusion (ependydoma), WNT, TP53, CTNNB1, APC (Medulloblastoma classification, 6q-, EGFR amplification/mutation

    NCCN guidelines:

    There are no identified targeted agents with demonstrated efficacy in glioblastoma. However, the panel encourages molecular testing of tumor because if a driver mutation is detected, it may be reasonable to treat with a targeted therapy on a compassionate use basis and/or the patient may have more treatment options in the context of a clinical trial. Molecular testing also has a valuable role in improving diagnostic accuracy and prognostic stratification that may inform treatment selection

    Follow-up and minimal residual disease (MRD)IDH1/2 (grade II & IIIastrocytoma), MGMT methylation, Codeletion of 1p, 19q/t(1;19), ATRX deletion/Mutation (tumor should not be diagnosed as Oligodendroma if IDH+ and 1p/19q+), TERT mutation/Expression, H3F3A mutation (Midline glioma), BRAF/ BRAF-KIAA1549 (fusion/mutation), RELA-C11orf95 fusion (ependydoma), WNT, TP53, CTNNB1, APC (Medulloblastoma classification, 6q-, EGFR amplification/mutationDetecting mutations

    Recommended Test:

    1)Solid Tumor Profile PLUS™ (FFPE block or unstained slides)

    2)Liquid Biopsy Solid Tumor™ (Liquid Biopsy) (Peripheral blood/cfDNA)

    Clinical Indication
    Genes/Molecular Abnormality
    Remarks
    Aiding in establishing diagnosis/stratificationPIK3CA, BRAF, KRAS, MET, NRA, HRAS, PTEN, BRCA1/2, EGFR, ERBB2, NOTCH1, KEAP1, CCND1, SMAD4, KIT, NTRK1/2/3, HPV, TP53, CDKN2A, FBXW7, RB1, TRAF3, FGFR1/2/3/4, TMB, MSI 
    PrognosisPIK3CA, BRAF, KRAS, MET, NRA, HRAS, PTEN, BRCA1/2, EGFR, ERBB2, NOTCH1, KEAP1, CCND1, SMAD4, KIT, NTRK1/2/3, HPV, TP53, CDKN2A, FBXW7, RB1, TRAF3, FGFR1/2/3/4, TMB, MSIMolecular classification based on gene expression: Classical, mesenchymal, and atypical.
    Selecting therapyPIK3CA, BRAF, KRAS, MET, NRA, HRAS, PTEN, BRCA1/2, EGFR, ERBB2, NOTCH1, KEAP1, CCND1, SMAD4, KIT, NTRK1/2/3, HPV, TP53, CDKN2A, FBXW7, RB1, TRAF3, FGFR1/2/3/4, TMB, MSI

    NCCN guidelines:

    Immunotherapy, targeted therapy, and combination immunotherapy + targeted therapy

    Follow-up and minimal residual disease (MRD)PIK3CA, BRAF, KRAS, MET, NRA, HRAS, PTEN, BRCA1/2, EGFR, ERBB2, NOTCH1, KEAP1, CCND1, SMAD4, KIT, NTRK1/2/3, HPV, TP53, CDKN2A, FBXW7, RB1, TRAF3, FGFR1/2/3/4, TMB, MSIDetecting mutations

    Recommended Test:

    1)Solid Tumor Profile PLUS™ (FFPE block or slides)

    2)Liquid Biopsy Solid Tumor™ (Liquid Biopsy) (Peripheral blood/cfDNA)

    Clinical Indication
    Genes/Molecular Abnormality
    Remarks
    Aiding in establishing diagnosis/stratificationPIK3CA, BRAF, KRAS, MET. NRA, HRAS, PTEN, BRCA1/2, EGFR, ERBB2, NOTCH1, KEAP1, CCND1, SMAD4, KIT, NTRK1/2/3, HPV, TP53, CDKN2A, FBXW7, RB1, TRAF3, FGFR1/2/3/4, TMB, MSI

    NCCN guidelines:

    The panel recommends that molecular/genomic testing be performed for stages IVA and IVB bladder cancer and may be considered for stage IIIB. This testing should be performed only in laboratories that are certified under the Clinical Laboratory Improvement Amendments of 1988 (CLIA-88) as qualified to perform highly complex molecular pathology testing.186 The NCCN bladder cancer panel recommends that molecular/genomic testing be carried out early, ideally at diagnosis of advanced bladder cancer, in order to facilitate treatment decision-making and to prevent delays in administering later lines of therapy. In addition to determining eligibility for FDA-approved therapies, molecular/genomic testing may be used to screen for clinical trial eligibility.

    PrognosisPIK3CA, BRAF, KRAS, MET. NRA, HRAS, PTEN, BRCA1/2, EGFR, ERBB2, NOTCH1, KEAP1, CCND1, SMAD4, KIT, NTRK1/2/3, HPV, TP53, CDKN2A, FBXW7, RB1, TRAF3, FGFR1/2/3/4, TMB, MSINCCN guidelines:
    Within each category of disease, more refined methods to determine prognosis and guide management, based on molecular staging, are under development with the goal of optimizing each patient’s likelihood of cure and chance for organ preservation.
    Selecting therapyPIK3CA, BRAF, KRAS, MET, NRA, HRAS, PTEN, BRCA1/2, EGFR, ERBB2, NOTCH1, KEAP1, CCND1, SMAD4, KIT, NTRK1/2/3, HPV, TP53, CDKN2A, FBXW7, RB1, TRAF3, FGFR1/2/3/4, TMB, MSI

    NCCN guidelines:

    Immunotherapy, targeted therapy, and combination immunotherapy + targeted therapy

    Follow-up and minimal residual disease (MRD)PIK3CA, BRAF, KRAS, MET, NRA, HRAS, PTEN, BRCA1/2, EGFR, ERBB2, NOTCH1, KEAP1, CCND1, SMAD4, KIT, NTRK1/2/3, HPV, TP53, CDKN2A, FBXW7, RB1, TRAF3, FGFR1/2/3/4, TMB, MSIDetecting mutations

    Recommended Test:

    1)Solid Tumor Profile PLUS™ (FFPE block or unstained slides)

    2)Liquid Biopsy Solid Tumor™ (Liquid Biopsy) (Peripheral blood/cfDNA)

    Clinical Indication
    Genes/Molecular Abnormality
    Remarks
    Aiding in establishing diagnosis/stratification

    ERBB2 (HER2) amplification, Mutation, overexpression

    MSI, BRCA1, BRCA2, ATM, TP53, PIK3CA,

    BRAF, KRAS, NRNA, PD-L1,

    EGFR amplification, NTRK 1/2/3, FGFR1/2/3/4, ERBB3, MET amplification, TMB, KEAP1, STK11, NF1, SETD2, RBM10, ARID1A, SMARCA4, RB1, CDKN2A, PTEN, AKT1, TMB, MSI

    Copy number change: CCND1, TOP2A, PPM1D, MYC, AKT1, CDK9, KRAS, MDM2, CDKN2A, RB1, PTEN, and TP53

    NCCN guidelines:

    Tumor molecular testing is recommended prior to initiation of therapy for persistent/recurrent disease. Validated molecular testing should be performed in a CLIA-approved facility using the most recent available tumor tissue. Testing recommended to include at least: BRCA1/2, and MSI or dMMR if not previously done. Evaluation of homologous recombination deficiency can be considered. Additional somatic tumor testing can be considered at the physician’s discretion to identify genetic alterations for which FDA-approved tumor-specific or tumor-agnostic targeted therapy options exist.

    Prognosis

    ERBB2 (HER2) amplification, Mutation, overexpression

    MSI, BRCA1, BRCA2, ATM, TP53, PIK3CA,

    BRAF, KRAS, NRNA, PD-L1,

    EGFR amplification, NTRK 1/2/3, FGFR1/2/3/4, ERBB3, MET amplification, TMB, KEAP1, STK11, NF1, SETD2, RBM10, ARID1A, SMARCA4, RB1, CDKN2A, PTEN, AKT1, TMB, MSI

    Copy number change: CCND1, TOP2A, PPM1D, MYC, AKT1, CDK9, KRAS, MDM2, CDKN2A, RB1, PTEN, and TP53

    NCCN guidelines:
    Molecular characterization of clear cell, mucinous, or low-grade (grade 1) serous tumors suggests that mutations in these histologies are different from those in higher grade tumors.125-127 Ovarian cancer can be divided into Types 1 and 2 based on these molecular alterations. Data suggest that serous tumors can be categorized as either low grade (most grade 1 serous tumors) or high grade (most grade 2 or 3 serous tumors).87,89-92,128,129 High-grade endometrioid tumors are difficult to distinguish from high-grade serous tumors.
    Selecting therapy

    ERBB2 (HER2) amplification, Mutation, overexpression

    MSI, BRCA1, BRCA2, ATM, TP53, PIK3CA,

    BRAF, KRAS, NRNA, PD-L1,

    EGFR amplification, NTRK 1/2/3, FGFR1/2/3/4, ERBB3, MET amplification, TMB, KEAP1, STK11, NF1, SETD2, RBM10, ARID1A, SMARCA4, RB1, CDKN2A, PTEN, AKT1, TMB, MSI

    Copy number change: CCND1, TOP2A, PPM1D, MYC, AKT1, CDK9, KRAS, MDM2, CDKN2A, RB1, PTEN, and TP53

    NCCN guidelines:

    Immunotherapy, targeted therapy, and combination immunotherapy + targeted therapy

    Follow-up and minimal residual disease (MRD)

    ERBB2 (HER2) amplification, Mutation, overexpression

    MSI, BRCA1, BRCA2, ATM, TP53, PIK3CA,

    BRAF, KRAS, NRNA, PD-L1,

    EGFR amplification, NTRK 1/2/3, FGFR1/2/3/4, ERBB3, MET amplification, TMB, KEAP1, STK11, NF1, SETD2, RBM10, ARID1A, SMARCA4, RB1, CDKN2A, PTEN, AKT1, TMB, MSI

    Copy number change: CCND1, TOP2A, PPM1D, MYC, AKT1, CDK9, KRAS, MDM2, CDKN2A, RB1, PTEN, and TP53

    Detecting mutations and copy number variation.

    Recommended Test:

    1) Solid Tumor Profile PLUS™ (FFPE block or unstained slides)

    2) Liquid Biopsy Solid Tumor™ (Liquid Biopsy) (Peripheral blood/cfDNA)

    Clinical Indication
    Genes/Molecular Abnormality
    Remarks
    Aiding in establishing diagnosis/stratification

    CDH1 (Hereditary diffuse gastric cancer), SMAD4 (Juvenile polyposis syndrome), STK11 (Peutz-Jeghers syndrome), PTEN (Cowden), PMS2, MSH2, EPCAM, MLH1, MSH6, (Lynch), MUTYH, APC, ERBB2 (HER2) amplification, mutation, over expression

    MSI, BRCA1, BRCA2, ATM, TP53, PIK3CA,

    BRAF, KRAS, NRNA, PD-L1,

    EGFR amplification, NTRK 1/2/3, FGFR1/2/3/4, ERBB3, MET amplification, TMB, KEAP1, NF1, SETD2, RBM10, ARID1A, SMARCA4, RB1, CDKN2A, AKT1, TMB

    NCCN guideline:

    Next-generation sequencing (NGS) offers the opportunity to assess numerous mutations simultaneously, along with other molecular events such as amplification, deletions, tumor mutation burden, and microsatellite instability status. When limited diagnostic tissue is available for testing and the patient is unable to undergo additional procedures, NGS can be considered instead of sequential testing for single biomarkers.

    Prognosis

    CDH1 (Hereditary diffuse gastric cancer), SMAD4 (Juvenile polyposis syndrome), STK11 (Peutz-Jeghers syndrome), PTEN (Cowden), PMS2, MSH2, EPCAM, MLH1, MSH6, (Lynch), MUTYH, APC, ERBB2 (HER2) amplification, Mutation, overexpression

    MSI, BRCA1, BRCA2, ATM, TP53, PIK3CA,

    BRAF, KRAS, NRNA, PD-L1,

    EGFR amplification, NTRK 1/2/3, FGFR1/2/3/4, ERBB3, MET amplification, TMB, KEAP1, NF1, SETD2, RBM10, ARID1A, SMARCA4, RB1, CDKN2A, AKT1, TMB

    NCCN guideline:

    HER2, inherited susceptibility, MSI, TMB

    Selecting therapy

    CDH1 (Hereditary diffuse gastric cancer), SMAD4 (Juvenile polyposis syndrome), STK11 (Peutz-Jeghers syndrome), PTEN (Cowden), PMS2, MSH2, EPCAM, MLH1, MSH6, (Lynch), MUTYH, APC, ERBB2 (HER2) amplification, mutation, over expression

    MSI, BRCA1, BRCA2, ATM, TP53, PIK3CA,

    BRAF, KRAS, NRNA, PD-L1,

    EGFR amplification, NTRK 1/2/3, FGFR1/2/3/4, ERBB3, MET amplification, TMB, KEAP1, NF1, SETD2, RBM10, ARID1A, SMARCA4, RB1, CDKN2A, AKT1, TMB

    NCCN guideline:

    MSI, TMB, RAS/RAF:

    Immunotherapy, targeted therapy, and combination immunotherapy + targeted therapy

    Follow-up and minimal residual disease (MRD)

    CDH1 (Hereditary diffuse gastric cancer), SMAD4 (Juvenile polyposis syndrome), STK11 (Peutz-Jeghers syndrome), PTEN (Cowden), PMS2, MSH2, EPCAM, MLH1, MSH6, (Lynch), MUTYH, APC, ERBB2 (HER2) amplification, mutation, overexpression

    BRCA1, BRCA2, ATM, TP53, PIK3CA,

    BRAF, KRAS, NRNA, PD-L1,

    EGFR amplification, NTRK 1/2/3, FGFR1/2/3/4, ERBB3, MET amplification, TMB, KEAP1, NF1, SETD2, RBM10, ARID1A, SMARCA4, RB1, CDKN2A, AKT1

    Detecting mutations

    Recommended Test:

    1) Solid Tumor Profile PLUS™ (FFPE block or unstained slides)

    2) Liquid Biopsy Solid Tumor™ (Liquid Biopsy) (Peripheral blood/cfDNA)

    Clinical Indication
    Genes/Molecular Abnormality
    Remarks
    Aiding in establishing diagnosis/stratification

    TMPRSS2-ERG, CDH1 (Hereditary diffuse gastric cancer), SMAD4 (Juvenile polyposis syndrome), STK11 (Peutz-Jeghers syndrome), PTEN (Cowden), PMS2, MSH2, EPCAM, MLH1, MSH6, (Lynch), MUTYH, APC, ERBB2 (HER2) amplification, Mutation, overexpression

    MSI, BRCA1, BRCA2, ATM, TP53, PIK3CA,

    BRAF, KRAS, NRNA, PD-L1,

    EGFR amplification, NTRK 1/2/3, FGFR1/2/3/4, ERBB3, MET amplification, TMB, KEAP1, NF1, SETD2, RBM10, ARID1A, SMARCA4, RB1, CDKN2A, AKT1

    NCCN guideline:

    Consider cancer predisposition next-generation sequencing (NGS) panel testing, which includes BRCA1, BRCA2, ATM, PALB2, CHEK2, MLH1, MSH2, MSH6, and PMS2.  Additional genes may be appropriate depending on clinical context. For example, HOXB13

    Prognosis

    TMPRSS2-ERG, CDH1 (Hereditary diffuse gastric cancer), SMAD4 (Juvenile polyposis syndrome), STK11 (Peutz-Jeghers syndrome), PTEN (Cowden), PMS2, MSH2, EPCAM, MLH1, MSH6, (Lynch), MUTYH, APC, ERBB2 (HER2) amplification, mutation, overexpression

    MSI, BRCA1, BRCA2, ATM, TP53, PIK3CA,

    BRAF, KRAS, NRNA, PD-L1,

    EGFR amplification, NTRK 1/2/3, FGFR1/2/3/4, ERBB3, MET amplification, TMB, KEAP1, NF1, SETD2, RBM10, ARID1A, SMARCA4, RB1, CDKN2A, AKT1

    Detecting mutations and copy number variation for stratification predicting response
    Selecting therapy

    TMPRSS2-ERG, CDH1 (Hereditary diffuse gastric cancer), SMAD4 (Juvenile polyposis syndrome), STK11 (Peutz-Jeghers syndrome), PTEN (Cowden), PMS2, MSH2, EPCAM, MLH1, MSH6, (Lynch), MUTYH, APC, ERBB2 (HER2) amplification, mutation, over expression

    MSI, BRCA1, BRCA2, ATM, TP53, PIK3CA,

    BRAF, KRAS, NRNA, PD-L1,

    EGFR amplification, NTRK 1/2/3, FGFR1/2/3/4, ERBB3, MET amplification, TMB, KEAP1, NF1, SETD2, RBM10, ARID1A, SMARCA4, RB1, CDKN2A, AKT1

    Immunotherapy, PARP inhibitors
    Follow-up and minimal residual disease (MRD)

    TMPRSS2-ERG, CDH1 (Hereditary diffuse gastric cancer), SMAD4 (Juvenile polyposis syndrome), STK11 (Peutz-Jeghers syndrome), PTEN (Cowden), PMS2, MSH2, EPCAM, MLH1, MSH6, (Lynch), MUTYH, APC, ERBB2 (HER2) amplification, mutation, overexpression

    MSI, BRCA1, BRCA2, ATM, TP53, PIK3CA,

    BRAF, KRAS, NRNA, PD-L1,

    EGFR amplification, NTRK 1/2/3, FGFR1/2/3/4, ERBB3, MET amplification, TMB, KEAP1, NF1, SETD2, RBM10, ARID1A, SMARCA4, RB1, CDKN2A, AKT1

     

    Recommended Test:

    1) Solid Tumor Profile PLUS™ (FFPE block or unstained slides)

    2) Liquid Biopsy Solid Tumor™ (Liquid Biopsy) (Peripheral blood/cfDNA)

    Clinical Indication
    Genes/Molecular Abnormality
    Remarks
    Aiding in establishing diagnosis/stratificationKIT (exons: 9,11,13,17), PDGFRA, NF1, KRAS, NRAS, HRAS, BRAF, SDHB, SDHC, CDKN2A, CDKN2B, RB1, TP53, CUL1, ATM

    Detecting mutations and copy number variation

    PrognosisKIT (exons: 9,11,13,17), PDGFRA, NF1, KRAS, NRAS, HRAS, BRAF, SDHB, SDHC, CDKN2A, CDKN2B, RB1, TP53, CUL1, ATMHeinrich et al (https://doi.org/10.1186/s13569-019-0112-7)
    Selecting therapyKIT (exons: 9,11,13,17), PDGFRA, NF1, KRAS, NRAS, HRAS, BRAF, SDHB, SDHC, CDKN2A, CDKN2B, RB1, TP53, CUL1, ATMKinase inhibitors
    Follow-up and minimal residual disease (MRD)KIT (exons: 9,11,13,17), PDGFRA, NF1, KRAS, NRAS, HRAS, BRAF, SDHB, SDHC, CDKN2A, CDKN2B, RB1, TP53, CUL1, ATM 

    Recommended Test:

    1) Solid Tumor Profile PLUS™ (FFPE block or unstained slides)

    2) Liquid Biopsy Solid Tumor™ (Liquid Biopsy) (Peripheral blood/cfDNA)

    Clinical Indication
    Genes/Molecular Abnormality
    Remarks
    Aiding in establishing diagnosis/stratification

    GEP (AI), MSI, TMB, fusions: ALK, ROS1, RET, TMPRSS2-ERG, NTRK1/2/3, FGFR1/2/3/4 mutations: CDH1 (Hereditary diffuse gastric cancer), SMAD4 (Juvenile polyposis syndrome), STK11 (Peutz-Jeghers syndrome), PTEN (Cowden), PMS2, MSH2, EPCAM, MLH1, MSH6, (Lynch), MUTYH,APC, ERBB2 (HER2) amplification, mutation, over expression

    BRCA1, BRCA2, ATM, TP53, PIK3CA, HRAS,

    BRAF, KRAS, NRNA, PD-L1,

    EGFR amplification, ERBB3, MET amplification, KEAP1, NF1, SETD2, RBM10, ARID1A, SMARCA4, RB1, CDKN2A, AKT1

    NCCN guideline:

    Since the identification of clinically relevant genomic alterations has the potential to influence therapy options, use of standardized comprehensive NGS assays may help identify novel treatment paradigms to address the limited treatment options and poor prognoses of patients with CUP

    Prognosis

    GEP (AI), MSI, TMB, fusions: ALK, ROS1, RET, TMPRSS2-ERG, NTRK1/2/3, FGFR1/2/3/4 mutations: CDH1 (Hereditary diffuse gastric cancer), SMAD4 (Juvenile polyposis syndrome), STK11 (Peutz-Jeghers syndrome), PTEN (Cowden), PMS2, MSH2, EPCAM, MLH1, MSH6, (Lynch), MUTYH,APC, ERBB2 (HER2) amplification, mutation, over expression

    BRCA1, BRCA2, ATM, TP53, PIK3CA, HRAS,

    BRAF, KRAS, NRNA, PD-L1,

    EGFR amplification, ERBB3, MET amplification, KEAP1, NF1, SETD2, RBM10, ARID1A, SMARCA4, RB1, CDKN2A, AKT1

    Detecting mutations and copy number variation for stratification predicting response
    Selecting therapy

    GEP (AI), MSI, TMB, fusions: ALK, ROS1, RET, TMPRSS2-ERG, NTRK1/2/3, FGFR1/2/3/4 mutations: CDH1 (Hereditary diffuse gastric cancer), SMAD4 (Juvenile polyposis syndrome), STK11 (Peutz-Jeghers syndrome), PTEN (Cowden), PMS2, MSH2, EPCAM, MLH1, MSH6, (Lynch), MUTYH, APC, ERBB2 (HER2) amplification, mutation, overexpression

    BRCA1, BRCA2, ATM, TP53, PIK3CA, HRAS,

    BRAF, KRAS, NRNA, PD-L1,

    EGFR amplification, ERBB3, MET amplification, KEAP1, NF1, SETD2, RBM10, ARID1A, SMARCA4, RB1, CDKN2A, AKT1

    Immunotherapy, Targeted therapy
    Follow-up and minimal residual disease (MRD)

    CDH1 (Hereditary diffuse gastric cancer), SMAD4 (Juvenile polyposis syndrome), STK11 (Peutz-Jeghers syndrome), PTEN (Cowden), PMS2, MSH2, EPCAM, MLH1, MSH6, (Lynch), MUTYH, APC, ERBB2 (HER2) amplification, mutation, over expression

    BRCA1, BRCA2, ATM, TP53, PIK3CA, HRAS

    BRAF, KRAS, NRNA, PD-L1,

    EGFR amplification, ERBB3, MET amplification, KEAP1, NF1, SETD2, RBM10, ARID1A, SMARCA4, RB1, CDKN2A, AKT1

     

    Hematology

    Recommended Test:
    Hematology Profile™ (Bone marrow or peripheral blood/cfDNA)

    Clinical Indication
    Genes/Molecular Abnormality
    Remarks
    Aiding in establishing diagnosisDNMT3A, ASXL1, EZH2, SF3B1, SRSF2, U2AF1, ZRSR2, RUNX1, TP53, STAG2, NRAS, CBL, NF1, JAK2, CALR, MPL, ETV6, GATA2, IDH2, SETBP1, BCOR, FLT3, WT1, NPM1, STAT3NCCN guidelines: "Bone marrow or peripheral blood cells should be assayed for MDS-associated gene mutations using gene panels that include genes listed on MDS-C. These gene mutations can establish the presence of clonal hematopoiesis, which can help exclude benign causes of cytopenias in cases with non-diagnostic morphology, but do not establish a diagnosis of MDS in the absence of clinical diagnostic criteria"
    Distinguishing MDS from CHIP or CCUS VAF and type of mutated genes NCCN guidelines:  >10% VAF and >=2 mutations or mutations in spliceosome or RUNX1 or JAK2 are predictor of MDS, MPN, or AML. TET2, DNMT3A, or ASXL1 have less prediction and may imply CHIP or CCUS
     DNMT3A, TET2, ASXL1, RUNX1, PPM1D, and TP53Mutations in these genes with VAF<10% are more associated with CHIP and CCUS
    Distinguishing MDS from LGLSTAT3 mutationNCCN guideline: distinguish LGL from MDS
    Subclassification (NCCN guidelines)TET2, SRSF2, ASXL1, RUNX1, NRAS, CBLCMML-0/CMML-1/CMML-2
    SETBP1, ETNK1aCML
    PTPN11, NF1, NRAS, KRAS, CBL, SETBP1, JAK3JMML
    TET2, NRAS, RUNX1, CBL, SETBP1, ASXL1MDS/MPN
    SF3B1, JAK2, MPL, CALRMDS/MPN-T
    CSF3RCNL
    PrognosisDNMT3A, ASXL1, EZH2, SF3B1, SRSF2, U2AF1, ZRSR2, RUNX1, TP53, STAG2, NRAS, CBL, NF1, JAK2, CALR, MPL, ETV6, GATA2, IDH2, SETBP1, BCOR, FLT3, WT1, NPM1NCCN guideline: Mutations in these genes are associated with more aggressive disease
    PrognosisIDH1, PHF6, PPM1D, PPM1D, TET2NCCN guideline: Mutations in these genes have neutral effects on prognosis
    HeterogeneityVAFUsed for monitoring, evolution into more aggressive disease, and evaluating efficacy of targeted therapy.
    Aiding in ruling out hereditary predisposition (Gene mutations associated with hereditary myeloid malignancies).These are used to recommend testing another tissue to rule in or out hereditary predisposition if these genes VAF around 50% and all other mutations are at significantly lower VAF
    CEBPA, DDX41, ANKRD, ETV6AML/MDS and other hematologic neoplasms
    GATA2MONO syndrome
    RUNX1Thrombocytopenia with mild bleeding
    SAMD9MIRAGE syndrome
    SAMD9LAtaxia-Pancytopenia
    SRP72Congenital sensorineural deafness.
    RPL5, RPL11, RPL15, RPL23, RPL26, RPL27, RPL31, RPL35A, RPS7, RPS10, RPS17, RPS19, RPS24, RPS26, RPS27, RPS28, RPS29, TSR2, GATA1Diamond-Blackfan anemia
    FANCA, FANCB, FANCC, FANCD1/BRCA2, FANCD2, FANCDE, FANCF, FANCG, FANCI, FANCJ/BRIP1/BACH1, FANCL, FANCM, FANCN/PALB2, FANCO/RAD51C, FANCP/SLX4, FANQ/ERCC4, FANCR/RAD51, FANCS/BRCA1, FANCT/UNE2T, FANCU/XRCC2, FANCV/REV7Fanconi anemia
    SBDS, EFL1, DNAJC21Shwachman-Diamond syndrome
    ACD, CTC1, DKC1, NAF1, NHP2, NOP10, PARN, POT1, RTEL1, TERC, TERT, TINF2, USB1, WRAP53Telomere biology disorders
    ELANE, G6PC3, GFI1, HAX1Congenital neutropenia
    GATA1Down syndrome, acute megakaryocytic leukemia
    TP53AML/MDS in patients with Li-Fraumeni syndrome
    EPCAM, MLH1, MSH2, MSH6, PMS2AML/MDS in constitutional mismatch repair deficiency
    BRCA1, BRCA2AML/MDS in hereditary breast and ovarian cancer
    CBL, KRAS, NF1, PTPN11AML/MDS/CMML/AMML in patients with RASopathies
    BLMAML/MDS in Bloom syndrome
    Aiding in deciding therapeutic approachFLT3, IDH1/2Presence of mutation any of these genes will trigger recommendation of ordering the single gene FDA-cleared test for confirmation and potential use of targeted therapy.
    TET2NCCN guidelines: "TET mutations have been shown to impact the response to hypomethylating agents. Patients with mutated TET2 had an 82% response rate to AzaC compared to 45% of patients with wildtype TET2(P = .007)."
    Aiding in monitoringVAFDisappearance or emergence of clones that may affect targeted therapy or overall therapeutic approach.
    Aiding in selecting potential clinical trialsFLT3 inhibitors, KIT inhibitors, PI3K/AKT/mTOR inhibitors, aurora and polo-like kinase inhibitors, CDK4/6 inhibitors, CHK1, WEE1, MPS1 inhibitors, SRC and HCK inhibitors, HDAC inhibitors, IDH1 inhibitors, IDH2 inhibitors, DOT1L inhibitors, BET-bromodomain inhibitors, EVI1 inhibitors, NPM1 inhibitors, hedgehog inhibitors, spliceosome inhibitors.

    Recommended Tests:

    1) Hematology Profile™ (Bone marrow or peripheral blood/cfDNA)

    2) Order Hematology Profile PLUS™ if chromosomal translocation is expected (Bone marrow or peripheral blood)

    3) Minimal residual disease (MRD): Hematology Profile™ (Peripheral blood/cfDNA)

    Clinical Indication
    Genes/Molecular Abnormality
    Remarks
    Aiding in establishing diagnosisc-KIT, FLT3-ITD, FLT3-TKD, NPM1, CEBPA, IDH1/IDH2, RUNX1, ASXL1, and TP53NCCN guidelines: "Several gene mutations are associated with specific prognoses in a subset of patients (category 2A), and may guide treatment decisions (category 2B). Presently, c-KIT, FLT3-ITD, FLT3-TKD, NPM1, CEBPA, IDH1/IDH2, RUNX1, ASXL1, and TP53 are included in this group. All patients should be tested for mutations in these genes, and multiplex gene panels and next-generation sequencing (NGS) analysis can be obtained to develop a more comprehensive prognostic assessment. FLT3 mutation status ideally should be resulted rapidly to allow for addition of FLT3 inhibitor (midostaurin) on day 8 of upfront intensive chemotherapy."
    Aiding in distinguishing de novo from secondary AMLAXL1, SF3B1, DNMT3A, TET2, SRSF2, EZH2, BCOR, STAG2ELN recommendation; "Mutations associated with secondary AML occur in genes encoding SRSF2, SF3B1, U2AF1, and ZRSR2 (splicing factors); ASXL1, EZH2, and BCOR (epigenetic regulators); and STAG2 (a member of the cohesin complex)."
    Determining heterogeneitycomparing VAF between mutated genesRelevant in selecting targeted therapy, monitoring and understanding clinical course.
    Distinguishing between transient myeloproliferative disorder Vs megakaryocytic leukemia in patients with down syndromeGATA1 mutation
    Ruling out hereditary predisposition (Gene mutations associated with hereditary myeloid malignancies)See MDS description
    Aiding in deciding therapeutic approachKITNCCN guideline: Potential adding Dasatinib in CBF leukemia with KIT mutation.
    FLT3, IDH1/2Presence of mutation any of these genes will trigger recommendation of ordering the single gene FDA-cleared test for confirmation and potential use of targeted therapy.
    TP53Allo-hematologic stem cell transplant or clinical trials.
    Determining molecular responseMolecular profiling abnormalitiesCR is determined by the counting of <5% blasts in bone marrow, but this is not reliable because these blasts can be leukemic of regenerating normal cells.  Molecular profiling helps in confirming CR (Molecular CR). It is not unusual in secondary AML that mutations in genes associated with acute phase (NPM1, FLT3) disappear, but the background MDS disease (TET2, ASXL...) remain.
    Monitoring clonal evolutionMonitoring VAF relative changes between various genesClonal evaluation and intensive therapy selection of aggressive subclone is well documented and therapy can be modified and adjusted accordingly.
    Aiding in monitoring residual diseaseMolecular profiling abnormalitiesNCCN guideline: "NGS-based assays can be used to detect mutated genes through targeted sequencing gene panels though higher sensitivities are observed in PCR- and flow cytometry-based methods compared to conventional NGS."
    Aiding in selecting potential clinical trialsFLT3 inhibitors, KIT inhibitors, PI3K/AKT/mTOR inhibitors, aurora and polo-like kinase inhibitors, CDK4/6 inhibitors, CHK1, WEE1, MPS1 inhibitors, SRC and HCK inhibitors, HDAC inhibitors, IDH1 inhibitors, IDH2 inhibitors, DOT1L inhibitors, BET-bromodomain inhibitors, EVI1 inhibitors, NPM1 inhibitors, hedgehog inhibitors, spliceosome inhibitors.

    Recommended Tests:

    1) Hematology Profile™ (Bone marrow or peripheral blood/cfDNA)

    2) Hematology Profile PLUS™ if chromosomal translocation is expected (Bone marrow or peripheral blood)

    Clinical Indication
    Genes/Molecular Abnormality
    Remarks
    Aiding in establishing diagnosisMolecular testing (blood) for JAK2 V617F mutation; if negative, test for CALR and MPL mutations (for patients with ET and MF) and JAK2 exon 12 mutations (for patients with PV) or molecular testing using multi-gene NGS panel that includes JAK2, CALR, and MPL"NCCN Guideline: "Molecular testing (blood)for JAK2 V617F mutation; if negative, test for CALR and MPL mutations (for patients with ET and MF) and JAK2 exon 12 mutations (for patients with PV) or molecular testing using multi-gene NGS panel that includes JAK2, CALR, and MPL".
    Distinguishing MPN from CMML, aCML, and JMMLDNMT3A, ASXL1, EZH2, SF3B1, SRSF2, U2AF1, ZRSR2, RUNX1, TP53, STAG2, NRAS, CBL, NF1, JAK2, CALR, MPL, ETV6, GATA2, IDH2, SETBP1, BCOR, FLT3, WT1, NPM1.
    PrognosisDNMT3A, ASXL1, EZH2, SF3B1, SRSF2, U2AF1, ZRSR2, RUNX1, TP53, STAG2, NRAS, CBL, NF1, JAK2, CALR, MPL, ETV6, GATA2, IDH2, SETBP1, BCOR, FLT3, WT1, NPM1.NCCN Guideline: "Additional molecular testing using multi-gene NGS panel should be considered to evaluate for higher-risk mutations associated with disease progression in patients with primary PMF.”
    Determining prognosis in primary myelofibrosis (NCCN guidelines)Mutated GenePrimary myelofibrosis (PMF)
    JAK2 V617FIntermediate prognosis and higher risk of thrombosis compared to patients with CALR mutation
    MPL W515L/KIntermediate prognosis and higher risk of thrombosis compared to patients with CALR mutation
    CALRImproved survival compared to JAK2 mutation and "triple-negative" PMF-Lower risk of thrombosis compared to JAK2 mutation
    CALR Type 1/Type 1-likeImproved overall survival compared to CALR type 2/type 2-like and JAK2 V617F mutation"
    Triple negative (non-mutated JAK2, MPL, and CALR)Inferior leukemia-free survival compared to patients with JAK2- and/or CALR-mutated PMF Inferior overall survival compared to patients with CALR-mutated PMF
    ASXL1Independently associated with inferior overall survival*and leukemia-free survival
    EZH2Independently associated with inferior overall survival
    IDH1/2Independently associated with inferior leukemia-free survival
    SRSF2Independently associated with inferior overall survival and leukemia-free survival
    Combined CALR and ASXL1 statusSurvival longest for CALR (+) ASXL1 (-) patients (median 10.4 years) and shortest in CALR (-) ASXL1 (+) patients (median 2.3 years) Intermediate survival (median 5.8 years) for CALR (+) ASXL1 (+) or CALR (-) ASXL1 (-) patients
    TP53Associated with leukemic transformation
    U2AF1 Q157Inferior overall survival compared to patients with U2AF1 S34 mutated or U2AF1 unmutated PMF. The effect was most evident in younger patients
    Aiding in selecting potential clinical trialsJAK2, CALR, MPL, Ph+

    Recommended Test:

    1)Hematology Profile PLUS™ (Bone marrow or peripheral blood)

    2)Minimal residual disease (MRD): Hematology Profile™ (Peripheral blood/cfDNA)

    Clinical Indication
    Genes/Molecular Abnormality
    Remarks
    Aiding in establishing diagnosis/stratificationBCR-ABL1 (190 vs 210), various fusions: t(v;11q23.3) [KMT2A rearranged]; t(12;21)(p13.2;q22.1) [ETV6-RUNX1]; t(1;19)(q23;p13.3) [TCF3-PBX1]; t(5;14)(q31.1;q32.3) [IL3-IGH]; Ph–like; B-lymphoblastic leukemia/lymphoma with iAMP21; early T-cell precursor lymphoblastic leukemia. Ph-like: ABL1, ABL2, CRLF2, CSF1R, EPOR, JAK2, or PDGFRB and mutations involving FLT3, IL7R, NTRK, SH2B3, JAK1, JAK3, and JAK2NCCN guideline: "The Ph-like phenotype is associated with recurrent gene fusions and mutations that activate tyrosine kinase pathways and includes gene fusions involving ABL1, ABL2, CRLF2, CSF1R, EPOR, JAK2, or PDGFRB and mutations involving FLT3, IL7R, SH2B3, JAK1, JAK3, and JAK2 (in combination with CRLF2 gene fusions). Testing for these abnormalities at diagnosis may aid in risk stratification."
    PrognosisGood: Cases with trisomy of chromosomes 4, 10, and 17 appear to have the most favorable outcome t(12;21)(p13;q22): ETV6-RUNX1a Poor: KMT2A rearranged (t[4;11] or others)  t(v;14q32)/IgH t(9;22)(q34;q11.2): BCR-ABL1 (defined as high risk in the pre-TKI era) Complex karyotype (5 or more chromosomal abnormalities) Ph-like ALL; intrachromosomal amplification of chromosome 21NCCN guideline as cytogenetic risk stratification
    Selecting therapyBosutinib: T315I, V299L, G250E, or F317L Dasatinib: T315I/A, F317L/V/I/C, or V299L NilotinibT315I, Y253H, E255K/V, or F359V/C/I or G250E Ponatinib ABL1, ABL2, CRLF2, CSF1R, EPOR, JAK1, JAK2, JAK3, PDGFRβ, EBF1, FLT3, IL7R, NTRK3, and SH2B3 genes. A genomic profiling study found kinase-activating alternations in 91% of Ph-like ALL cases,56 suggesting potential for ABL-class tyrosine kinase inhibitors (TKIs) or other targeted therapies to significantly improve patient outcomes in this subgroup B-ALL with iAMP21 (RUNx1)Ph-Positive ALL Ph-like ALL PH-negative ALL (COG AALL-0031 regimen, EsPhALL, TKIs combined with hyper-CVAD, TKIs combined with multiagent chemotherapy, TKIs Combined with Vincristine and Dexamethasone, HSC transplant, CAR-T….) Ph-Like: ABL1, ABL2, PDGFRB, and CSF1R: Dasatinib CRLF2, JAK2 , EPOR , TSLP: JAK2 inhibitors IL2RB:  JAK1/JAK3 inhibitor TYK2: TYK2 inhibitor NTRK3: Crizotinib/NTRK inhibitors PTK2B: FAK inhibitor
    Follow-up and minimal residual disease (MRD)ABL1, ABL2, CRLF2, CSF1R, EPOR, JAK1, JAK2, JAK3, PDGFRβ, EBF1, FLT3, IL7R, NTRK3, NRAS, KRAS, FLT3, IL7R, JAK3, JAK1, SH2B3, BRAF, GATA3, ETV6, RUNX1, IKZF1NCCN guideline: PCR/NGS methods can detect leukemic cells at a sensitivity threshold of <1 x 10-6 (<0.0001%) bone MNCs. The concordance rate for detecting MRD between these methods is generally high.
    Aiding in selecting potential clinical trialsPh+, Ph-like

    Recommended Test:

    1)Hematology Profile PLUS™ (Lymph node, fresh tissue, bone marrow and peripheral blood)

    2)Minimal residual disease (MRD): Hematology Profile™ (Peripheral blood/cfDNA)

    Clinical Indication
    Genes/Molecular Abnormality
    Remarks
    Aiding in establishing diagnosis/stratificationBCL2, MYC, BCL6, 1p36, IRF4/MUM1, Ki-67, cyclin D1, TNFRSF14, STAT6, t(1;14); t(3;14); t(11;18),TP63 rearrangement, MYD88, ATM, del(17p)/TP53 mutation, +12; del(11q); del(13q); BRAF, IgvH4-31, IgVH3-21, MYD88, CXCR4 Double expressor GCB vs ABCNCCN: MYD88 distinguish between WM and SMZL Hodgkin Vs T-cell lymphoma, Mantle Vs marginal, AITL vs B-cell, Double expressor GCB vs ABC
    PrognosisBCL2, MYC, BCL6, 1p36, IRF4/MUM1, Ki-67, cyclin D1, TNFRSF14, STAT6, t(1;14); t(3;14); t(11;18), MYD88, ATM, del(17p)/TP53 mutation, +12; del(11q); del(13q); BRAF, IgvH4-31, IgVH3-21, MYD88, CXCR4 Double expressor GCB vs ABCTP53 mutation/loss ATM mutation/loss MYC, NOTCH1, 6q-, DLBCL subclassification CLL: SF3B1, NOTCH1, TP53 IgvH mutation status in CLL Double expressor GCB vs ABC
    Selecting therapyBCL2, MYC, BCL6, 1p36, IRF4/MUM1, Ki-67, cyclin D1, TNFRSF14, STAT6, t(1;14); t(3;14); t(11;18), MYD88, ATM, del(17p)/TP53 mutation, +12; del(11q); del(13q); Double expressor GCB vs ABCNCCN guideline: Useful in certain circumstances Brentuximab vedotin for CD30+ disease Bendamustinek ± rituximab (category 2B) Ibrutinibm (non-GCB DLBCL) Lenalidomide ± rituximab (non-GCB DLBCL) - BTK and PLCG2 mutations ALK-positive DLBCL DLBCL with IRF4/MUM1
    Follow-up and minimal residual disease (MRD)BCL2, MYC, BCL6, 1p36, IRF4/MUM1, Ki-67, cyclin D1, TNFRSF14, STAT6, t(1;14); t(3;14); t(11;18), MYD88, TP53, ATMMutation detection (cfDNA) is highly sensitive for MRD

    Recommended Test:

    1)Hematology Profile PLUS™ (Lymph node, fresh tissue, bone marrow and peripheral blood)

    2)Minimal residual diease (MRD): Hematology Profile™ (Peripheral blood/cfDNA)

    Clinical Indication
    Genes/Molecular Abnormality
    Remarks
    Aiding in establishing diagnosis/stratificationSTAT3, STT5B, ALK expression/fusion, DUSP22, IRF4, TP63 rearrangement, TCL1A, MTCP1-B1, IDH, TET2, DNMT3A, RHOA, CCR4, TP53Hodgkin Vs T-cell lymphoma, PTCL, BIAA, ALCL, LK-Pos, EATL, MEITL, PTCL-TFH, FTCL, ATIL, TPLL, NKTL, HSTCL, MF/Sezary, large granular lymphocytic leukemia (STAT3 and STAT5B)  
    PrognosisSTAT3, STT5B, ALK expression/fusion, DUSP22, IRF4, TP63, TCL1A, MTCP1-B1, IDH, TET2, DNMT3A, RHOA, TP53 inv(14) (q11;q32); t(14;14)(q11;q32); t(X;14)(q28;q11); trisomy 8Hodgkin Vs T-cell lymphoma, PTCL, BIAA, ALCL, LK-Pos, EATL, MEITL, PTCL-TFH, FTCL, ATIL, TPLL, NKTL, HSTCL, MF/Sezary, large granular lymphocytic leukemia (STAT3 and STAT5B)    
    Selecting therapySTAT3, STT5B, ALK expression/fusion, DUSP22, IRF4, TP63 rearrangement, TCL1A, MTCP1-B1, IDH, TET2, DNMT3A, RHOA, inv(14) (q11;q32); t(14;14) (q11;q32); t(X;14) (q28;q11); trisomy 8NCCN guideline: CCR4 gain-of-function mutations have been reported to be predictive of sensitivity to mogamulizumab treatment
    Follow-up and minimal residual disease (MRD)STAT3, STT5B, ALK expression/fusion, DUSP22, IRF4, TP63, TCL1A, MTCP1-B1, IDH, TET2, DNMT3A, RHOA, TP53 inv(14) (q11;q32); t(14;14)(q11;q32); t(X;14)(q28;q11); trisomy 8Mutation detection (cfDNA) is highly sensitive for MRD

    Recommended Test:

    1)Hematology Profile PLUS™ (Bone marrow or peripheral blood)

    2)Minimal residual disease (MRD): Hematology Profile™ (Peripheral blood/cfDNA)

    Clinical Indication
    Genes/Molecular Abnormality
    Remarks
    Aiding in establishing diagnosis/stratificationKRAS, NRAS, TP53, FAM46C, DIS3 and BRAF, MYD88, IRF4, TP53, ATM, XBP1, PSMB5, del 13, del 17p13, t(4;14), t(11;14), t(14;16), t(14:20), (4p16 FGFR3/MMSET, 16q23 c-maf, 20q11 mafB, 11q13 CCND1, 6p21 CCND3) 1q21 amplification, 1p deletionMGUS, solitary plasmacytoma, smoldering myeloma, multiple myeloma, monoclonal gammopathy of renal significance.
    PrognosisKRAS, NRAS, TP53, FAM46C, DIS3 and BRAF, MYD88, IRF4, TP53, ATM, XBP1, PSMB5, del 13, del 17p13, t(4;14), t(11;14), t(14;16), t(14:20), (4p16 FGFR3/MMSET, 16q23 c-maf, 20q11 mafB, 11q13 CCND1, 6p21 CCND3) 1q21 amplification, 1p deletionShort PFS, OS: t(4;14) or del(17p) Treating Vs observing in sMM: del(17p13), del(13q), del(1p12), ampl(1q21), t(11;14), t(4;14), and t(14;16)
    Selecting therapyXBP1, CRBN, PSMG2, NR3C1, KRAS, NRAS, TP53, FAM46C, DIS3 and BRAF, MYD88, IRF4, TP53, ATM, XBP1, PSMB5, del 13, del 17p13, t(4;14), t(11;14), t(14;16), t(14:20), (4p16 FGFR3/MMSET, 16q23 c-maf, 20q11 mafB, 11q13 CCND1, 6p21 CCND3) 1q21 amplification, 1p deletionTreating Vs observing in sMM: del(17p13), del(13q), del(1p12), ampl(1q21), t(11;14), t(4;14), and t(14;16) Resistance to bortezomib: XBP1, CRBN, PSMG2, NR3C1 Drug inhibitors: BRAF, MDM2, RAS, TP53
    Follow-up and minimal residual disease (MRD)KRAS, NRAS, TP53, FAM46C, DIS3 and BRAF, MYD88, IRF4, TP53, ATM, XBP1, PSMB5,NCCN: MRD negativity in the marrow (next-generation flow [NGF], next-generation sequencing [NGS], or both) and by imaging as defined below, confirmed minimum of 1 year apart. Subsequent evaluations can be used to further specify the duration of negativity (eg, MRD-negative at 5 years).

    Recommended Test:

    1)Hematology Profile PLUS™ (Bone marrow or peripheral blood) + IgH Mutation status

    2)Minimal residual disease (MRD): Hematology Profile™ (Peripheral blood/cfDNA)

    Clinical Indication
    Genes/Molecular Abnormality
    Remarks
    Aiding in establishing diagnosis/stratificationIGHV4-34, BRAF, MAP2K1, DUSP2, MAPK15, ARID1A, ARID1B, EZH2, KDM6A, CREBBP, TP53, CDKN1B, XPO1, KLF2, CXCR4, NOTH1, NOTCH2, MYD88, ANXA1, U2AF1, BCOR, and ABCA8NCCN guideline: IGHV4-34 rearrangement behaves more like HCLv, IGHV4-34 HCL typically lacks BRAF V600E mutations. MAP2K1 mutation in HCLv
    PrognosisBRAF, MAP2K1, DUSP2, MAPK15, ARID1A, ARID1B, EZH2, KDM6A, CREBBP, TP53, CDKN1B, XPO1, KLF2, CXCR4, NOTH1, NOTCH2, MYD88, ANXA1, U2AF1, BCOR, and ABCA8NCCN guideline: IGHV4-34 rearrangement behaves more like HCLv, IGHV4-34 HCL typically lacks BRAF V600E mutations. MAP2K1 mutation associated with resistance
    Selecting therapyBRAF, MAP2K1, DUSP2, MAPK15, ARID1A, ARID1B, EZH2, KDM6A, CREBBP, TP53, CDKN1B, XPO1, KLF2, CXCR4, NOTH1, NOTCH2, MYD88, ANXA1, U2AF1, BCOR, and ABCA8, BTK, PCLG2Drug inhibitors: BRAF, BTK inhibitors
    Follow-up and minimal residual disease (MRD)BRAF, MAP2K1, DUSP2, MAPK15, ARID1A, ARID1B, EZH2, KDM6A, CREBBP, TP53, CDKN1B, XPO1, KLF2, CXCR4, NOTH1, NOTCH2, MYD88, ANXA1, U2AF1, BCOR, and ABCA8

    Recommended Test:

    1)Hematology profile PLUS™ (Bone marrow or peripheral blood)

    2)Minimal residual disease (MRD): Hematology Profile™ (Peripheral blood/cfDNA and BCR-ABL1 by PCR)

    Clinical Indication
    Genes/Molecular Abnormality
    Remarks
    Aiding in establishing diagnosis/stratificationBCR-ABL1 fusion, AB1, DNMT3A, EZH2, RUNX1, TET2, TP53, U2AF1 and ZRSR2.
    PrognosisBCR-ABL1 fusion, AB1, DNMT3A, EZH2, RUNX1, TET2, TP53, U2AF1 and ZRSR2.Relevant upon evidence of progression NCCN guideline: E255K/V, F359C/V, Y253H, and T315I mutants are most commonly associated with disease progression and relapse.
    Selecting therapyBCR-ABL1 fusion, AB1, DNMT3A, EZH2, RUNX1, TET2, TP53, U2AF1 and ZRSR2.NCCN guidelines: The T315A, F317L/I/V/C, and V299L mutants are resistant to Dasatinib and E255K/V, F359V/C, and Y253H mutants are resistant to nilotinib. Bosutinib has demonstrated activity in patients with BCR-ABL1 mutants resistant Todasatinib (F317L) and nilotinib (Y253H, E255K/V, and F359C/I/V). However, bosutinib has minimal activity against F317Lmutant while in vitro studies suggest that F317L is highly sensitive to nilotinib. Nilotinib may be preferred over bosutinib in patients with F317Lmutation. T315I, G250E, and V299L mutants are resistant to bosutinib. Ponatinib is active against BCR-ABL1 mutants resistant to Dasatinib or Nilotinib, including E255V, Y253H, and F359V, in addition to T315I.
    Follow-up and minimal residual disease (MRD)BCR-ABL1 fusion by PCR

    Recommended Test:

    Hematology Profile™ (Peripheral blood/cfDNA)

    Clinical Indication
    Genes/Molecular Abnormality
    Remarks
    Aiding in establishing diagnosis/stratificationTET2, DNMT3A, ASXL1, JAK2, SF3B1, TP53-Low levels (VAF <10%) in individuals above the age of 50 - Clonal cytopenias of undetermined significance (CCUS): Presence of cytopenia (anemia, low platelets, or white cells) -19% in individuals with history of cancer treated with myelotoxic chemotherapy
    PrognosisTET2, DNMT3A, ASXL1, JAK2, SF3B1, TP53-VAF: 10-20% - Progression to myeloid or lymphoid neoplasm: 0.5–1% per year VAF: 10-20
    Selecting therapyTET2, DNMT3A, ASXL1, JAK2, SF3B1, TP53Monitoring VAF
    Follow-up and minimal residual disease (MRD)TET2, DNMT3A, ASXL1, JAK2, SF3B1, TP53Monitoring VAF