What Test Should I Order?
Based on the Clinical Indications for Molecular Testing
Solid Tumors
Recommended Test:1) Solid Tumor Profile PLUS™ (FFPE block or unstained slides)2) Liquid Trace™ Solid Tumor (Peripheral blood/cfDNA/cfRNA) | ||
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 Trace™ Solid Tumor (Peripheral blood/cfDNA/cfRNA) | ||
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 Trace™ Solid Tumor (Peripheral blood/cfDNA/cfRNA) | ||
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 Trace™ Solid Tumor (Peripheral blood/cfDNA/cfRNA) | ||
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, IDH1/2 | See 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, IDH1/2 | Detecting mutations |
Recommended Test:1) Solid Tumor Profile PLUS™ (FFPE block or unstained slides)2) Liquid Trace™ Solid Tumor (Peripheral blood/cfDNA/cfRNA) | ||
Clinical Indication | Genes/Molecular Abnormality | Remarks |
| Aiding in establishing diagnosis/stratification | 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/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 |
| Prognosis | 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/mutation | See diagnostics |
| Selecting therapy | 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/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/mutation | Detecting mutations |
Recommended Test:1) Solid Tumor Profile PLUS™ (FFPE block or unstained slides)2) Liquid Trace™ Solid Tumor (Peripheral blood/cfDNA/cfRNA) | ||
Clinical Indication | Genes/Molecular Abnormality | Remarks |
| Aiding in establishing diagnosis/stratification | 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, MSI | |
| Prognosis | 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, MSI | Molecular classification based on gene expression: Classical, mesenchymal, and atypical. |
| Selecting therapy | 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, 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, MSI | Detecting mutations |
Recommended Test:1) Solid Tumor Profile PLUS™ (FFPE block or slides)2) Liquid Trace™ Solid Tumor (Peripheral blood/cfDNA/cfRNA) | ||
Clinical Indication | Genes/Molecular Abnormality | Remarks |
| Aiding in establishing diagnosis/stratification | 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, 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. |
| Prognosis | 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, MSI | NCCN 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 therapy | 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, 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, MSI | Detecting mutations |
Recommended Test:1) Solid Tumor Profile PLUS™ (FFPE block or unstained slides)2) Liquid Trace™ Solid Tumor (Peripheral blood/cfDNA/cfRNA) | ||
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 Trace™ Solid Tumor (Peripheral blood/cfDNA/cfRNA) | ||
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 Trace™ Solid Tumor (Peripheral blood/cfDNA/cfRNA) |
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 Trace™ Solid Tumor (Peripheral blood/cfDNA/cfRNA) | ||
Clinical Indication | Genes/Molecular Abnormality | Remarks |
| Aiding in establishing diagnosis/stratification | KIT (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 |
| Prognosis | KIT (exons: 9,11,13,17), PDGFRA, NF1, KRAS, NRAS, HRAS, BRAF, SDHB, SDHC, CDKN2A, CDKN2B, RB1, TP53, CUL1, ATM | Heinrich et al (https://doi.org/10.1186/s13569-019-0112-7) |
| Selecting therapy | KIT (exons: 9,11,13,17), PDGFRA, NF1, KRAS, NRAS, HRAS, BRAF, SDHB, SDHC, CDKN2A, CDKN2B, RB1, TP53, CUL1, ATM | Kinase 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 Trace™ Solid Tumor (Peripheral blood/cfDNA/cfRNA) | ||
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: | ||
Clinical Indication | Genes/Molecular Abnormality | Remarks |
| Aiding in establishing diagnosis | DNMT3A, ASXL1, EZH2, SF3B1, SRSF2, U2AF1, ZRSR2, RUNX1, TP53, STAG2, NRAS, CBL, NF1, JAK2, CALR, MPL, ETV6, GATA2, IDH2, SETBP1, BCOR, FLT3, WT1, NPM1, STAT3 | NCCN 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 TP53 | Mutations in these genes with VAF<10% are more associated with CHIP and CCUS | |
| Distinguishing MDS from LGL | STAT3 mutation | NCCN guideline: distinguish LGL from MDS |
| Subclassification (NCCN guidelines) | TET2, SRSF2, ASXL1, RUNX1, NRAS, CBL | CMML-0/CMML-1/CMML-2 |
| SETBP1, ETNK1 | aCML | |
| PTPN11, NF1, NRAS, KRAS, CBL, SETBP1, JAK3 | JMML | |
| TET2, NRAS, RUNX1, CBL, SETBP1, ASXL1 | MDS/MPN | |
| SF3B1, JAK2, MPL, CALR | MDS/MPN-T | |
| CSF3R | CNL | |
| Prognosis | DNMT3A, 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: Mutations in these genes are associated with more aggressive disease |
| Prognosis | IDH1, PHF6, PPM1D, PPM1D, TET2 | NCCN guideline: Mutations in these genes have neutral effects on prognosis |
| Heterogeneity | VAF | Used 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, ETV6 | AML/MDS and other hematologic neoplasms | |
| GATA2 | MONO syndrome | |
| RUNX1 | Thrombocytopenia with mild bleeding | |
| SAMD9 | MIRAGE syndrome | |
| SAMD9L | Ataxia-Pancytopenia | |
| SRP72 | Congenital sensorineural deafness. | |
| RPL5, RPL11, RPL15, RPL23, RPL26, RPL27, RPL31, RPL35A, RPS7, RPS10, RPS17, RPS19, RPS24, RPS26, RPS27, RPS28, RPS29, TSR2, GATA1 | Diamond-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/REV7 | Fanconi anemia | |
| SBDS, EFL1, DNAJC21 | Shwachman-Diamond syndrome | |
| ACD, CTC1, DKC1, NAF1, NHP2, NOP10, PARN, POT1, RTEL1, TERC, TERT, TINF2, USB1, WRAP53 | Telomere biology disorders | |
| ELANE, G6PC3, GFI1, HAX1 | Congenital neutropenia | |
| GATA1 | Down syndrome, acute megakaryocytic leukemia | |
| TP53 | AML/MDS in patients with Li-Fraumeni syndrome | |
| EPCAM, MLH1, MSH2, MSH6, PMS2 | AML/MDS in constitutional mismatch repair deficiency | |
| BRCA1, BRCA2 | AML/MDS in hereditary breast and ovarian cancer | |
| CBL, KRAS, NF1, PTPN11 | AML/MDS/CMML/AMML in patients with RASopathies | |
| BLM | AML/MDS in Bloom syndrome | |
| Aiding in deciding therapeutic approach | FLT3, IDH1/2 | Presence 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. |
| TET2 | NCCN 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 monitoring | VAF | Disappearance or emergence of clones that may affect targeted therapy or overall therapeutic approach. |
| Aiding in selecting potential clinical trials | FLT3 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 diagnosis | c-KIT, FLT3-ITD, FLT3-TKD, NPM1, CEBPA, IDH1/IDH2, RUNX1, ASXL1, and TP53 | NCCN 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 AML | AXL1, SF3B1, DNMT3A, TET2, SRSF2, EZH2, BCOR, STAG2 | ELN 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 heterogeneity | comparing VAF between mutated genes | Relevant in selecting targeted therapy, monitoring and understanding clinical course. |
| Distinguishing between transient myeloproliferative disorder Vs megakaryocytic leukemia in patients with down syndrome | GATA1 mutation | |
| Ruling out hereditary predisposition (Gene mutations associated with hereditary myeloid malignancies) | See MDS description | |
| Aiding in deciding therapeutic approach | KIT | NCCN guideline: Potential adding Dasatinib in CBF leukemia with KIT mutation. |
| FLT3, IDH1/2 | Presence 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. | |
| TP53 | Allo-hematologic stem cell transplant or clinical trials. | |
| Determining molecular response | Molecular profiling abnormalities | CR 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 evolution | Monitoring VAF relative changes between various genes | Clonal evaluation and intensive therapy selection of aggressive subclone is well documented and therapy can be modified and adjusted accordingly. |
| Aiding in monitoring residual disease | Molecular profiling abnormalities | NCCN 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 trials | FLT3 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 diagnosis | 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” | 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 JMML | DNMT3A, ASXL1, EZH2, SF3B1, SRSF2, U2AF1, ZRSR2, RUNX1, TP53, STAG2, NRAS, CBL, NF1, JAK2, CALR, MPL, ETV6, GATA2, IDH2, SETBP1, BCOR, FLT3, WT1, NPM1. | |
| Prognosis | DNMT3A, 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 Gene | Primary myelofibrosis (PMF) |
| JAK2 V617F | Intermediate prognosis and higher risk of thrombosis compared to patients with CALR mutation | |
| MPL W515L/K | Intermediate prognosis and higher risk of thrombosis compared to patients with CALR mutation | |
| CALR | Improved survival compared to JAK2 mutation and “triple-negative” PMF-Lower risk of thrombosis compared to JAK2 mutation | |
| CALR Type 1/Type 1-like | Improved 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 | |
| ASXL1 | Independently associated with inferior overall survival*and leukemia-free survival | |
| EZH2 | Independently associated with inferior overall survival | |
| IDH1/2 | Independently associated with inferior leukemia-free survival | |
| SRSF2 | Independently associated with inferior overall survival and leukemia-free survival | |
| Combined CALR and ASXL1 status | Survival 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 | |
| TP53 | Associated with leukemic transformation | |
| U2AF1 Q157 | Inferior 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 trials | JAK2, 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/stratification | BCR-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 JAK2 | NCCN 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.” |
| Prognosis | Good: 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 21 | NCCN guideline as cytogenetic risk stratification |
| Selecting therapy | Bosutinib: 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, IKZF1 | NCCN 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 trials | Ph+, 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/stratification | BCL2, 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 ABC | NCCN: MYD88 distinguish between WM and SMZL Hodgkin Vs T-cell lymphoma, Mantle Vs marginal, AITL vs B-cell, Double expressor GCB vs ABC |
| Prognosis | BCL2, 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 ABC | TP53 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 therapy | BCL2, 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 ABC | NCCN 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, ATM | Mutation 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/stratification | STAT3, STT5B, ALK expression/fusion, DUSP22, IRF4, TP63 rearrangement, TCL1A, MTCP1-B1, IDH, TET2, DNMT3A, RHOA, CCR4, TP53 | Hodgkin 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) |
| Prognosis | 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 8 | Hodgkin 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 therapy | STAT3, 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 8 | NCCN 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 8 | Mutation 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/stratification | 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 deletion | MGUS, solitary plasmacytoma, smoldering myeloma, multiple myeloma, monoclonal gammopathy of renal significance. |
| Prognosis | 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 deletion | Short 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 therapy | XBP1, 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 deletion | Treating 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) + IgVH Mutation status2)Minimal residual disease (MRD): Hematology Profile™ (Peripheral blood/cfDNA) | ||
Clinical Indication | Genes/Molecular Abnormality | Remarks |
| Aiding in establishing diagnosis/stratification | IGHV4-34, BRAF, MAP2K1, DUSP2, MAPK15, ARID1A, ARID1B, EZH2, KDM6A, CREBBP, TP53, CDKN1B, XPO1, KLF2, CXCR4, NOTH1, NOTCH2, MYD88, ANXA1, U2AF1, BCOR, and ABCA8 | NCCN guideline: IGHV4-34 rearrangement behaves more like HCLv, IGHV4-34 HCL typically lacks BRAF V600E mutations. MAP2K1 mutation in HCLv |
| Prognosis | BRAF, MAP2K1, DUSP2, MAPK15, ARID1A, ARID1B, EZH2, KDM6A, CREBBP, TP53, CDKN1B, XPO1, KLF2, CXCR4, NOTH1, NOTCH2, MYD88, ANXA1, U2AF1, BCOR, and ABCA8 | NCCN guideline: IGHV4-34 rearrangement behaves more like HCLv, IGHV4-34 HCL typically lacks BRAF V600E mutations. MAP2K1 mutation associated with resistance |
| Selecting therapy | BRAF, MAP2K1, DUSP2, MAPK15, ARID1A, ARID1B, EZH2, KDM6A, CREBBP, TP53, CDKN1B, XPO1, KLF2, CXCR4, NOTH1, NOTCH2, MYD88, ANXA1, U2AF1, BCOR, and ABCA8, BTK, PCLG2 | Drug 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/stratification | BCR-ABL1 fusion, AB1, DNMT3A, EZH2, RUNX1, TET2, TP53, U2AF1 and ZRSR2. | |
| Prognosis | BCR-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 therapy | BCR-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/stratification | TET2, 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 |
| Prognosis | TET2, DNMT3A, ASXL1, JAK2, SF3B1, TP53 | -VAF: 10-20% – Progression to myeloid or lymphoid neoplasm: 0.5–1% per year VAF: 10-20 |
| Selecting therapy | TET2, DNMT3A, ASXL1, JAK2, SF3B1, TP53 | Monitoring VAF |
| Follow-up and minimal residual disease (MRD) | TET2, DNMT3A, ASXL1, JAK2, SF3B1, TP53 | Monitoring VAF |