Table 1.
Category A variants: actionable findings resulting in change or refinement of diagnosis
| Standard clinical analysis | KiCS/NGS analysis | |||
|---|---|---|---|---|
| KiCS ID | Initial pathologic diagnosis and results from relevant clinical testing | Refined diagnosis based on KiCS analysis | Actionable finding | Impact |
| Solid tumors | ||||
| 59 | 8805/3—undifferentiated sarcoma (M1, C2) | BCOR-fused sarcoma | BCOR-CCNB3 fusion | No change in therapy |
| 87 |
8805/3—undifferentiated sarcoma vs. 9150/3—hemangiopericytoma, malignant (C3) |
BCOR-fused sarcoma | BCOR-CCNB3 fusion | Changed to Ewing sarcoma-like therapy |
| 141 | 9180/3—osteosarcoma, NOS (C40._, C41._) | BCOR-fused sarcoma | BCOR-CCNB3 fusion | At relapse following osteosarcoma therapy, treated according to refined diagnosis with Ewing sarcoma-like therapy |
| 239 | Malignant small round blue cell tumor with EWSR1 gene rearrangement (C4, M5) | 8562/3—epithelial–myoepithelial carcinoma | EWSR1-ZNF444 fusion | Selection of appropriate chemotherapy and improved prognostication |
| 123 | 8825/1—myofibroblastic tumor, NOS (‘fibroblastic/myofibroblastic proliferation’) (I6, C7) | 8821/1—aggressive fibromatosis/desmoid tumor | CTNNB1 p.T41A | Selection of desmoid-tailored chemotherapy instead of morbid surgical resection |
| 241 | 8825/1—myofibroblastic tumor, NOS (‘fibroblastic neoplasm with nuclear β-catenin immunoreactivity, favor desmoid-type fibromatosis’) (C8, M9, I10) | 8821/1—aggressive fibromatosis/desmoid tumor | Somatic APC copy number loss, exons 5–22, with homozygous loss of exons 10–15 | Selection of desmoid-tailored chemotherapy instead of morbid surgical resection |
| 356 | 8805/3—undifferentiated sarcoma (C49.2) (C11, M12, I13) | CIC-fused sarcoma | CIC-NUTM2A fusion | No change (patient deceased) |
| 379 | 8800/3—sarcoma, NOS (C76.3) (I14, M15) | Primitive myxoid mesenchymal tumor of infancy |
BCOR p.*1722Lext*34; RNA-seq: ITD and BCOR-driven tumor expression cluster |
Selection of appropriate chemotherapy and improved prognostication |
| Leukemia and lymphoma | ||||
| 192 | 9812/3—B lymphoblastic leukemia/lymphoma with t(9;22)(q34;q11.2); BCR-ABL1 (C16) | 9836/3—precursor B cell lymphoblastic leukemia |
EWSR1-PBX3 fusion (no BCR-ABL fusion) |
Change of therapy (taken off TKI) |
| 104 |
Preliminary: melanotic neuroectodermal tumor of infancy Final: ‘pseudo-sarcomatous mass with infiltrates of a primitive hematolymphoid neoplasm with predominance of blasts of M7 acute megakaryoblastic leukemia features’ (F17, C18, M19, I20) |
9910/3—acute megakaryoblastic leukemia | RBM15-MKL1 fusion | Initially treated as melanotic neuroectodermal tumor of infancy; changed to AMKL therapy |
| 155 | 9960/3—myeloproliferative neoplasm, NOS (M21, C22) | Myeloproliferative neoplasm with ETV6-ABL1 rearrangement | ETV6-ABL1 fusion |
Initiation of TKI (eventual allogeneic transplantation) |
| 227 | 9801/3—acute leukemia, NOS (F23, M24) | 9837/3—T lymphoblastic leukemia/lymphoma | SET-NUP214 fusion, PHF6 p.V268Tfs*5 and NOTCH1 p.N386S | T-ALL therapy after other failed induction regimens, with omission of steroids |
| 262 | 9946/3—juvenile myelomonocytic leukemia (C42.1) vs. acute myeloid leukemia (C25, F26, M27) | 9946/3—juvenile myelomonocytic leukemia (C42.1) | KRAS p.G12A and monosomy 7 | Confirmed decision to proceed to allogeneic hematopoietic stem cell transplantation |
| 310 | 9836/3—precursor B cell lymphoblastic leukemia (C42.1) (F28, C29, M30) | 9836/3—precursor B cell lymphoblastic leukemia (C42.1), Ph-like |
SH2B3 p.F146Lfs*52; RNA-seq expression cluster: B-ALL, Ph-like, JAK–STAT |
No change in therapy, but improved subclassification, prognostication and future treatment options |
| 346 | 9910/3—acute megakaryoblastic leukemia (C42.1) (F31, C32) | 9898/3—myeloid leukemia associated with Down syndrome | GATA1 c.186_190delCTACA (p.Y62*) | Selection of appropriate chemotherapy (lower intensity for myeloid leukemia of Down syndrome, instead of high-intensity AML therapy) |
| CNS tumors | ||||
| 70 | 9440/3—glioblastoma (C71._) | Low-grade glioma |
FGFR1 p.K656M and germline NF1 p.S1468G |
Initiation of targeted therapy instead of radiation therapy |
| 323 | 8990/1—mesenchymal tumor (C71.0) (I33, C34, M35) | 8824/0—myofibroma (C71.0) | PDGFRB p.P588delinsLP | Confirmed plan for no adjuvant therapy after resection, given benign entity |
The original tumor diagnosis is presented along with the extent of clinical testing carried out, including cytogenetic (C), molecular (M), immunohistochemical (I) and flow cytometry (F) analyses. A refined diagnosis was suggested by cancer panel and/or RNA-seq findings, with the noted impact on clinical management. The results of clinical testing are indicated by the superscript numbers: (1) negative for EWS-FLI1, CIC-DUX4 and SSX-SYT fusion transcripts; (2) negative for SYT and EWS gene rearrangements; (3) no malignant cells; (4) positive for EWSR1 gene rearrangement; (5) negative for EWS-WT1 (RT–PCR) and negative Nanostring assay for fusion transcripts; (6) β-catenin mostly cytoplasmic and perinuclear with possible focal nuclear staining; (7) negative for FUS gene rearrangement; (8) negative for FUS, USPS and EWSR1 rearrangements; (9) negative Nanostring assay for fusion transcripts; (10) positive for β-catenin nuclear expression; (11) negative for EWSR1 rearrangement; (12) failed analysis; (13) positive for CD99 membrane staining, WT1; negative for CKAE1/AE3, S100, SOX10, melanA, SMA, desmin, myogenin, TFE3, IN1 retained; (14) positive for vimentin and TLE-1, patchy staining for CD99, focal positivity for S100 and SOX0, BAF47 intact; negative for NB84, CD45, EMA, pan-keratin, myogenin, SMA, actin, caldesmon, CD34, CD31, GFAP, PLAP, glypican-3, WT-1, OCT4 and CD30; (15) negative Nanostring assay for fusion transcripts and negative Trusight RNA-seq for oncogenic fusion transcripts and mutations; (16) interpreted as being consistent with BCR-ABL; (17) negative for CD41 and CD61 (BMA); (18) negative for MLL rearrangement (BMA); (19) negative for t(1;22)(p13;q13)/RBM15-MKL1 and negative sarcoma fusion panel (BMA); (20) negative for CD56, CD61 and factor VIII (BMBx), negative large panel and positive for CD43, CD61 and factor VIII (maxillary mass); (21) negative for BCR-ABL p210/p190, PDGFRA-FIP1L1 and t(5;14)(q31;q32)/IL3-IGH, JAK2 V617F, JAK2 exon 12 mutations, CALR, FLT3-ITD, clonal rearrangements of TCR genes and IGH gene fusion; (22) negative for FIP1L1-CHIC2-PDGFRA, PDGFRB and MYC; (23) positive for CD34, CD2, CD7, CD33, CD38, CD11 and CD71 and negative for Tdt, MPO and cCD3; (24) negative for 29 recurrently mutated myeloid leukemia genes and positive for TCR rearrangement-γ-chain; (25) monosomy 7; (26) myeloblasts and population with monocytic differentiation; (27) negative RT–PCR for AML fusion transcripts and negative for FLT3-ITD; (28) consistent with precursor B lymphoblasts; (29) positive for iAMP21 and normal FISH analysis for CRLF2, IGH, MYC, CDKN2A and TCF3; (30) negative RT–PCR for canonical ALL fusion transcripts, positive LDA screen and negative Trusight RNA-seq for Ph-like fusion transcripts or mutations; (31) consistent with megakaryoblasts; (32) 49,XX,del(6)(q13q21),+8,+21,+21(20); (33) large panel; (34) negative for whole and segmental chromosome aberrations; (35) negative Nanostring assay for fusion transcripts and negative Trusight RNA-seq for oncogenic fusions and mutations. BMA, bone marrow aspirate; BMBx, bone marrow biopsy; LDA, low density array; TKI, tyrosine kinase inhibitor.