Table 2.
Subgroup-specific diagnostic marker and candidate genes involved in recurrent chromosomal abnormalities in pediatric EPNs.
| Molecular Group | Implicated Gene * | Gene Name | Cytogenetic Band | Pathogenic Impact | Evidence Level ** | Evidence-Based Categorization *** | Hallmark of Cancer **** | |
|---|---|---|---|---|---|---|---|---|
| Promotes | Suppresses | |||||||
| ST-EPN-ZFTA | ZFTA | Zinc finger translocation associated | 11q13.1 | 5′-partner gene in ZFTA–RELA fusion | I | Tier I, level A |
Genome instability | |
| RELA | V-Rel avian reticuloendotheliosis viral oncogene homolog A | 11q13.1 | 3′-partner gene in ZFTA–RELA fusion | I | Tier I, level A |
Escaping programmed cell death; tumor promoting inflammation | ||
| MAML2 | Mastermind-like transcriptional coactivator 2 | 11q21 | 3′-partner gene in ZFT–MAML2 fusion | III | Tier II, level C |
Proliferative signaling; angiogenesis | ||
| NCOA1 | Nuclear receptor coactivator 1 | 2p23.3 | 3′-partner gene in ZFTA–NCOA1 fusion | III | Tier II, level C |
Proliferative signaling; change of cellular energetics | ||
| NCOA2 | Nuclear receptor coactivator 2 | 8q13.3 | 3′-partner gene in ZFTA–NCOA2 fusion | III | Tier II, level C |
Proliferative signaling; change of cellular energetics; escaping programmed cell death | ||
| ST-EPN-YAP1 | YAP1 | Yes1-associated transcriptional regulator | 11q22.1 | 5′-partner gene in YAP1–MAMLD1 fusion | II | Tier I, level A |
Proliferative signaling; escaping programmed cell death; invasion and metastasis | Escaping programmed cell death |
| MAMLD1 | Mastermind-like domain-containing 1 | Xq28 | 3′-partner gene in YAP1–MAMLD1 fusion | II | Tier I, level A |
Proliferative signaling; angiogenesis | Escaping programmed cell death | |
| FAM118B | Family with sequence similarity 118 member B | 11q24.2 | 3′-partner gene in YAP1–FAM118B fusion | IV | Tier II, level D |
Unknown | ||
| Non-ZFTA/Non-YAP1 ST-EPNs | PLAGL1 | PLAG1-like zinc finger 1 | 6q24.2 | 3′-partner gene in EWSR1-PLAGL1 fusion; 5′-partner gene in PLAGL1–FOXO1 or PLAGL1–EP300 fusion | IV | Tier II, level D |
Suppression of growth | Escaping immunic response to cancer; tumor promoting inflammation; invasion and metastasis; angiogenesis |
| EWSR1 | EWS RNA binding protein 1 | 22q12.2 | 5′-partner gene in EWSR1–PLAGL1 or EWSR1–PATZ1 fusion | IV | Tier II, level D |
Proliferative signaling; escaping programmed cell death; angiogenesis; invasion and metastasis | Genome instability and mutations | |
| FOXO1 | Forkhead box O1 | 13q14.11 | 3′-partner gene in PLAGL1–FOXO1 fusion | IV | Tier II, level D |
Change of cellular energetics | Escaping programmed cell death | |
| EP300 | E1A binding protein P300 | 22q13.2 | 3′-partner gene in PLAGL1–EP300 fusion | IV | Tier II, level D |
Suppression of growth | Escaping programmed cell death | |
| PATZ1 | POZ/BTB and AT hook-containing zinc finger 1 | 22q12.2 | 3′-partner gene in EWSR1–PATZ1 or MN1–PATZ1 fusion | IV | Tier II, level D |
Proliferative signaling; escaping programmed cell death | ||
| MN1 | MN1 proto-oncogene, transcriptional regulator | 22q12.1 | 5′-partner gene in MN1-PATZ1 fusion | IV | Tier II, level D |
Suppression of growth | Escaping programmed cell death | |
| PF-EPN-A | EZHIP | EZH inhibitory protein | Xp11.22 | Overexpression | IV | Tier II, level D |
EZH1/EZH2-mediated trimethylation of H3K27 | |
| EPOP | Elongin BC and polycomb repressive complex 2-associated protein | 17q12 | Overexpression | IV | Tier II, level D |
EZH2-mediated trimethylation of H3K27 | ||
| HIST1H3C | H3 clustered histone 3 | 6p22.2 | Somatic mutation | IV | Tier II, level D |
EZH2-mediated trimethylation of H3K27 | ||
| HIST1H3B | H3 clustered histone 2 | 6p22.2 | Somatic mutation | IV | Tier II, level D |
EZH2-mediated trimethylation of H3K27 | ||
| H3F3A | H3.3 histone A | 1q42.12 | Somatic mutation | IV | Tier II, level D |
EZH2-mediated trimethylation of H3K27 | ||
| BCL9 | BCL9 transcription coactivator | 1q21.2 | Oncogene, involved in 1q gain | V | NA | Proliferative signaling; invasion and metastasis; angiogenesis | ||
| ARNT | Aryl hydrocarbon receptor nuclear translocator | 1q21.3 | Oncogene, involved in 1q gain | V | NA | Angiogenesis; change of cellular energetics | Invasion and metastasis | |
| SETDB1 | SET domain bifurcated histone lysine methyltransferase 1 | 1q21.3 | Oncogene, involved in 1q gain | V | NA | Epigenetic transcriptional repression by recruiting HP1 (CBX1, CBX3 and/or CBX5) proteins to methylated histones | ||
| NTRK1 | Neurotrophic receptor tyrosine kinase 1 | 1q23.1 | Oncogene, involved in 1q gain | V | NA | Proliferative signaling; escaping programmed cell death; angiogenesis | ||
| FCRL4 | Fc receptor-like 4 | 1q23.1 | Oncogene, involved in 1q gain | V | NA | Escaping immunic response to cancer | ||
| FCGR2B | Fc fragment of IgG receptor IIb | 1q23.3 | Oncogene, involved in 1q gain | V | NA | Suppression of growth | Escaping programmed cell death | |
| DDR2 | Discoidin domain receptor tyrosine kinase 2 | 1q23.3 | Oncogene, involved in 1q gain | V | NA | Invasion and metastasis | ||
| PBX1 | PBX homeobox 1 | 1q23.3 | Oncogene, involved in 1q gain | V | NA | Angiogenesis; escaping programmed cell death; change of cellular energetics | ||
| ABL2 | ABL proto-oncogene 2, non-receptor tyrosine kinase | 1q25.2 | Oncogene, involved in 1q gain | V | NA | Proliferative signaling; invasion and metastasis; angiogenesis; genome instability and mutations; change of cellular energetics | Escaping programmed cell death | |
| MDM4 | MDM4 regulator of P53 | 1q32.1 | Oncogene, involved in 1q gain | V | NA | Proliferative signaling; invasion and metastasis; angiogenesis; escaping programmed cell death | Suppression of growth | |
| ELK4 | ETS transcription factor ELK4 | 1q32.1 | Oncogene, involved in 1q gain | V | NA | Proliferative signaling; escaping programmed cell death | ||
| RGS7 | Regulator of G protein signaling 7 | 1q43 | Oncogene, involved in 1q gain | V | NA | Change of cellular energetics | ||
| AKT3 | AKT serine/threonine Kinase 3 | 1q43-q44 | Oncogene, involved in 1q gain | V | NA | Proliferative signaling; suppression of growth; invasion and metastasis; angiogenesis; escaping programmed cell death; change of cellular energetics | Invasion and metastasis; angiogenesis; genome instability and mutations | |
| EPHA7 | EPH receptor A7 | 6q16.1 | Tumor suppressor gene, involved in 6q loss | V | NA | Escaping programmed cell death | ||
| CCNC | Cyclin C | 6q16.2 | Tumor suppressor gene, involved in 6q loss | V | NA | Proliferative signaling | ||
| PRDM1 | PR/SET domain 1 | 6q21 | Tumor suppressor gene, involved in 6q loss | V | NA | Suppression of growth | Escaping immunic response to cancer | |
| FOXO3 | Forkhead box O3 | 6q21 | Tumor suppressor gene, involved in 6q loss | V | NA | Change of cellular energetics | Escaping programmed cell death | |
| PTPRK | Protein tyrosine phosphatase receptor type K | 6q22.33 | Tumor suppressor gene, involved in 6q loss | V | NA | Escaping immunic response to cancer | Proliferative signaling | |
| BCLAF1 | BCL2-associated transcription factor 1 | 6q23.3 | Tumor suppressor gene, involved in 6q loss | V | NA | Escaping programmed cell death | ||
| TNFAIP3 | TNF alpha-induced protein 3 | 6q23.3 | Tumor suppressor gene, involved in 6q loss | V | NA | Escaping immunic response to cancer; tumor promoting inflammation | ||
| LATS1 | Large tumor suppressor kinase 1 | 6q25.1 | Tumor suppressor gene, involved in 6q loss | V | NA | Suppression of growth | Genome instability and mutations; escaping programmed cell death | |
| ESR1 | Estrogen receptor 1 | 6q25.1 | Tumor suppressor gene, involved in 6q loss | V | NA | Proliferative signaling; suppression of growth; escaping immunic response to cancer; invasion and metastasis | Invasion and metastasis | |
| ARID1B | AT-rich interaction domain 1B | 6q25.3 | Tumor suppressor gene, involved in 6q loss | V | NA | Suppression of growth; cell replicative immortality | Cell replicative immortality; invasion and metastasis; genome instability and mutations; escaping programmed cell death | |
| QKI | QKI, KH domain-containing RNA binding | 6q26 | Tumor suppressor gene, involved in 6q loss | V | NA | Suppression of growth; escaping programmed cell death | Escaping programmed cell death | |
| PF-EPN-B | LATS2 | Large tumor suppressor kinase 2 | 13q12.11 | Tumor suppressor gene, involved in 13 q loss | V | NA | Suppression of growth; invasion and metastasis | Invasion and metastasis; genome instability and mutations; escaping programmed cell death |
| CDX2 | Caudal type homeobox 2 | 13q12.2 | Tumor suppressor gene, involved in 13 q loss | V | NA | Proliferative signaling | ||
| BRCA2 | BRCA2 DNA repair associated | 13q13.1 | Tumor suppressor gene, involved in 13 q loss | V | NA | Genome instability and mutations; escaping programmed cell death | ||
| RB1 | RB transcriptional corepressor 1 | 13q14.2 | Tumor suppressor gene, involved in 13 q loss | V | NA | Suppression of growth; escaping programmed cell death; change of cellular energetics | Escaping immunic response to cancer; invasion and metastasis; genome instability and mutations; escaping programmed cell death | |
| GPC5 | Glypican 5 | 13q31.3 | Tumor suppressor gene, involved in 13 q loss | V | NA | Suppression of growth; invasion and metastasis | ||
| SOX21 | SRY-box transcription factor 21 | 13q32.1 | Tumor suppressor gene, involved in 13 q loss | V | NA | Suppression of growth | Proliferative signaling | |
| ERCC5 | ERCC excision repair 5, endonuclease | 13q33.1 | Tumor suppressor gene, involved in 13 q loss | V | NA | Genome instability and mutations; escaping programmed cell death | Genome instability and mutations | |
| SP-MPE | HOXB13 | Homeobox B13 | 17q21.32 | Amplification | III | Tier II, level C |
Change of cellular energetics | Escaping programmed cell death |
| SP-EPN-MYCN | MYCN | MYCN proto-oncogene, BHLH transcription factor | 2p24.3 | Amplification | II | Tier I, level A |
Proliferative signaling; escaping immunic response to cancer; angiogenesis; genome instability and mutations; change of cellular energetics | Cell replicative immortality; invasion and metastasis; escaping programmed cell death |
* The list of genes is selected from the Catalogue of Somatic Mutations in Cancer (COSMIC) Cancer Gene Census (https://cancer.sanger.ac.uk/census, accessed on 20 September 2021). Oncogenes and tumor suppressor genes are viewed as candidates for recurrent aberrations resulting in gain-of-function (1q gains) and loss-of-function (6q losses, 13q losses), respectively. ** Strength of evidence for gene diagnostic value based on Strength-of-evidence rating scheme of the Centre for Evidence-Based Medicine (https://www.cebm.net, accessed on 20 September 2021). *** Evidence-based variant (nucleotide substitution, copy-number variation, and fusion) of listed genes categorization based on the Joint Consensus Recommendation of the Association for Molecular Pathology, American Society of Clinical Oncology, and College of American Pathologists (AMP/ASCO/CAP recommendations). **** Potential roles of the cancer hallmark genes are annotated using COSMIC Cancer Gene Census (https://cancer.sanger.ac.uk/census, accessed on 20 September 2021), GeneCards: The Human Gene Database (https://www.genecards.org/, accessed on 20 September 2021), and KEGG: Kyoto Encyclopedia of Genes and Genomes (https://www.kegg.jp/kegg/, accessed on 20 September 2021). NA—nonapplicable.