Fusion genes as biomarkers in pediatric cancers: A review of the current state and applicability in diagnostics and personalized therapy

Abstract

The incidence of pediatric cancers is rising steadily across the world, along with the challenges in understanding the molecular mechanisms and devising effective therapeutic strategies. Pediatric cancers are presented with diverse molecular characteristics and more distinct subtypes when compared to adult cancers. Recent studies on the genomic landscape of pediatric cancers using next-generation sequencing (NGS) approaches have redefined this field by providing better subtype characterization and novel actionable targets. Since early identification and personalized treatment strategies influence therapeutic outcomes, survival, and quality of life in pediatric cancer patients, the quest for actionable biomarkers is of great value in this field. Fusion genes that are prevalent and recurrent in several pediatric cancers are ideally suited in this context due to their disease-specific occurrence. In this review, we explore the current status of fusion genes in pediatric cancer subtypes and their use as biomarkers for diagnosis and personalized therapy. We discuss the technological advancements made in recent years in NGS sequencing and their impact on fusion detection algorithms that have revolutionized this field. Finally, we also discuss the advantages of pairing liquid biopsy protocols for fusion detection and their eventual use in diagnosis and treatment monitoring.

Keywords: Fusion genes; Next-generation sequencing; Pediatric cancer; ctDNA.

Figure 1:

Types of pediatric cancers, along with recurrent fusions identified in each cancer. Only fusions that were reported to be recurrent or had participating genes associated functionally to cancer or tissue type are included. Cancer incidence data were compiled from the SEER incidence report and CBTRUS Statistical Report. Craniopharyngioma: CP, Germ cell tumors: GCT, Pilocytic Astrocytoma: PA; Neuronal & mixed neuronal-glial tumors: NMN-GT, Nerve sheath tumors: NST, Tumors of the pituitary: PT, Meningioma: MGM, Glioblastoma: GBM, Ependymal tumors: ET, Glioma malignant NOS; GMNOS. Acute myeloid leukemia: AML, Chronic myeloproliferative diseases: CMD, Myelodysplastic syndrome and other myeloproliferative: MS&M, Unspecified and other specified leukemias: U&SL, Hodgkin lymphoma: HL, Non-Hodgkin lymphoma (except Burkitt lymphoma): N-HL, Unspecified lymphomas: US-L, Miscellaneous lymphoreticular neoplasms: MLN, Neuroblastoma: NB, Retinoblastoma: RB, Primitive neuroectodermal tumor: PNET, Atypical Teratoid Rhabdoid Tumors: ATRT.

Figure 2:

Distribution of fusion genes in pediatric cancers with known oncogenic function along with fusion gene partners that are drug targets. The pie denotes the distribution of fusions with known functional activity. The blue and the red dots denote their function, i.e.,if they act through transcriptional regulation or epigenetic regulation, respectively. Genes in the inner part of the pie denote drug targets that are currently approved for treatment or are at various stages of clinical trials in several cancers, which could be explored further for drug repurposing studies. T-ALL: T-cell acute lymphoblastic leukemia, B-ALL: B-cell acute lymphoblastic leukemia, AML: Acute myeloid leukemia, ARS: Alveolar rhabdosarcoma, EWS: Ewings sarcoma, SS: Synovial sarcoma, NB: neuroblastoma, RC: Renal carcinoma, RS: renal sarcoma, OS: osteosarcoma.

Figure 3:

Upset plot demonstrates shared fusions across different pediatric cancers. Shared fusions between cancers are given in the boxes below the graph. T-ALL: T-cell acute lymphoblastic leukemia, B-ALL: B-cell acute lymphoblastic leukemia, AML: Acute myeloid leukemia, ARS: Alveolar rhabdosarcoma, EWS: Ewing’s sarcoma, SS: Synovial sarcoma, NB: neuroblastoma, RC: Renal carcinoma, RS: renal sarcoma, OS: osteosarcoma, MB: medulloblastoma, ASPS: Alveolar soft part sarcoma, HRS: Homogeneous type of well-differentiated rhabdomyosarcoma (defined by specific translocations of the SRF (serum response factor) gene. Cancers that share two or more fusions are color-coded, and the fusions are highlighted. A complete list of shared fusions can be found in supplementary Table 3.