Genomic Profiling of a Large Set of Diverse Pediatric Cancers Identifies Known and Novel Mutations across Tumor Spectra

Abstract

Pediatric cancers are generally characterized by low mutational burden and few recurrently mutated genes. Recent studies suggest that genomic alterations may help guide treatment decisions and clinical trial selection. Here, we describe genomic profiles from 1,215 pediatric tumors representing sarcomas, extracranial embryonal tumors, brain tumors, hematologic malignancies, carcinomas, and gonadal tumors. Comparable published datasets identified similar frequencies of clinically relevant alterations, validating this dataset as biologically relevant. We identified novel ALK fusions in a neuroblastoma (BEND5-ALK) and an astrocytoma (PPP1CB-ALK), novel BRAF fusions in an astrocytoma (BCAS1-BRAF) and a ganglioglioma (TMEM106B-BRAF), and a novel PAX3-GLI2 fusion in a rhabdomyosarcoma. Previously characterized ALK, NTRK1, and PAX3 fusions were observed in unexpected malignancies, challenging the "disease-specific" alterations paradigm. Finally, we identified recurrent variants of unknown significance in MLL3 and PRSS1 predicted to have functional impact. Data from these 1,215 tumors are publicly available for discovery and validation.

Olaratumab Exerts Antitumor Activity in Preclinical Models of Pediatric Bone and Soft Tissue Tumors through Inhibition of Platelet-Derived Growth Factor Receptor α

“…Although PDGFRA is not frequently altered in childhood cancers (19,38,39), receptor expression is associated with progressive disease and poor prognosis in some pediatric malignancies of bone and soft tissue (11,26,40). Expression of the receptor was readily detected in several osteosarcoma cell lines and PDX models, which was expected, as 50% of osteosarcoma primary samples were previously found to be PDGFRa positive (23).…”

“…Although the prevalence of PDGFRA genetic aberrations in pediatric cancer is reported to be only about 2% (19), members of the PDGF pathway are highly expressed in several subtypes of pediatric bone and soft tissue tumors, including rhabdomyosarcoma (20,21), synovial sarcoma (22), osteogenic sarcoma (23), Ewing sarcoma (24), and MRT (25). In addition, PDGFRa expression is linked to adverse outcomes in pediatric patients with rhabdomyosarcoma (26).…”

Advances in ALK Targeted Therapy for Neuroblastoma

“…So far, more than 35 ALK variants have been detected in neuroblastoma, predominantly point mutations [21], with fewer cases of truncated extracellular domain [22,23] and BEND5-ALK fusion protein [7]. ALK mutations are found in almost all cases of familial neuroblastoma (<2% of all neuroblastoma) [24].…”

“…[3][4][5][6]. Next-generation sequencing-based genomic profiling identified the most frequent alterations including MYCN (26.5%), ALK (17.8%), ATRX (6.5%), CDKN2A (4.8%) and RPTOR (4.8%) in 230 neuroblastoma patient samples [7]. Both ALK and MYCN genes are located in chromosome 2p, a chromosomal alteration identified as a statistically significant prognostic factor [8].…”

Neuroblastoma: Genetic, Epigenetic Mechanisms and Targeted Therapy Approaches: Review

“…Özellikle, tümör baskılayıcı ve aday tümör baskılayıcı genlerin kodlamayan bölgelerin-deki mutasyonlar, yüksek risk nöroblastomda oldukça etkilidir. 9 Konvansiyonel nöroblastom tedavisi, hastaların risk grubuna bağlı olarak primer tümörün cerrahi olarak çıkarılması, kemoterapi, otolog hema topoietik kök hücre nakli, radyoterapi yaklaşımla-rını içermektedir. Tedaviyi izleyen süreçte, hastada kemoterapötiklere karşı direnç gelişimi ya da nüks sıklıkla ortaya çıkmaktadır.…”