New advances in the molecular classification of pediatric mesenchymal tumors

Abstract

Pediatric soft tissue tumors are relatively rare and show significant overlap in morphology and immunoprofile, often posing diagnostic and management challenges. Thus, their classification remains often subjective or lumped under "unclassified categories," as a number of lesions lack objective and reproducible criteria in diagnosis. Although in a subset of cases immunohistochemistry has been proved useful to identify a specific line of differentiation, most tumors lack a readily defined histogenesis, being characterized by a rather non-specific immunoprofile. Furthermore, tumors with an ambiguous diagnosis are difficult to grade and their risk of malignancy or clinical management remains uncertain. Advances in molecular genetics, including the more wide application of next generation sequencing in routine clinical practice, have improved diagnosis and refined classification based on objective molecular markers. Importantly, some soft tissue tumors in children are characterized by recurrent gene fusions involving either growth factors (eg, PDGFB) or protein kinases (eg, ALK, ROS, NTRK, BRAF), which have paved the way for new targeted treatments that block the respective upregulated downstream pathways. However, the majority of gene fusions or mutations detected in soft tissue tumors result in an abnormal function of transcription factors or chromatin remodeling. The present review focuses on the latest genetic discoveries in the spectrum of both benign and malignant pediatric soft tissue neoplasia. These genetic abnormalities promise to provide relevant insight for their proper classification, prognosis, and treatment. The entities discussed herein are grouped either based on their shared genetic mechanism or based on their presumed line of differentiation.

Hippo pathway effectors YAP1/TAZ induce an EWS–FLI1‐opposing gene signature and associate with disease progression in Ewing sarcoma

“…Another fact that supports the relevance of YAP1/TAZ and other Hippo signaling effectors in sarcomas is their involvement in recurrent fusion genes in certain histological types . Notwithstanding, aberrant activation of YAP1/TAZ in cancer is often promoted by mechanisms not involving somatic alterations.…”

Pediatric fibromyxoid soft tissue tumor with PLAG1 fusion: A novel entity?

“…Over the past few decades, it has been determined that many pediatric soft tissue neoplasms possess gene fusions that are diagnostic, or become so in the context of the histopathologic findings of the particular tumor 1,2 . Yet, there remain tumors that lack morphologies and immunohistochemical profiles distinctive enough to allow a definitive and reproducible diagnosis, and instead are labeled descriptively, such as “unclassified spindle cell neoplasm.” This category is decreasing at an accelerated pace due to the application of more modern molecular genetic techniques including next‐generation sequencing panels, anchored multiplex polymerase chain reaction systems to detect the partner for a known fusion gene, and comprehensive RNA sequencing.…”

Coiled‑coil domain‑containing 68 promotes non‑small cell lung cancer cell proliferation <em>in&nbsp;vitro</em>

“…During the past two decades, there has been a focus on identifying potential biomarkers for the diagnosis and treatment of malignant tumors, such as DNA methylation ( 15 ), growth factors and protein kinases ( 16 ). Research on lung cancer is more prominent ( 17 ), and specific driver mutations, such as those in epidermic growth factor receptor, anaplastic lymphoma kinase and v-ros avian UR2 sarcoma virus oncogene homolog 1, can be used to identify patients that are sensitive to certain inhibitors, such as gefitinib, crizotinib, and others ( 18 – 20 ).…”