A Step Forward in Realizing the Promise of Genomic Medicine for Childhood Rhabdomyosarcoma
Menée à partir d'échantillons tumoraux prélevés sur 641 patients pédiatriques atteints d'un rhabdomyosarcome, cette étude identifie les caractéristiques génomiques des tumeurs et analyse leur association avec les résultats cliniques
Rhabdomyosarcoma (RMS) is a rare mesenchymal malignancy that is primarily a disease of children and adolescents with approximately 50% of patients being diagnosed in the first decade of life.1 Clinicians recognized early the value of histologic classification dividing RMS broadly into embryonal rhabdomyosarcoma (ERMS) and alveolar rhabdomyosarcoma (ARMS) subtypes with the former having a more favorable prognosis.2 The earliest known molecular finding in RMS was the loss of heterozygosity at chromosome 11p15.3 Soon after, almost 30 years ago, the discovery of the recurring translocations between chromosome 2 or 1 and chromosome 13 resulting in the fusion of the PAX3 or PAX7 gene with the FOXO1 (FKHR) gene became pathognomonic of ARMS as it was seen in the majority of cases.4-6 In addition to loss of heterozygosity at 11p15 that was more frequently noted in ERMS, loss of imprinting at the same locus was noted in ARMS.7 Subsequently, a smaller subset of alveolar histology that did not harbor the FOXO1 fusion was found to have a gene expression profile and a more favorable prognosis similar to ERMS.8,9 However, there was significant hesitancy for many years to classify RMS molecularly into two broad categories of FOXO1 fusion–positive (FP) or FOXO1 fusion–negative (FN) subgroups.10 It is relatively recent that sufficient data have been generated to broadly use this molecular classification together with Clinical Stage and Group.11,12 Other molecular findings described in RMS include copy number variations including gene amplifications, and point mutations culminating in a landmark report of the genomic landscape of childhood RMS13-15 and have been recently summarized.16 As such, ERMS may be considered a malignancy featured by point mutations and aneuploidy, whereas ARMS is a malignancy of gene fusions and amplifications. Pleomorphic rhabdomyosarcoma represents a third genomic form of RMS, with greater kinship to undifferentiated pleomorphic sarcoma than ERMS or ARMS.17,18 Pleomorphic rhabdomyosarcoma is found nearly exclusively in adults and is not studied in pediatric clinical trials.
Journal of Clinical Oncology , éditorial en libre accès, 2020