Integrated genetic and epigenetic analysis defines novel molecular subgroups in rhabdomyosarcoma

Abstract

Rhabdomyosarcoma (RMS) is the most common soft-tissue sarcoma in childhood. Here we studied 60 RMSs using whole-exome/-transcriptome sequencing, copy number (CN) and DNA methylome analyses to unravel the genetic/epigenetic basis of RMS. On the basis of methylation patterns, RMS is clustered into four distinct subtypes, which exhibits remarkable correlation with mutation/CN profiles, histological phenotypes and clinical behaviours. A1 and A2 subtypes, especially A1, largely correspond to alveolar histology with frequent PAX3/7 fusions and alterations in cell cycle regulators. In contrast, mostly showing embryonal histology, both E1 and E2 subtypes are characterized by high frequency of CN alterations and/or allelic imbalances, FGFR4/RAS/AKT pathway mutations and PTEN mutations/methylation and in E2, also by p53 inactivation. Despite the better prognosis of embryonal RMS, patients in the E2 are likely to have a poor prognosis. Our results highlight the close relationships of the methylation status and gene mutations with the biological behaviour in RMS.

Pharmacological targeting of the ephrin receptor kinase signalling by GLPG1790 in vitro and in vivo reverts oncophenotype, induces myogenic differentiation and radiosensitizes embryonal rhabdomyosarcoma cells

“…Furthermore, GLPG1790 was able to radiosensitize ERMS cells by affecting the radiation-induced activation of the DNA-repair mechanisms. At molecular levels, GLPG1790 inhibited MAPK and AKT signal transduction pathways, two well-established major drivers of ERMS oncogenicity [22][23][24][25]. Similar effects were obtained by silencing EPH-A2 and/or EPH-B2, the principal EPH receptors targeted by GPLG1790 [21], this suggesting the specificity of GLPG1790 activity.…”

DNA Methylation–Based Classifier for Accurate Molecular Diagnosis of Bone Sarcomas

“…Methylation also provides novel insights into sarcomabiology, for example OS appears to be characterized by a consistently hypomethylated strip along chromosome 1q43, among other features. Furthermore, with development and integration of additional sarcoma classifiers, such as rhabdomyosarcoma [49], molecular diagnostics of all major sarcoma subgroups could be cost efficiently performed using a single, methylation based platform. A prospective study comparing the performance and cost-effectiveness of our methylation classifier and traditional immunohistochemical and FISH testing could represent a fruitful avenue of future research.…”

Frequent HRAS Mutations in Malignant Ectomesenchymoma

“…The lysine (K) amino acid shows a positive-charged side chain rather than the hydrophobic side chains of leucine (L). The prevalence of RAS mutations in ERMS ranges from 11.7% to 22.6% 20,21,30,31 . Among the 44 RAS -mutant ERMS from 4 series 20,21,30,31 , NRAS mutations are the most common (27, 61%), followed by KRAS (11, 25%) and HRAS mutations (6, 14%).…”

“…The prevalence of RAS mutations in ERMS ranges from 11.7% to 22.6% 20,21,30,31 . Among the 44 RAS -mutant ERMS from 4 series 20,21,30,31 , NRAS mutations are the most common (27, 61%), followed by KRAS (11, 25%) and HRAS mutations (6, 14%). The hot spots for both NRAS and HRAS mutations in ERMS occur in the codon 61 11,20,21,30 .…”