Genomic and transcriptomic characterization of desmoplastic small round cell tumors

Abstract

Desmoplastic small round cell tumor (DSRCT) is a highly aggressive soft tissue tumor primarily affecting children and young adults. Most cases display a pathognomonic EWSR1‐WT1 gene fusion, presumably constituting the primary driver event. Little is, however, known about secondary genetic changes that may affect tumor progression. We here studied 25 samples from 19 DSRCT patients using single nucleotide polymorphism arrays and found that all samples had copy number alterations. The most common imbalances were gain of chromosomes/chromosome arms 1/1q and 5/5p and loss of 6/6q and 16/16q, all occurring in at least eight of the patients. Five cases showed homozygous deletions, affecting a variety of known tumor suppressor genes, for example, CDKN2A and NF1. As almost all patients died of their disease, the impact of individual imbalances on survival could not be evaluated. Global gene expression analysis using mRNA sequencing on fresh‐frozen samples from seven patients revealed a distinct transcriptomic profile, with enrichment of genes involved in neural differentiation. Two genes ‐ GJB2 and GAL ‐ that showed higher expression in DSRCT compared to control tumors could be further investigated for their potential as diagnostic markers at the protein level.

Amplification of ERBB2 (HER2) in embryonal rhabdomyosarcoma: A potential treatment target in rare cases?

“…Here, the tumor DNA was re‐examined using the Affymetrix Cytoscan HD array (Affymetrix, Santa Clara, CA). The analysis was performed as described 11 . Tumor Aberration Prediction Suite (TAPS) and Rawcopy, with an adaptation for genome build hg38, were used for segmentation of copy number shifts, copy number evaluation, and visualization of the data 12,13 .…”

“…The analysis was performed as described. 11 Tumor Aberration Prediction Suite (TAPS) and Rawcopy, with an adaptation for genome build hg38, were used for segmentation of copy number shifts, copy number evaluation, and visualization of the data. 12,13 ASCAT was further employed to assess purity, ploidy, and copy number levels.…”

Application of Multi-Omics Approach in Sarcomas: A Tool for Studying Mechanism, Biomarkers, and Therapeutic Targets

“…In sarcoma research above, plenty characteristics of different omics were discovered (Table 2). Several types of sarcomas exhibit relatively low rate of somatic mutation, and such phenomenon was observed in some of the multi-omics studies, whereas a large number of CNVs were discovered, along with structural mutations and DNA methylation (13,19,20,23,29,32,37,42,46). The few tumorigenic driver genes, together with the genetic amplifications and deletions, construct an environment suitable for the development of malignancy.…”

“…The upregulation of WT1 was confirmed in a study using RNA-seq, as well as other neural differentiation-related gene such as GJB2, GAL, GALP, and ASCL1. Meanwhile, the SNP arrays showed extensive copy number changes, the most frequent being gain of chromosome arm 1/1q and 5/5p and loss of 6/6q or 16/16q (13). The mechanism underneath needs further exploration.…”

Biology-guided precision medicine in rare cancers: Lessons from sarcomas and neuroendocrine tumours

“…Ewing sarcoma and alveolar rhabdomyosarcoma are highly susceptible subtypes. In contrast, desmoplastic small round cell tumour, which is often treated according to chemotherapy schedules for Ewing sarcoma, is characterised by a high rate of secondary drug resistance and worse outcome, possibly due to extensive acquired DNA copy number changes [34], and alveolar soft part sarcoma and clear cell sarcoma are almost uniformly refractory to chemotherapy.…”