A genomic case study of desmoplastic small round cell tumor: comprehensive analysis reveals insights into potential therapeutic targets and development of a monitoring tool for a rare and aggressive disease

Abstract

BackgroundGenome-wide profiling of rare tumors is crucial for improvement of diagnosis, treatment, and, consequently, achieving better outcomes. Desmoplastic small round cell tumor (DSRCT) is a rare type of sarcoma arising from mesenchymal cells of abdominal peritoneum that usually develops in male adolescents and young adults. A specific translocation, t(11;22)(p13;q12), resulting in EWS and WT1 gene fusion is the only recurrent molecular hallmark and no other genetic factor has been associated to this aggressive tumor. Here, we present a comprehensive genomic profiling of one DSRCT affecting a 26-year-old male, who achieved an excellent outcome.MethodsWe investigated somatic and germline variants through whole-exome sequencing using a family based approach and, by array CGH, we explored the occurrence of genomic imbalances. Additionally, we performed mate-paired whole-genome sequencing for defining the specific breakpoint of the EWS-WT1 translocation, allowing us to develop a personalized tumor marker for monitoring the patient by liquid biopsy.ResultsWe identified genetic variants leading to protein alterations including 12 somatic and 14 germline events (11 germline compound heterozygous mutations and 3 rare homozygous polymorphisms) affecting genes predominantly involved in mesenchymal cell differentiation pathways. Regarding copy number alterations (CNA) few events were detected, mainly restricted to gains in chromosomes 5 and 18 and losses at 11p, 13q, and 22q. The deletions at 11p and 22q indicated the presence of the classic translocation, t(11;22)(p13;q12). In addition, the mapping of the specific genomic breakpoint of the EWS-WT1 gene fusion allowed the design of a personalized biomarker for assessing circulating tumor DNA (ctDNA) in plasma during patient follow-up. This biomarker has been used in four post-treatment blood samples, 3 years after surgery, and no trace of EWS-WT1 gene fusion was detected, in accordance with imaging tests showing no evidence of disease and with the good general health status of the patient.ConclusionsOverall, our findings revealed genes with potential to be associated with risk assessment and tumorigenesis of this rare type of sarcoma. Additionally, we established a liquid biopsy approach for monitoring patient follow-up based on genomic information that can be similarly adopted for patients diagnosed with a rare tumor.Electronic supplementary materialThe online version of this article (doi:10.1186/s40246-016-0092-0) contains supplementary material, which is available to authorized users.

Clinicopathologic and molecular features of intracranial desmoplastic small round cell tumors

“…Inactivating mutations in STAG2 are the most frequent accompanying somatic mutation in Ewing sarcoma, occurring in approximately 17% of cases, and are associated with poor outcome (10,51). To the best of our knowledge, among the relatively few cases of DSRCT that have either undergone extensive genetic sequencing (13,16,46) or sequencing focused specifically on accompanying STAG2 or TP53 mutations (45), only one additional case with a STAG2 mutation has been reported (45). This patient's EWSR1-WT1 gene fusion and accompanying inactivating STAG2 splice site mutation were detected within tumor tissue and within plasma derived cell free DNA (45).…”

Primary desmoplastic small-round-cell tumor of the ovary

“…The typical histopathological appearance of DSRCTs includes large necrotic area, sharply demarcated nests of different sizes containing small round cells with hyperchromatic nuclei and scanty faint eosinophilic cytoplasm, or spindle cells embedded in a desmoplastic stroma. These cells mostly exhibit epithelial, mesenchymal, and neural markers like cytokeratin, desmin, and smooth muscle actin (SMA) [14]. Desmoplastic smallround-cell tumor arises from mesenchymal cells of the abdominopelvic peritoneum.…”

Mini-Review on Targeted Treatment of Desmoplastic Small Round Cell Tumor

“…The authors subsequently classified the affected genes by biological function and more than a quarter of the mutated genes belonged to either DNA damage-response network (DDR) or genes that belong to mesenchymal-epithelial reverse transition (MErT), and EMT (epithelial-mesenchymal transition). Of interest, another WES study in DSRCT in one patient with DSRCT showed 12 somatic and 14 germline events in genes which were predominantly involved in mesenchymal differentiation (24) Poly(ADP-ribose) polymerase or PARP inhibitor has been suggested to be active in tumors with deficiency in DDR and in combination with DNA damaging agents (25). Currently there is a clinical trial underway for refractory pediatric solid tumors, which is investigating PARP inhibition using olaparib (26).…”