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Hum Genomics. 2016 Nov 18;10(1):36.

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.

Author information

1
International Research Center/CIPE, A.C. Camargo Cancer Center, São Paulo, SP, Brazil.
2
Instituto Metrópole Digital, Federal University of Rio Grande do Norte, Natal, RN, Brazil.
3
Institute of Biosciences, University of São Paulo, São Paulo, SP, Brazil.
4
Departament of Abdominal Surgery, A.C. Camargo Cancer Center, São Paulo, SP, Brazil.
5
Department of Anatomic Pathology, A.C. Camargo Cancer Center, São Paulo, SP, Brazil.
6
Federal University of Rio Grande do Norte, Natal, RN, Brazil.
7
International Research Center/CIPE, A.C. Camargo Cancer Center, São Paulo, SP, Brazil. dirce.carraro@cipe.accamargo.org.br.

Abstract

BACKGROUND:

Genome-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.

METHODS:

We 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.

RESULTS:

We 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.

CONCLUSIONS:

Overall, 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.

KEYWORDS:

Desmoplastic small round cell tumor; EWS-WT1 gene fusion; Genomic profiling; Liquid biopsy; Personalized biomarker; Whole-exome sequencing

PMID:
27863505
PMCID:
PMC5116179
DOI:
10.1186/s40246-016-0092-0
[Indexed for MEDLINE]
Free PMC Article

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