title: 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: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: International Research Center/CIPE, A.C. Camargo Cancer Center, São Paulo, SP, Brazil.
authors.forename: Elisa Napolitano
authors.initials: EN
authors.lastname: Ferreira
authors.affiliation: International Research Center/CIPE, A.C. Camargo Cancer Center, São Paulo, SP, Brazil.
authors.forename: Bruna Durães Figueiredo
authors.initials: BD
authors.lastname: Barros
authors.affiliation: Instituto Metrópole Digital, Federal University of Rio Grande do Norte, Natal, RN, Brazil.
authors.forename: Jorge Estefano
authors.initials: JE
authors.lastname: de Souza
authors.affiliation: International Research Center/CIPE, A.C. Camargo Cancer Center, São Paulo, SP, Brazil.
authors.forename: Renan Valieris
authors.initials: RV
authors.lastname: Almeida
authors.affiliation: International Research Center/CIPE, A.C. Camargo Cancer Center, São Paulo, SP, Brazil.
authors.forename: Giovana Tardin
authors.initials: GT
authors.lastname: Torrezan
authors.affiliation: International Research Center/CIPE, A.C. Camargo Cancer Center, São Paulo, SP, Brazil.
authors.forename: Sheila
authors.initials: S
authors.lastname: Garcia
authors.affiliation: Institute of Biosciences, University of São Paulo, São Paulo, SP, Brazil.
authors.forename: Ana Cristina Victorino
authors.initials: AC
authors.lastname: Krepischi
authors.affiliation: Departament of Abdominal Surgery, A.C. Camargo Cancer Center, São Paulo, SP, Brazil.
authors.forename: Celso Abdon Lopes de
authors.initials: CA
authors.lastname: Mello
authors.affiliation: Department of Anatomic Pathology, A.C. Camargo Cancer Center, São Paulo, SP, Brazil.
authors.forename: Isabela Werneck da
authors.initials: IW
authors.lastname: Cunha
authors.affiliation: Department of Anatomic Pathology, A.C. Camargo Cancer Center, São Paulo, SP, Brazil.
authors.forename: Clóvis Antonio Lopes
authors.initials: CA
authors.lastname: Pinto
authors.affiliation: Department of Anatomic Pathology, A.C. Camargo Cancer Center, São Paulo, SP, Brazil.
authors.forename: Fernando Augusto
authors.initials: FA
authors.lastname: Soares
authors.affiliation: International Research Center/CIPE, A.C. Camargo Cancer Center, São Paulo, SP, Brazil.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Dias-Neto
authors.affiliation: Departament of Abdominal Surgery, A.C. Camargo Cancer Center, São Paulo, SP, Brazil.
authors.forename: Ademar
authors.initials: A
authors.lastname: Lopes
authors.affiliation: Federal University of Rio Grande do Norte, Natal, RN, Brazil.
authors.forename: Sandro José
authors.initials: SJ
authors.lastname: de Souza
authors.affiliation: International Research Center/CIPE, A.C. Camargo Cancer Center, São Paulo, SP, Brazil. dirce.carraro@cipe.accamargo.org.br.
authors.forename: Dirce Maria
authors.identifier: 0000-0001-5667-1418
authors.initials: DM
authors.lastname: Carraro
mesh_terms: D000008:Abdominal Neoplasms / Q000000981:diagnostic imaging* / Q000235:genetics / Q000628:therapy; D000328:Adult; D014408:Biomarkers, Tumor / Q000097:blood / Q000235:genetics; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics; D004273:DNA, Neoplasm / Q000097:blood / Q000235:genetics; D058405:Desmoplastic Small Round Cell Tumor / Q000000981:diagnostic imaging* / Q000235:genetics / Q000628:therapy; D006801:Humans; D008297:Male; D025202:Molecular Diagnostic Techniques; D011110:Polymorphism, Genetic; D014178:Translocation, Genetic
chemical_list: D014408:Biomarkers, Tumor; D004273:DNA, Neoplasm
keywords: Desmoplastic small round cell tumor; EWS-WT1 gene fusion; Genomic profiling; Liquid biopsy; Personalized biomarker; Whole-exome sequencing