A case study of an integrative genomic and experimental therapeutic approach for rare tumors: identification of vulnerabilities in a pediatric poorly differentiated carcinoma

Genome Med. 2016 Oct 31;8(1):116. doi: 10.1186/s13073-016-0366-0.


Background: Precision medicine approaches are ideally suited for rare tumors where comprehensive characterization may have diagnostic, prognostic, and therapeutic value. We describe the clinical case and molecular characterization of an adolescent with metastatic poorly differentiated carcinoma (PDC). Given the rarity and poor prognosis associated with PDC in children, we utilized genomic analysis and preclinical models to validate oncogenic drivers and identify molecular vulnerabilities.

Methods: We utilized whole exome sequencing (WES) and transcriptome analysis to identify germline and somatic alterations in the patient's tumor. In silico and in vitro studies were used to determine the functional consequences of genomic alterations. Primary tumor was used to generate a patient-derived xenograft (PDX) model, which was used for in vivo assessment of predicted therapeutic options.

Results: WES revealed a novel germline frameshift variant (p.E1554fs) in APC, establishing a diagnosis of Gardner syndrome, along with a somatic nonsense (p.R790*) APC mutation in the tumor. Somatic mutations in TP53, MAX, BRAF, ROS1, and RPTOR were also identified and transcriptome and immunohistochemical analyses suggested hyperactivation of the Wnt/ß-catenin and AKT/mTOR pathways. In silico and biochemical assays demonstrated that the MAX p.R60Q and BRAF p.K483E mutations were activating mutations, whereas the ROS1 and RPTOR mutations were of lower utility for therapeutic targeting. Utilizing a patient-specific PDX model, we demonstrated in vivo activity of mTOR inhibition with temsirolimus and partial response to inhibition of MEK.

Conclusions: This clinical case illustrates the depth of investigation necessary to fully characterize the functional significance of the breadth of alterations identified through genomic analysis.

Keywords: BRAF; MAX; Patient-derived xenograft (PDX) models; Poorly differentiated carcinoma (PDC); Precision medicine; Temsirolimus; Whole exome sequencing (WES); mTOR.

Publication types

  • Case Reports

MeSH terms

  • Adolescent
  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Carboplatin / adverse effects
  • Carcinoma / diagnostic imaging
  • Carcinoma / drug therapy*
  • Carcinoma / genetics*
  • DNA Mutational Analysis
  • Etoposide / adverse effects
  • Fatal Outcome
  • Genomics / methods*
  • Humans
  • Male
  • Mice, Inbred NOD
  • Mice, Knockout
  • Mice, SCID
  • Paclitaxel / adverse effects
  • Rare Diseases / diagnostic imaging
  • Rare Diseases / drug therapy*
  • Rare Diseases / genetics*
  • Scalp / drug effects
  • Scalp / metabolism
  • Scalp / pathology
  • Xenograft Model Antitumor Assays


  • Etoposide
  • Carboplatin
  • Paclitaxel