title: A case study of an integrative genomic and experimental therapeutic approach for rare tumors: identification of vulnerabilities in a pediatric poorly differentiated carcinoma.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  This clinical case illustrates the depth of investigation necessary to fully characterize the functional significance of the breadth of alterations identified through genomic analysis.
authors: Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA. delacrf1@mskcc.org.
authors: Filemon S
authors: FS
authors: Dela Cruz
authors: Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
authors: Daniel
authors: D
authors: Diolaiti
authors: Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY, 10032, USA.
authors: Andrew T
authors: AT
authors: Turk
authors: Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
authors: Allison R
authors: AR
authors: Rainey
authors: Department of Systems Biology, Columbia University Medical Center, New York, NY, 10032, USA.
authors: Alberto
authors: A
authors: Ambesi-Impiombato
authors: Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY, 10032, USA.
authors: Stuart J
authors: SJ
authors: Andrews
authors: Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY, 10032, USA.
authors: Mahesh M
authors: MM
authors: Mansukhani
authors: Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY, 10032, USA.|Present Address: Medical Neurogenetics Laboratories, Atlanta, GA, 30342, USA.
authors: Peter L
authors: PL
authors: Nagy
authors: Darwin Health Inc., New York, NY, 10032, USA.
authors: Mariano J
authors: MJ
authors: Alvarez
authors: Department of Systems Biology, Columbia University Medical Center, New York, NY, 10032, USA.
authors: Andrea
authors: A
authors: Califano
authors: Department of Biological Sciences, Columbia University, New York, NY, 10027, USA.
authors: Farhad
authors: F
authors: Forouhar
authors: Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
authors: Beata
authors: B
authors: Modzelewski
authors: Department of Pediatrics, Columbia University Medical Center, New York, NY, 10032, USA.
authors: Chelsey M
authors: CM
authors: Mitchell
authors: Department of Pediatrics, Columbia University Medical Center, New York, NY, 10032, USA.
authors: Darrell J
authors: DJ
authors: Yamashiro
authors: Department of Pediatrics, Columbia University Medical Center, New York, NY, 10032, USA.
authors: Lianna J
authors: LJ
authors: Marks
authors: Department of Pediatrics, Columbia University Medical Center, New York, NY, 10032, USA.
authors: Julia L
authors: JL
authors: Glade Bender
authors: Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA. kunga@mskcc.org.
authors: Andrew L
authors: AL
authors: Kung
mesh_terms: D000293:Adolescent; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D016190:Carboplatin / Q000009:adverse effects; D002277:Carcinoma / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000235:genetics*; D004252:DNA Mutational Analysis; D005047:Etoposide / Q000009:adverse effects; D017809:Fatal Outcome; D023281:Genomics / Q000379:methods*; D006801:Humans; D008297:Male; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D017239:Paclitaxel / Q000009:adverse effects; D035583:Rare Diseases / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000235:genetics*; D012535:Scalp / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
chemical_list: D005047:Etoposide; D016190:Carboplatin; D017239:Paclitaxel
keywords: BRAF; MAX; Patient-derived xenograft (PDX) models; Poorly differentiated carcinoma (PDC); Precision medicine; Temsirolimus; Whole exome sequencing (WES); mTOR