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

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

Author information

1
Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA. delacrf1@mskcc.org.
2
Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
3
Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY, 10032, USA.
4
Department of Systems Biology, Columbia University Medical Center, New York, NY, 10032, USA.
5
Present Address: Medical Neurogenetics Laboratories, Atlanta, GA, 30342, USA.
6
Darwin Health Inc., New York, NY, 10032, USA.
7
Department of Biological Sciences, Columbia University, New York, NY, 10027, USA.
8
Department of Pediatrics, Columbia University Medical Center, New York, NY, 10032, USA.
9
Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA. kunga@mskcc.org.

Abstract

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

PMID:
27799065
PMCID:
PMC5088685
DOI:
10.1186/s13073-016-0366-0
[Indexed for MEDLINE]
Free PMC Article

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