Related Experiment Video
Updated: May 28, 2026
Testing Targeted Therapies in Cancer using Structural DNA Alteration Analysis and Patient-Derived Xenografts
Published on: July 25, 2020
High-throughput genotyping in osteosarcoma identifies multiple mutations in phosphoinositide-3-kinase and other
Edwin Choy1, Francis Hornicek, Laura MacConaill
1Division of Hematology Oncology, Massachusetts General Hospital, Boston, Massachusetts 02114, USA. echoy@partners.org
Background:
The identification of new genes that are mutated in osteosarcomas is critical to developing a better understanding of the molecular pathogenesis of this disease and discovering new targets for therapeutic development.
Methods:
The authors identified somatic nonsynonymous coding mutations in oncogenes associated with human cancers and hotspot mutations from tumor suppressor genes that were either well described in the literature or observed multiple times in human cancer sequencing efforts. Then, 961 mutations in 89 genes were systematically characterized across 98 osteosarcoma tumor samples and cell lines. All identified mutations were replicated on an independent platform using homogeneous mass extend matrix-assisted laser desorption/ionization time-of-flight mass spectrometry.
Results:
In total, 14 mutations were identified in at least 1 osteosarcoma tumor sample or cell line. Some of the genetic changes identified were in tumor suppressor genes previously identified as altered in osteosarcoma: p53 (arginine→histidine at codon 273 [R273H], R→cysteine at codon 723 [R273C], and tyrosine→C at codon 163 [Y163C]) and retinoblastoma 1 (RB1) (glutamic acid→* at codon 137 [E137*]). Notably, multiple mutations were identified in phosphoinositide-3-kinase (PI3K), catalytic, alpha polypeptide (PIK3CA) (H1047R, E→lysine at codon 545 [E545K], and H→proline at codon 701 [H701P]) that were not observed previously in osteosarcoma. In addition, mutations in v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) (glycine→serine at codon 12 [G12S]); cubilin (CUBN) (isolucine→valine at codon 3189 [I3189V]; observed in 2 separate tumor samples); cadherin 1, type 1, epithelial (CDH1) (alanine→threonine at codon 617 [A617T]; observed in 2 separate tumor samples); catenin (cadherin-associated protein), beta 1, 88 kDa (CTNNB1) (asparagine→S at codon 287 [N287S]); and fibrous sheath CABYR binding protein (FSCB) (S→leucine at codon 775 [S775L]) were observed.
Conclusions:
In this largest mutational profiling of osteosarcoma to date, the authors identified for the first time several mutations involving the PI3K pathway, adding osteosarcoma to the growing list of malignancies with PI3K mutations. In addition, they initiated a mutational map detailing DNA sequence changes across a variety of osteosarcoma subtypes and offered new candidates for therapeutic targeting.
Insights
This study identified novel mutations in osteosarcoma, including PI3K pathway alterations, providing new therapeutic targets. This research advances understanding of osteosarcoma
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Osteosarcoma molecular pathogenesis requires identification of new mutated genes.
- Discovering novel therapeutic targets is critical for osteosarcoma treatment.
Purpose of the Study:
- To perform comprehensive mutational profiling of osteosarcoma.
- To identify novel genetic alterations and potential therapeutic targets in osteosarcoma.
Main Methods:
- Systematic characterization of 961 mutations across 89 genes in 98 osteosarcoma samples.
- Identification of somatic nonsynonymous coding mutations in oncogenes and hotspot mutations in tumor suppressor genes.
- Replication of identified mutations using homogeneous mass extend matrix-assisted laser desorption/ionization time-of-flight mass spectrometry.
Main Results:
- 14 mutations were identified in osteosarcoma samples.
- Mutations in known osteosarcoma genes (p53, RB1) were confirmed.
- Novel mutations were found in PI3K pathway genes (PIK3CA), KRAS, CUBN, CDH1, CTNNB1, and FSCB.
Conclusions:
- This study represents the largest mutational profiling of osteosarcoma to date.
- Novel PI3K pathway mutations were identified in osteosarcoma, linking it to other malignancies with PI3K alterations.
- A mutational map of osteosarcoma subtypes was created, offering new therapeutic targets.
