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Cancer. 2012 Jun 1;118(11):2905-14. doi: 10.1002/cncr.26617. Epub 2011 Oct 17.

High-throughput genotyping in osteosarcoma identifies multiple mutations in phosphoinositide-3-kinase and other oncogenes.

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  • 1Division of Hematology Oncology, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.



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.


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.


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.


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.

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