PMID- 22006429 OWN - NLM STAT- MEDLINE DCOM- 20120727 LR - 20211020 IS - 1097-0142 (Electronic) IS - 0008-543X (Print) IS - 0008-543X (Linking) VI - 118 IP - 11 DP - 2012 Jun 1 TI - High-throughput genotyping in osteosarcoma identifies multiple mutations in phosphoinositide-3-kinase and other oncogenes. PG - 2905-14 LID - 10.1002/cncr.26617 [doi] AB - 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. CI - Copyright (c) 2011 American Cancer Society. FAU - Choy, Edwin AU - Choy E AD - Division of Hematology Oncology, Massachusetts General Hospital, Boston, Massachusetts 02114, USA. echoy@partners.org FAU - Hornicek, Francis AU - Hornicek F FAU - MacConaill, Laura AU - MacConaill L FAU - Harmon, David AU - Harmon D FAU - Tariq, Zeeshan AU - Tariq Z FAU - Garraway, Levi AU - Garraway L FAU - Duan, Zhenfeng AU - Duan Z LA - eng GR - KL2 RR025757/RR/NCRR NIH HHS/United States GR - KL2 RR025757-01/RR/NCRR NIH HHS/United States GR - 1KL2RR025757-01/RR/NCRR NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20111017 PL - United States TA - Cancer JT - Cancer JID - 0374236 RN - 0 (Tumor Suppressor Proteins) RN - EC 2.7.1.- (Phosphatidylinositol 3-Kinases) RN - EC 2.7.1.137 (Class I Phosphatidylinositol 3-Kinases) RN - EC 2.7.1.137 (PIK3CA protein, human) SB - IM MH - Adult MH - Aged MH - Aged, 80 and over MH - Bone Neoplasms/*genetics MH - Cell Line, Tumor MH - Class I Phosphatidylinositol 3-Kinases MH - Gene Expression Profiling MH - Genotyping Techniques MH - Humans MH - Middle Aged MH - *Mutation MH - Oncogenes MH - Osteosarcoma/*genetics MH - Phosphatidylinositol 3-Kinases/*genetics MH - Signal Transduction/genetics MH - Tumor Suppressor Proteins/genetics PMC - PMC3272156 MID - NIHMS326752 EDAT- 2011/10/19 06:00 MHDA- 2012/07/28 06:00 PMCR- 2013/06/01 CRDT- 2011/10/19 06:00 PHST- 2011/07/08 00:00 [received] PHST- 2011/09/09 00:00 [revised] PHST- 2011/09/12 00:00 [accepted] PHST- 2011/10/19 06:00 [entrez] PHST- 2011/10/19 06:00 [pubmed] PHST- 2012/07/28 06:00 [medline] PHST- 2013/06/01 00:00 [pmc-release] AID - 10.1002/cncr.26617 [doi] PST - ppublish SO - Cancer. 2012 Jun 1;118(11):2905-14. doi: 10.1002/cncr.26617. Epub 2011 Oct 17.