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

Abstract

Background 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 We identified somatic non-synonymous coding mutations in oncogenes associated with human cancers and hotspot mutations from tumor suppressor genes that were either well-described in literature or seen multiple times in human cancer sequencing efforts. We then systematically characterized 961 mutations in 89 genes across 98 osteosarcoma tumor samples and cell lines. All identified mutations were replicated on an independent platform using homogeneous mass extend MALDI-TOF (Sequenom hME Genotyping). Results We identified 14 mutations in at least one osteosarcoma tumor sample or cell line. Some of the genetic changes identified were in tumor suppressor genes previously known to be altered in osteosarcoma: p53 (R273H, R273C, and Y163C) and RB1 (E137*). Notably, we identified multiple mutations in PIK3CA (H1047R, E545K, and H701P) which have never previously been observed in osteosarcoma. Additionally, we observed mutations in KRAS (G12S), CUBN (I3189V, seen in two separate tumor samples), CDH1 (A617T, seen in two separate tumor samples), CTNNB1 (N287S), and FSCB (S775L). Conclusion We performed the largest mutational profiling of osteosarcoma to date and identified for the first time several mutations involving the PI3 kinase pathway – adding osteosarcoma on to the growing list of malignancies with PI3 kinase mutations. Additionally, we initiated a mutational map detailing DNA sequence changes across a variety of osteosarcoma subtypes and offered new candidates for therapeutic targeting.

Cytotoxic mechanism of PLK1 inhibitor GSK461364 against osteosarcoma: Mitotic arrest, apoptosis, cellular senescence, and synergistic effect with paclitaxel

“…Non-translocationrelated sarcomas can be further grouped as sarcomas with a simple genetic profile based on limited amplifications, such as dedifferentiated liposarcomas and parosteal OS (10,11), and major sarcomas with extremely complex genomic imbalances, such as leiomyosarcomas, undifferentiated pleomorphic sarcomas, pleomorphic liposarcomas and conventional OS (12). In conventional OS, these genomic aberrations cause oncogenic changes in such diverse processes as cell cycle regulation, cell death/cytokine pathways, proliferative signaling pathways, telomere dysfunction, metastasis and tumor suppression (13)(14)(15)(16)(17)(18)(19)(20). Recently, several studies have revealed that the PI3K-mTOR pathway is crucial in conventional OS (15,16).…”

“…In conventional OS, these genomic aberrations cause oncogenic changes in such diverse processes as cell cycle regulation, cell death/cytokine pathways, proliferative signaling pathways, telomere dysfunction, metastasis and tumor suppression (13)(14)(15)(16)(17)(18)(19)(20). Recently, several studies have revealed that the PI3K-mTOR pathway is crucial in conventional OS (15,16). However, the result of a clinical study of the mTOR inhibitor in OS treatment was unsatisfactory (21).…”

Review of the Molecular Pathogenesis of Osteosarcoma

“…AKT prevents apoptosis by activating anti-apoptotic signals through phosphorylating glycogen synthase kinase 3 (GSK3), Bad and caspase-9 and through activating transcriptional factors, such as forkhead (FOXO-1) and NF-kappa B (Yu et al, 2006;Cardone et al, 1998;Brunet et al, 1999;Romashkova et al, 1999). In addition, abnormal function of the PI3K/AKT pathway has been reported in many human tumors (Roy et al, 2002), including the OSA developed by PI3KCA gene mutation (Choy et al, 2012) and this signal pathway has been suggested to be a potential target for cancer chemotherapy. Suppressing the phosphorylation of Akt and its substrates FOXO transcription factor and GSK3 in OSA cells cause the suppression of proliferation and induction of mitochondria-and caspase-dependent apoptosis, induced the release of cytochrome c accompanied by activation of caspase-9, caspase-3 and cleavage of poly (ADP-ribose) polymerase (PARP) ( Jin et al, 2007).…”

Advancing Personalized Cancer Medicine in Lung Cancer

“…35 This panel has been optimized and refined during several years, and has demonstrated utility in profiling a wide variety of rare and common cancers for mutational events, regardless of the site of origin of the cancer. [36][37][38][39][40] Using our current panel of OncoMap, comprising 439 assays designed to detect 471 unique mutations in 41 cancer genes (Table 1), we interrogated 244 lung adenocarcinomas. Anonymized tumor specimens were obtained from the Cooperative Human Tissue Network, the Dana-Farber Cancer Institute, and the clinical archives of the departments of pathology at Brigham and Women's Hospital, Boston, Massachusetts.…”