Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0029463 (osteosarcoma)
 16,637 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We describe a patient who had nine primary malignant tumors and a germline mutation in the p53 tumor-suppressor gene, characteristically found in the Li-Fraumeni syndrome (LFS). A 15-year-old girl with no family history of cancer was referred to our hospital because of pain and swelling of the right knee. Osteosarcoma was diagnosed. The patient received chemotherapy followed by surgery and had a remission. After the age of 28 years, nine primary malignant tumors developed successively, including right breast cancer, colon cancer, malignant fibrous histiocytoma (MFH) of the abdominal wall, right lung double cancers, bilateral breast cancers, and MFH of the left thigh. This is the second highest number of types of primary malignant tumors to be reported in LFS. All tumors were treated by a multidisciplinary approach, including surgery. Genetic analysis revealed a germline missense mutation in the p53 gene (c.659 A > G), resulting in Y220C, which has been reported in three families with LFS. The patient died of lung metastasis from MFH at the age of 37 years. Despite the multiple tumors, repeated induction of remissions resulted in long survival. Our findings suggest that a multidisciplinary approach to treatment, including surgery, is beneficial in patients with LFS.
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PMID:A Japanese patient with Li-Fraumeni syndrome who had nine primary malignancies associated with a germline mutation of the p53 tumor-suppressor gene. 1830 25

In 1990, an 18-month-old Micronesian girl was initially diagnosed with a right adrenocortical carcinoma. More than a decade later (2003), she was diagnosed with metastatic osteosarcoma with the primary in her right proximal fibula. Given this child's remarkable history of malignancy, she underwent testing for a genetic mutation that is associated with increased cancer formation. One such cancer syndrome is called Li-Fraumeni syndrome where approximately 70% of patients carry a genetic mutation in the p53 tumor suppressor gene. Patients with LFS are at risk for developing cancers of the breast, soft tissues, brain, bone, adrenal gland, and blood cells. Mutational analysis of our patient did reveal the presence of a germline mutation of the p53 tumor suppressor gene. She was found to have a base pair change (A-->C) at nucleotide 394 resulting in a lysine to glutamine amino acid change at codon 132 (K132Q), which remarkably has never been described in association with either adrenocortical carcinoma or osteosarcoma.
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PMID:Germline p53 mutation in a Micronesian child with adrenocortical carcinoma and subsequent osteosarcoma. 1898 56

We present a girl who developed adrenocortical adenoma at the age of 1 year and osteosarcoma at the age of 5 years. There was no history of cancer in her parents and their relatives. However, both tumors were typical for the Li-Fraumeni syndrome (LFS), and the patient met criteria for germline TP53 mutation testing. A mutation in codon 282 (Arg282Trp) was identified in her blood lymphocyte genomic DNA. The substitution was found in neither of her parents, which indicated a possibility of a de novo mutation. Unexpectedly, sequencing of the DNA of the patient repeatedly showed allelic imbalance in favor of the normal allele. This observation prompted us to investigate the putative somatic mosaicism in the patient consisting of normal cells and cells heterozygous for the mutation. The imbalance was also examined in two other non-invasively sampled tissues, buccal cells, and cells from the urine sediment, and sequencing was confirmed with two other independent methods. While the findings in blood and the urine sediment were similar, in buccal cells both alleles were present in equal amounts. The allele ratio in lymphocytes was consistent with a mosaic where about 2/3 of cells carried two normal alleles and only 1/3 was heterozygous for the mutation. Despite the mosaicism the girl developed two early childhood tumors of mesodermal origin, and her phenotype was thus not milder than that of other germline TP53 mutation carriers. To our knowledge this is the first description of somatic mosaicism for a de novo TP53 mutation in LFS.
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PMID:Somatic TP53 mutation mosaicism in a patient with Li-Fraumeni syndrome. 1901 32

Background. The purpose of this work was to study clinical and histopathological tumor characteristics of patients treated for synchronous or metachronous skeletal osteosarcoma at The Norwegian Radium Hospital from January 1, 1980 to January 1, 2008. Patients and methods. The hospital sarcoma database and patient records were reviewed to identify cases with synchronous or metachronous skeletal osteosarcoma. Patients with more than one skeletal lesion in the absence of pulmonary or other soft tissue tumor manifestations were included in the study, and histopathological slides from these tumors were reviewed. Results. Among a total of 297 registered osteosarcoma patients, six with synchronous (2.0%) and 10 with metachronous (3.4%) skeletal osteosarcomas were identified. All tumors were of high-grade malignancy. Treatment at the time of the first osteosarcoma diagnosis was in most cases wide resections and multi-agent chemotherapy according to international protocols, whereas the treatment for metachronous tumors was individualized and in general much less intensive. One patient was diagnosed with Li-Fraumeni syndrome, two other individuals may be suspected to have the same syndrome, and yet another patient had previously been treated for a bilateral retinoblastoma. Thirteen patients are dead, 11 from metastatic osteosarcoma, one from myelodysplastic syndrome, and one from wound infection and methotrexate-related nephrotoxicity; whereas three patients are still alive with no evidence of osteosarcoma. Conclusions. The prognosis for patients with synchronous and metachronous skeletal osteosarcoma is poor. However, because long-term survival is seen, aggressive treatment to selected cases, e.g., patients with an osteosarcoma predisposing syndrome and/or late occurring metachronous tumours, is justified. Revealing a possible clonal relationship between these tumors, e.g., by karyotyping, may be of interest for estimating prognosis and guide therapy intensiveness.
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PMID:Synchronous and metachronous skeletal osteosarcomas: the Norwegian Radium Hospital experience. 1986 25

It has been difficult to identify the molecular features central to the pathogenesis of osteosarcoma owing to a lack of understanding of the cell or origin, the absence of identifiable precursor lesions, and its marked genetic complexity at the time of presentation. Interestingly, several human genetic disorders and familial cancer syndromes, such as Li-Fraumeni syndrome, are linked to an increased risk of osteosarcoma. Association of these same genetic alterations and osteosarcoma risk have been confirmed in murine models. Osteosarcoma is associated with a variety of genetic abnormalities that are among the most commonly observed in human cancer; it remains unclear, however, what events initiate and are necessary to form osteosarcoma. The availability of new resources for studying osteosarcoma and newer research methodologies offer an opportunity and promise to answer these currently unanswered questions. Even in the absence of a more fundamental understanding of osteosarcoma, association studies and preclinical drug testing may yield clinically relevant information.
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PMID:Osteosarcoma. 2020 69

Studies to determine the etiology of osteosarcoma involve epidemiologic and environmental factors and genetic impairments. Factors related to patient characteristics include age, gender, ethnicity, growth and height, genetic and familial factors, and preexisting bone abnormalities. Rapidly proliferating cells may be particularly susceptible to oncogenic agents and mitotic errors which lead to neoplastic transformation. Genetic aberrations that accompany osteosarcoma have received increasing recognition as an important factor in its etiology. Osteosarcoma tumor cells exhibit karyotypes with a high degree of complexity which has made it difficult to determine whether any recurrent chromosomal aberrations characterize osteosarcoma. Although extremely rare, osteosarcoma has occasionally been observed in several members of the same family. No other clinical abnormalities in the proband or the affected members were reported. Pathologic examination of the tumors revealed no unusual features. Genetic testing was not available in most of these reports. The patients generally responded to conventional therapy. A genetic predisposition to osteosarcoma is found in patients with hereditary retinoblastoma, characterized by mutation of the retinoblastoma gene RB1 on chromosome 13q14. The Rothmund-Thomson syndrome is an autosomal recessive disorder with a heterogeneous clinical profile. Patients may have a few or multiple clinical features including skin rash, small stature, skeletal dysplasias, sparse or absent scalp hair, eyebrows or eyelashes, juvenile cataracts, and gastrointestinal disturbance including chronic emesis and diarrhea; its molecular basis is the mutation in the RECQL4 gene in a subset of cases. The Li-Fraumeni syndrome is an autosomal dominant disorder characterized by a high risk of developing osteosarcoma and has been found in up to 3% of children with osteosarcoma. It is associated with a germline mutation of the p53, a suppressor gene. The following three criteria must be met for a diagnosis of Li-Fraumeni syndrome: (1) A proband diagnosed with sarcoma when younger than 45 years; (2) A first-degree relative with any cancer diagnosed when younger than 45 years; (3) Another first- or second-degree relative of the same genetic lineage with any cancer diagnosed when younger than 45 years or sarcoma diagnosed at any age. A second recessive p53 oncogene on chromosome 17p13.1 may also play a role in the development and progression of osteosarcoma. Osteosarcoma has also been associated with solitary or multiple osteochondroma, solitary enchondroma or enchondromatosis (Ollier's disease), multiple hereditary exostoses, fibrous dysplasia, chronic osteomyelitis, sites of bone infarcts, sites of metallic prostheses and sites of prior internal fixation. Ionizing radiation is a well-documented etiologic factor. Osteosarcoma has also been associated with the use of intravenous radium and Thorotrast. Exposure to alkylating agents may also contribute to its development ,and it is apparently independent of the administration of radiotherapy.
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PMID:The etiology of osteosarcoma. 2021 84

Cellular senescence is an irreversible growth arrest that is activated in normal cells upon shortening of telomere and other cellular stresses. Bypassing cellular senescence is a necessary step for cells to become immortal during oncogenic transformation. During the spontaneous immortalization of Li-Fraumeni Syndrome (LFS) fibroblasts, we found that CREG1 (Cellular Repressor of E1A-stimulated Genes 1) expression was decreased during immortalization and increased in senescence. Moreover, we found that repression of CREG1 expression occurs via an epigenetic mechanism, promoter DNA methylation. Ectopic expression of CREG1 in the immortal LFS cell lines decreases cell proliferation but does not directly induce senescence. We confirmed this in osteosarcoma and fibrosarcoma cancer cell lines, cancers commonly seen in Li-Fraumeni Syndrome. In addition, we found that p16 (INK4a) is also downregulated in immortal cells and that coexpression of CREG1 and p16 (INK4a) , an inhibitor of CDK4/6 and Rb phosphorylation, has a greater effect than either CREG1 and p16 (INK4a) alone to reduce cell growth, induce cell cycle arrest and cellular senescence in immortal LFS fibroblasts, osteosarcoma and fibrosarcoma cell lines. Moreover, cooperation of CREG1 and p16 (INK4a) inhibits the expression of cyclin A and cyclin B by inhibiting promoter activity thereby decreasing mRNA and protein levels; these proteins are required for S-phase entry and G2/M transition. In conclusion, this is the first evidence to demonstrate that CREG1 enhances p16 (INK4a) -induced senescence by transcriptional repression of cell cycle-regulated genes.
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PMID:CREG1 enhances p16(INK4a) -induced cellular senescence. 2126 17

Osteosarcoma is the most common form of bone cancer. Pivotal insight into the genes involved in human osteosarcoma has been provided by the study of rare familial cancer predisposition syndromes. Three kindreds stand out as predisposing to the development of osteosarcoma: Li-Fraumeni syndrome, familial retinoblastoma and RecQ helicase disorders, which include Rothmund-Thomson Syndrome in particular. These disorders have highlighted the important roles of P53 and RB respectively, in the development of osteosarcoma. The association of OS with RECQL4 mutations is apparent but the relevance of this to OS is uncertain as mutations in RECQL4 are not found in sporadic OS. Application of the knowledge or mutations of P53 and RB in familial and sporadic OS has enabled the development of tractable, highly penetrant murine models of OS. These models share many of the cardinal features associated with human osteosarcoma including, importantly, a high incidence of spontaneous metastasis. The recent development of these models has been a significant advance for efforts to improve our understanding of the genetics of human OS and, more critically, to provide a high-throughput genetically modifiable platform for preclinical evaluation of new therapeutics.
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PMID:Genetically engineered mouse models and human osteosarcoma. 2303 72

A 28-year-old man presented with osteosarcoma of the occipital bone 16 years after 24 Gy of craniospinal irradiation for acute lymphocytic leukemia. The tumor had both intra- and extra-cranial components. However, the affected skull appeared to be normal on imaging because of permeative infiltration by the tumor. Subtotal resection was achieved and the tumor was verified histologically as an osteosarcoma. The residual tumor soon showed remarkable enlargement and disseminated to the spinal cord. Both of the enlarged and disseminated tumor masses were treated by surgical intervention and chemotherapy. However, the patient deteriorated due to the tumor regrowth and died 11 months after the initial diagnosis. This patient had previously developed a leukemia, a colon cancer, a rectal cancer and a hepatocellular carcinoma. His brother also died of leukemia. The patient had a heterozygous TP53 germ-line mutation of codon 248 in the exon 7. In conclusion, we consider the present tumor to be a rare example of radiation-induced skull osteosarcoma in a member of the cancer-prone family with TP53 germ-line mutation which is associated with Li-Fraumeni syndrome.
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PMID:[Radiation-induced intracranial osteosarcoma after radiation for acute lymphocytic leukemia associated with Li-Fraumeni syndrome]. 2373 61

p53(R172H/+) mice inherit a p53 mutation found in Li-Fraumeni syndrome and develop metastatic tumors at much higher frequency than p53(+/-) mice. To explore the mutant p53 metastatic phenotype, we used expression arrays to compare primary osteosarcomas from p53(R172H/+) mice with metastasis to osteosarcomas from p53(+/-) mice lacking metastasis. For this study, 213 genes were differentially expressed with a P value <0.05. Of particular interest, Pla2g16, which encodes a phospholipase that catalyzes phosphatidic acid into lysophosphatidic acid and free fatty acid (both implicated in metastasis), was increased in p53(R172H/+) osteosarcomas. Functional analyses showed that Pla2g16 knockdown decreased migration and invasion in mutant p53-expressing cells, and vice versa: overexpression of Pla2g16 increased the invasion of p53-null cells. Furthermore, Pla2g16 levels were increased upon expression of mutant p53 in both mouse and human osteosarcoma cell lines, indicating that Pla2g16 is a downstream target of the mutant p53 protein. ChIP analysis revealed that several mutant p53 proteins bind the Pla2g16 promoter at E26 transformation-specific (ETS) binding motifs and knockdown of ETS2 suppressed mutant p53 induction of Pla2g16. Thus, our study identifies a phospholipase as a transcriptional target of mutant p53 that is required for metastasis.
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PMID:Pla2g16 phospholipase mediates gain-of-function activities of mutant p53. 2502 3


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