<i>TP53</i> Mutations and Outcome in Osteosarcoma: A Prospective, Multicenter Study

Wunder, Jay S.; Gökgöz, Nalan; Parkes, Robert; Bull, Shelley B.; Eskandarian, Sasha; Davis, Aileen M.; Beauchamp, C.P.; Conrad, Ernest U.; Grimer, R. J.; Healey, John H.; Malkin, David; Mangham, D. C.; Rock, Michael J.; Bell, Robert S.; Andrulis, Irene L.

doi:10.1200/jco.2005.04.074

Cited by 126 publications

(95 citation statements)

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“…There are few clinical predictors of outcome for osteosarcoma. 15,16,18 Patients who present with metastases at diagnosis have the worst prognosis and are rarely curable. In comparison, patients with localized tumors at presentation have a 25% to 40% risk of developing metastases after chemotherapy and radical surgery.…”

Section: Discussionmentioning

confidence: 99%

“…Patients were selected from a larger cohort [14][15][16] on the basis of availability of tumor material. Each eligible patient provided a signed consent form before study entry, as approved by each participating institution's Research Ethics Board.…”

Section: Methodsmentioning

confidence: 99%

“…We previously showed that P53 mutations do not have an effect on clinical outcome in osteosarcoma. 15 However, it is interesting to note that those patients whose tumors had alterations of both P53 and COPS3 tended to have shorter disease-free survival compared with patients with COPS3 amplification alone (HR, 1.61; 95% CI, 0.63-4.12), although power was insufficient to detect an effect of this size (P ¼ .32). The small numbers of patients whose tumors had amplification of PMP22, NCOR1, or TOM1L2 as well as a P53 mutation (1, 4, and 2, respectively) precluded meaningful statistical analysis of synergism between these genes.…”

Section: Clinical Implication Of Both Cops3 Amplification and P53 Mutmentioning

confidence: 98%

“…14 However, in a cohort of 196 patients with high-grade nonmetastatic osteosarcoma we found that P53 mutations were not associated with diseasefree survival. 15 We determined the amplification status of COPS3 and 3 other candidate genes, NCOR1, TOM1L2, and PMP22, that map to 17p11.2 ( Fig. 1) in 155 high-grade osteosarcoma tumor samples and found that COPS3 was the most frequently amplified gene.…”

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COPS3 amplification and clinical outcome in osteosarcoma

Yan

Wunder

Gökgöz

et al. 2007

Cancer

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BACKGROUND.Amplification of several genes that map to a region of chromosome 17p11.2, including COPS3, was observed in high‐grade osteosarcoma. These genes were also shown to be overexpressed and may be involved in osteosarcoma tumorigenesis. COPS3 encodes a subunit of the COP9 signalosome implicated in the ubiquitination and ultimately degradation of the P53 tumor suppressor. To determine the relation between COPS3 amplification, P53 mutation, and patient outcome in osteosarcoma, tumors from a large cohort of patients with high‐grade osteosarcoma and long‐term clinical follow‐up were examined.METHODS.Quantitative real‐time polymerase chain reaction (PCR) was performed to detect copy number changes for COPS3, as well as additional genes (NCOR1, TOM1L2, and PMP22) from the 17p11.2 amplicon, in 155 osteosarcomas from a prospective collection of tumors with corresponding clinical data. Univariate and multivariate analyses were performed to assess differences in survival between groups.RESULTS.Amplification of COPS3, detected in 31% of the osteosarcomas, was strongly associated with large tumor size (P = .0009), but was not associated with age at diagnosis, site, sex, and tumor necrosis. COPS3 amplification was significantly correlated with a shorter time to metastasis with an estimated hazard ratio (HR) of 1.61 (95% confidence interval [CI], 1.02–2.55) in univariate analysis (log‐rank test, P = .042). However, in an a priori multivariate Cox model including the other clinical parameters, the HR for COPS3 amplification decreased to 1.32 (95% CI, 0.82–2.13, P = .25), mainly due to the strong correlation with tumor size. COPS3 amplification and P53 mutation frequently occurred in the same tumors, suggesting that these are not mutually exclusive events in osteosarcoma. Although not statistically significant, patients whose tumors exhibited both molecular alterations tended to be more likely to develop metastasis compared with patients with either COPS3 amplification or P53 mutation alone.CONCLUSIONS.COPS3 is the likely target of the 17p11.2 amplicon. COPS3 may function as an oncogene in osteosarcoma, and an increased copy number may lead to an unfavorable prognosis. Cancer 2007. © 2007 American Cancer Society.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Clinical Implication Of Both Cops3 Amplification and P53 Mutmentioning

confidence: 98%

mentioning

confidence: 99%

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COPS3 amplification and clinical outcome in osteosarcoma

Yan

Wunder

Gökgöz

et al. 2007

Cancer

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“…Large cooperative groups (eg, Children's Oncology Group or COG, the Southwest Oncology Group or SWOG) have failed due to their cumbersome structure and an inability to channel resources to orthopaedic problems. The greatest success has been in ad hoc collaborations such as that coordinated by the MSTS to review the outcome of patients treated by limb salvage or amputation for distal femoral osteosarcoma [2], or the Toronto Group's prospective evaluation of prognostic genetic markers (p53 and RB) in osteosarcoma patients from six centers [3].…”

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confidence: 99%

Contemporary Musculoskeletal Tumor Research: Selected Papers Presented at the 2008 Meeting of the Musculoskeletal Tumor Society: Editorial Comment

Healey

2009

Clinical Orthopaedics &Amp; Related Research

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Osteosarcoma

Bauer¹

2006

TNM Online

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Primary bone tumors are rare with an incidence of 2 to 3 per million, and of these, high‐grade osteosarcoma is the most common, representing 35% of all bone sarcomas. The typical patient diagnosed with osteosarcoma is male, between the ages of 10 and 20 years, and complains of pain for one to three months. The tumor is most commonly at the metaphysis of a long bone, with a predilection to the knee region. Dramatic improvements in disease‐free (DFS) and overall survival (OS) were demonstrated with the advent of doxorubicin and methotrexate chemotherapy regimes. The current standard of treatment for the patient with osteosarcoma is chemotherapy and resection of the primary tumor, most commonly preserving the limb. Despite the advances in radiological imaging, chemotherapy and surgery, 40 to 50% of patients will develop distant metastases and die of their disease. This chapter discusses the prognostic factors of disease outcome for osteosarcoma patients, specifically disease‐ or tumor‐related factors, host‐related factors, and environment‐ or treatment‐related factors.

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TP53 Mutations and Outcome in Osteosarcoma: A Prospective, Multicenter Study

Abstract: We found no evidence that TP53 mutations predict for development of metastases in patients with high-grade osteosarcoma. Identification of other genes that influence chemotherapy response and clinical outcome in osteosarcoma is needed to facilitate further improvements in patient outcomes.

Cited by 126 publications

References 58 publications

COPS3 amplification and clinical outcome in osteosarcoma

COPS3 amplification and clinical outcome in osteosarcoma

Contemporary Musculoskeletal Tumor Research: Selected Papers Presented at the 2008 Meeting of the Musculoskeletal Tumor Society: Editorial Comment

Osteosarcoma

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