Amplification of 17p11.2∼p12, including PMP22, TOP3A, and MAPK7, in high-grade osteosarcoma

Dartel, Maaike van; Cornelissen, Peter W.A.; Redeker, Sandra; Tarkkanen, Maija; Knuutila, Sakari; Hogendoorn, Pancras C.W.; Westerveld, A.; Gomes, Ingrid; Bras, Johannes; Hulsebos, Theo J.M.

doi:10.1016/s0165-4608(02)00627-1

Cited by 68 publications

(57 citation statements)

References 12 publications

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“…7,11 In previous studies with small sample sizes, COPS3 had been found to be amplified in 32% to 63% of osteosarcoma specimens. [3][4][5]7 To determine whether amplification of COPS3 has clinical importance in osteosarcoma, we studied 155 highgrade osteosarcomas with corresponding clinical data and analyzed the association of COPS3 amplification, P53 mutation, and patient outcome.…”

Section: Discussionmentioning

confidence: 99%

“…Several cytogenetic and molecular genetic studies have reported amplification of 17p11.2 in osteosarcoma. [3][4][5] In these studies some of the genes on the 17p11.2 amplicon were analyzed for amplification and subsequent expression. ADORA2B, DRG2, TOP3A, MAPK7 were excluded from the candidate genes list of 17p11.2 amplicon.…”

Section: Discussionmentioning

confidence: 99%

“…1,2 Between 13% and 47% of high-grade osteosarcomas have been found to contain amplification of several genes that map to a region of chromosome 17p11.2, including COP9 constitutive photomorphogenic homolog subunit 3 (COPS3), nuclear receptor corepressor (NCOR1), target of myb1-like 2 (TOM1L2), and peripheral myelin protein 22 (PMP22), and may be involved in osteosarcoma tumorigenesis. [3][4][5][6][7][8] COPS3 encodes 1 subunit of a highly conserved complex, the COP9 signalosome (CSN), which has been implicated in the ubiquitination and ultimately degradation of the p53 tumor suppressor. [9][10][11] Another protein involved in loss of the p53 tumor suppressor function is MDM2, whose amplification and/or overexpression has been observed in some osteosarcomas.…”

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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: Discussionmentioning

confidence: 99%

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COPS3 amplification and clinical outcome in osteosarcoma

Yan

Wunder

Gökgöz

et al. 2007

Cancer

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“…42,[59][60][61][62] Gains as well as high-level amplifications at 17p11.p12 seem to be frequently involved in other sarcomas, including osteosarcoma, chondrosarcoma, and malignant fibrous histiocytoma. 21,23,27,34,44,[51][52][53]63,64 This suggests that different sarcoma entities most probably share a common pathogenic pathway.…”

Section: Similarities and Differences In Dna Sequence Copy Number Chamentioning

confidence: 99%

Do DNA copy number changes differentiate uterine from non-uterine leiomyosarcomas and predict metastasis?

et al. 2006

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DNA copy number changes were investigated in 51 (19 uterine and 32 nonuterine) primary leiomyosarcomas by comparative genomic hybridization. The aim was to evaluate whether true biological differences exist between uterine and nonuterine leiomyosarcoma and whether changes revealed by comparative genomic hybridization have prognostic value. Genomic imbalances were found in 48 (94%) cases. The most frequent DNA copy number changes were losses in 10q (35%), 13q (57%), and 16q (41%), gains in 1q (41%), and gains and high-level amplifications in 17p (39%). Gains were nearly as frequent as losses in both uterine and nonuterine leiomyosarcoma. Correlation-based tree modeling revealed two clusters that segregated significantly a group of uterine (gains at 1q11-q24) and a group of nonuterine (losses at 13q14-q34, 16q11.1-q24, and 10q21-q26) cases. The nonuterine cluster was associated with subcutaneous origin and a trend toward increased metastasis-free survival. Further explorative analyses identified aberrations associated with shorter metastasisfree survival time, including losses at 2q32.1-q37 and gains at 8q24.1-q24.3, whereas the cases with losses at 6cen-p25 showed longer metastasis-free survival time.

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“…In addition to its expression in neural cells, PMP22 is also observed in nonneural cells and tissues during development, such as in the epithelial cells of the lung and intestine (Taylor et al 1995;Wulf et al 1999), and downregulation of PMP22 expression has been associ-ated with the development of lung cancer in mice (Re et al 1992). Furthermore, amplification of the chromosome 17p11.2 region and PMP22 expression has been observed in osteosarcoma, as well as in glioblastoma tissues and cell lines (Huhne et al 1999;Huehne and Rautenstrauss 2001;van Dartel et al 2002van Dartel et al ,2003van Dartel and Hulsebos 2004). PMP22 expression in osteosarcoma cells may result in alternative availability of the PMP22 protein during the cell cycle and aberrant regulation of cell growth (van Dartel and Hulsebos 2004).…”

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Expression Analysis of PMP22/Gas3 in Premalignant and Malignant Pancreatic Lesions

Kleeff

Espósito

et al. 2005

J Histochem Cytochem.

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S U M M A R YPMP22 is a structural protein of Schwann cells, but it also influences cell proliferation. In the present study, quantitative RT-PCR (QRT-PCR) and immunohistochemistry were used to determine PMP22 mRNA levels and to localize PMP22 in the normal pancreas ( n ϭ 20), chronic pancreatitis (CP) ( n ϭ 22), pancreatic ductal adenocarcinoma (PDAC) ( n ϭ 31), intraductal papillary mucinous neoplasms (IPMN) ( n ϭ 9), mucinous cystic tumors (MCN) ( n ϭ 4), and in a panel of PanIN lesions ( n ϭ 29). PMP22 mRNA levels were significantly higher in CP (3-fold) and PDAC (2.5-fold), compared to normal pancreatic tissues. PMP22 expression was restricted to nerves in the normal pancreas, while in CP and PDAC PMP22 was also expressed in PanIN lesions and in a small percentage of pancreatic cancer cells. PMP22 was weak to absent in the tumor cells of IPMNs and MCNs. PMP22 mRNA was present at different levels in cultured pancreatic cancer cells and up-regulated by transforming growth factor (TGF)-␤ 1 in 2 of 8 of these cell lines. In conclusion, PMP22 expression is present in both CP and PDAC tissues. Its expression in PanIN lesions and some pancreatic cancer cells in vitro and in vivo suggests a role of PMP22 in the neoplastic transformation process from the normal pancreas to pre-malignant lesions to pancreatic cancer.

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Amplification of 17p11.2∼p12, including PMP22, TOP3A, and MAPK7, in high-grade osteosarcoma

Cited by 68 publications

References 12 publications

COPS3 amplification and clinical outcome in osteosarcoma

COPS3 amplification and clinical outcome in osteosarcoma

Do DNA copy number changes differentiate uterine from non-uterine leiomyosarcomas and predict metastasis?

Expression Analysis of PMP22/Gas3 in Premalignant and Malignant Pancreatic Lesions

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