Chromosomal imbalances in malignant peripheral nerve sheath tumor detected by metaphase and microarray comparative genomic hybridization

Nakagawa, Yoshifumi; Yoshida, Aki; Numoto, Kunihiko; Kunisada, Toshiyuki; Wai, Daniel; Ohata, Norihide; Takeda, Ken; Kawai, Akira; Ozaki, Toshifumi

doi:10.3892/or.15.2.297

Cited by 17 publications

(22 citation statements)

References 24 publications

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“…To compensate for the small sample size of human tumors, we analyzed large-scale changes using an increased sensitivity threshold while ensuring that the resulting calls were largely consistent with the previously reported results [41]. In general agreement with prior studies of human MPNSTs [6], [57]–[59], we found that 5 chromosomes or chromosome arms were over-represented and 13 chromosomes or chromosome arms were under-represented (Table 1, Figure S4, Table S3, Dataset S4). Similar to findings in other human solid tumors [4], [6], [7], chromosome (arm)-level changes in human MPNSTs generally exhibited low amplitudes, but appeared at high frequency.…”

Section: Resultssupporting

confidence: 82%

Comparative Oncogenomic Analysis of Copy Number Alterations in Human and Zebrafish Tumors Enables Cancer Driver Discovery

et al. 2013

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The identification of cancer drivers is a major goal of current cancer research. Finding driver genes within large chromosomal events is especially challenging because such alterations encompass many genes. Previously, we demonstrated that zebrafish malignant peripheral nerve sheath tumors (MPNSTs) are highly aneuploid, much like human tumors. In this study, we examined 147 zebrafish MPNSTs by massively parallel sequencing and identified both large and focal copy number alterations (CNAs). Given the low degree of conserved synteny between fish and mammals, we reasoned that comparative analyses of CNAs from fish versus human MPNSTs would enable elimination of a large proportion of passenger mutations, especially on large CNAs. We established a list of orthologous genes between human and zebrafish, which includes approximately two-thirds of human protein-coding genes. For the subset of these genes found in human MPNST CNAs, only one quarter of their orthologues were co-gained or co-lost in zebrafish, dramatically narrowing the list of candidate cancer drivers for both focal and large CNAs. We conclude that zebrafish-human comparative analysis represents a powerful, and broadly applicable, tool to enrich for evolutionarily conserved cancer drivers.

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Section: Resultssupporting

confidence: 82%

Comparative Oncogenomic Analysis of Copy Number Alterations in Human and Zebrafish Tumors Enables Cancer Driver Discovery

et al. 2013

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“…Taking into account previously analyzed tumors [2] the amplicon is present in about 15% of MPNST and encompasses numerous genes. Previous studies on chromosomal imbalances found chromosomal gains more frequently than losses [9], [10]. This finding supports the idea that oncogenes are more frequently affected in MPNST than tumor suppressor genes, at least in the later stage of the disease.…”

Section: Discussionsupporting

confidence: 83%

The 4q12 Amplicon in Malignant Peripheral Nerve Sheath Tumors: Consequences on Gene Expression and Implications for Sunitinib Treatment

et al. 2010

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BackgroundMalignant peripheral nerve sheath tumors (MPNST) are highly aggressive tumors which originate from Schwann cells and develop in about 10% of neurofibromatosis type 1 (NF1) patients. The five year survival rate is poor and more effective therapies are needed. Sunitinib is a drug targeting receptor tyrosine kinases (RTK) like PDGFRα, c-Kit and VEGFR-2. These genes are structurally related and cluster on chromosomal segment 4q12.Methodology/Principal FindingsHere we characterize this region by multiplex ligation-dependent probe amplification (MLPA) in MPNST. Our probe set encompasses the 3 adjacent RTK genes (PDGFRA, KIT, KDR) and 6 flanking genes. We found amplification of several genes within this region in a subset of MPNST and MPNST cell lines. Transcript and protein expression of PDGFRA matched well with its increased copy number suggesting a central role of PDGFRA within the amplicon. Studying the effect of sunitinib on 5 MPNST cell lines revealed that cell line S462 harboring the 4q12 amplicon was extremely sensitive to the drug with an IC50 below 1.0µM. Moreover, sunitinib induced apoptosis and prevented PDGF-AA induced signaling via PDGFRα as determined by western blotting. Co-expression of VEGF and its receptor VEGFR-2 (KDR) was present in MPNST cell lines suggesting an autocrine loop. We show that VEGF triggered signal transduction via the MAPK pathway, which could be blocked by sunitinib.Conclusions/SignificanceSince multiple receptors targeted by sunitinib are expressed or over-expressed by MPNST cells sunitinib appears as an attractive drug for treatment of MPNST patients. Presence of the 4q12 amplicon and subsequent over-expression of PDGFRA might serve as predictive markers for efficacy of sunitinib.

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“…It should briefly be mentioned here that other members of the K2P family as well have been linked to different cancer entities, like TWIK-related K + -channel gene-1 (TREK1) to prostate carcinoma (130) and ALL (127), THIK2 to tubular breast carcinoma, synovial sarcoma and malignant peripheral nerve sheet tumor (94,95,113) and TASK5 to colon cancer and acute lymphoblastic leukemia (ALL) (119).…”

Section: Experimental Datamentioning

confidence: 99%

From the Background to the Spotlight: TASK Channels in Pathological Conditions

Bittner

Budde²,

Wiendl³

et al. 2010

Brain Pathology

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TWIK-related acid-sensitive potassium channels (TASK1-3) belong to the family of two-pore domain (K(2P) ) potassium channels. Emerging knowledge about an involvement of TASK channels in cancer development, inflammation, ischemia and epilepsy puts the spotlight on a leading role of TASK channels under these conditions. TASK3 has been especially linked to cancer development. The pro-oncogenic potential of TASK3 could be shown in cell lines and in various tumor entities. Pathophysiological hallmarks in solid tumors (e.g. low pH and oxygen deprivation) regulate TASK3 channels. These conditions can also be found in (autoimmune) inflammation. Inhibition of TASK1,2,3 leads to a reduction of T cell effector function. It could be demonstrated that TASK1(-/-) mice are protected from experimental autoimmune inflammation while the same animals display increased infarct volumes after cerebral ischemia. Furthermore, TASK channels have both an anti-epileptic as well as a pro-epileptic potential. The relative contribution of these opposing influences depends on their cell type-specific expression and the conditions of the cellular environment. This indicates that TASK channels are per se neither protective nor detrimental but their functional impact depends on the "pathophysiological" scenario. Based on these findings TASK channels have evolved from "mere background" channels to key modulators in pathophysiological conditions.

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Chromosomal imbalances in malignant peripheral nerve sheath tumor detected by metaphase and microarray comparative genomic hybridization

Cited by 17 publications

References 24 publications

Comparative Oncogenomic Analysis of Copy Number Alterations in Human and Zebrafish Tumors Enables Cancer Driver Discovery

Comparative Oncogenomic Analysis of Copy Number Alterations in Human and Zebrafish Tumors Enables Cancer Driver Discovery

The 4q12 Amplicon in Malignant Peripheral Nerve Sheath Tumors: Consequences on Gene Expression and Implications for Sunitinib Treatment

From the Background to the Spotlight: TASK Channels in Pathological Conditions

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