Genomic imbalances in 61 renal cancers from the proximal tubulus detected by comparative genomic hybridization

Reutzel, Dirk; Mende, Michael; Naumann, Sabine; Störkel, Stephan; Brenner, Walburgis; Zabel, Bernard; Decker, Jared E.

doi:10.1159/000056987

Cited by 36 publications

(29 citation statements)

References 25 publications

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“…Loss of chromosome 1 was observed in about 90% of chromophobe RCCs (Kovacs and Kovacs, 1992;Speicher et al, 1994;Bugert et al, 1997;Nagy et al, 2004) and 25-46% of renal oncocytomas Fuzesi et al, 2005). A loss of 1q was also detected in about 15% of papillary RCCs (Jiang et al, 1998;Reutzel et al, 2001) and in less than 10% of clear cell RCCs . In Wilms tumors, 1q gain was described to be a predominant alteration in comparative genomic hybridization analyses (Hing et al, 2001).…”

Section: Discussionmentioning

confidence: 99%

Sporadic human renal tumors display frequent allelic imbalances and novel mutations of the HRPT2 gene

et al. 2006

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Inactivation of the HRPT2 gene encoding parafibromin was recently linked to the familial hyperparathyroidismjaw tumor syndrome. Patients with this syndrome carry an increased risk of parathyroid and renal tumors. To determine the relevance of HRPT2 for sporadic renal tumors, clear cell, papillary and chromophobe renal cell carcinomas as well as oncocytomas and Wilms tumors were analysed for HRPT2 gene alterations. Loss of heterozygosity (LOH) of HRPT2 was found in seven of 56 (12.5%) clear cell, three of 14 (21%) papillary, six of 10 (60%) chromophobe renal cell carcinomas, three of eight (38%) oncocytomas and four of 10 (40%) Wilms tumors. In addition, two novel HRPT2 point mutations, causing K34Q and R292K changes in parafibromin, were detected in one clear cell carcinoma and one Wilms tumor, respectively. These tumors displayed LOH of the remaining wild-type allele, but interestingly no von HippelLindau (VHL) mutation. Functional analysis revealed that the K34Q mutant species of parafibromin is, unlike wild-type protein, defective in suppressing cyclin D1 expression in vivo. Taken together, these results suggest that renal cancer-associated mutations in parafibromin occur in the absence of VHL mutation, which in turn may contribute to constitutively elevated cyclin D1 expression and abnormal cell proliferation.

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Section: Discussionmentioning

confidence: 99%

Sporadic human renal tumors display frequent allelic imbalances and novel mutations of the HRPT2 gene

et al. 2006

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“…1D) (18)(19)(20). To confirm that LRRK2 and MET are coordinately amplified in papillary RCC tumors, we performed dual-color FISH on renal tumors with probes targeted to LRRK2 (12q12) and MET (7q31) (Fig.…”

Section: Resultsmentioning

confidence: 99%

Chromosomal amplification of leucine-rich repeat kinase-2 (LRRK2) is required for oncogenic MET signaling in papillary renal and thyroid carcinomas

Looyenga

Furge²,

Dykema³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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The receptor tyrosine kinase MET is frequently amplified in human tumors, resulting in high cell surface densities and constitutive activation even in the absence of growth factor stimulation by its endogenous ligand, hepatocyte growth factor (HGF). We sought to identify mechanisms of signaling crosstalk that promote MET activation by searching for kinases that are coordinately dysregulated with wild-type MET in human tumors. Our bioinformatic analysis identified leucine-rich repeat kinase-2 (LRRK2), which is amplified and overexpressed in papillary renal and thyroid carcinomas. Downregulation of LRRK2 in cultured tumor cells compromises MET activation and selectively reduces downstream MET signaling to mTOR and STAT3. Loss of these critical mitogenic pathways induces cell cycle arrest and cell death due to loss of ATP production, indicating that MET and LRRK2 cooperate to promote efficient tumor cell growth and survival in these cancers.kidney cancer | kinase bioinformatics | thyroid cancer C onstitutive and unregulated activation of receptor tyrosine kinases (RTKs) is a common oncogenic mechanism in human cancers (1). Oncogenic activation of RTKs can be achieved by several different mechanisms that include somatic mutation, genetic amplification, autocrine growth factor stimulation, dysregulation of receptor trafficking pathways, or crosstalk with other kinase signaling cascades (2, 3). In many cases these separate mechanisms work in tandem to promote increased oncogenic signaling by an RTK. Prominent examples of these combinatorial mechanisms include coordinate amplification and somatic mutation of EGF receptor (EGFR) in lung cancer and coordinate overexpression of several different growth factor receptors and their cognate ligands in melanoma (4, 5).The receptor tyrosine kinase MET, located at 7q31, is frequently amplified and highly activated in human tumors (6, 7). Although activating mutations to MET have been discovered, they are found in relatively few human tumor types (8-10). Tumors that contain genomic amplification of MET may also overexpress its ligand, hepatocyte growth factor (HGF), thereby establishing an autocrine signaling loop to achieve constitutive MET activation (11-13). However, a number of tumor types demonstrate genomic amplification of MET without somatic mutation or coordinate overexpression of HGF, suggesting the existence of alternative mechanisms that activate MET in the absence of activating mutations or abundant ligand (6).In this study we sought to identify oncogenic mechanisms that promote ligand-independent MET activation by searching for kinases that are coordinately dysregulated with MET in sporadic type 1 papillary renal cell carcinoma (RCC), which is a prototypical tumor type driven by amplification and overexpression of MET (14,15). Unlike hereditary cases of papillary RCC in which MET activation is driven by specific point mutations, sporadic type 1 papillary tumors rarely demonstrate MET mutations (16, 17). Because HGF is also not significantly expressed in these tumors...

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“…Additionally, random loss of chromosomes 6,8,13,15,16,17,18,19,20,21,22, and Y, gain of chromosome 3, and a questionable structural rearrangement involving the short arm of chromosome 16 were also seen in different cells (data not shown). As those random alterations appeared only a single time, they did not meet the criteria for 'clonal' change, 4 and were not described in the nomenclature, but their presence was noted for eventual future studies.…”

Section: Cytogenetics and Fish Studies On Cultured Tumor Cells From Tmentioning

confidence: 89%

“…19 Numeric abnormalities of chromosome 4 including both gains and losses have been shown to be associated with tumor stage and lymph node involvement in cases of breast carcinoma. 20 Deletion of chromosome 4 or part of chromosome 4 has been reported in esthesioneuroblastoma 21 and clear-cell renal cell carcinomas; 22 suppression of transformed phenotype and tumorigenicity was seen after the transfer of chromosome 4 into U251 human glioma cells, 23 indicating the presence of tumor suppressor genes on chromosome 4. 24 On the other hand, amplification or extra copies of chromosome 4, which is the site of wild-type KIT gene, has been commonly observed in many tumors, the significance of which remains unclear.…”

Section: Discussionmentioning

confidence: 99%

Clonal trisomy 4 cells detected in the ossifying renal tumor of infancy: study of 3 cases

et al. 2013

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The ossifying renal tumor of infancy is a rare neoplasm diagnosed in the first 2 years of life, predominantly in boys. The neoplasm is primarily characterized by the presence of a large ossifying component. Its most common mode of presentation is hematuria, and it has a uniformly benign behavior. The karyotypic makeup of the process has not been reported. Thus, a study was undertaken and it allowed demonstration of clonal trisomy 4, which was confirmed by the fluorescent in-situ hybridization-probing of two additional archival formalin-fixed, paraffin-imbedded similar tumors. On the basis of the findings in these three cases, it seems that clonal trisomy 4 may be considered as a characteristic of the tumor, which makes it distinct from any other infantile renal tumor.

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Genomic imbalances in 61 renal cancers from the proximal tubulus detected by comparative genomic hybridization

Cited by 36 publications

References 25 publications

Sporadic human renal tumors display frequent allelic imbalances and novel mutations of the HRPT2 gene

Sporadic human renal tumors display frequent allelic imbalances and novel mutations of the HRPT2 gene

Chromosomal amplification of leucine-rich repeat kinase-2 (LRRK2) is required for oncogenic MET signaling in papillary renal and thyroid carcinomas

Clonal trisomy 4 cells detected in the ossifying renal tumor of infancy: study of 3 cases

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