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Anesthesiology 08/2011; 115(4):685-6. · 5.36 Impact Factor
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ABSTRACT: Deletions within the short arm of chromosome 7 are observed in approximately 25% of adult and 10% of Wilms pediatric renal tumors. Within Wilms tumors, the region of interest has been delineated to a 2-Mb minimal region that includes ten known genes. Two of these ten candidate genes, SOSTDC1 and MEOX2, are particularly relevant to tumor development and maintenance. This finding, coupled with evidence that SOSTDC1 is frequently downregulated in adult renal cancer and regulates both Wingless-Int (Wnt)- and bone morphogenetic protein (BMP)-induced signaling, points to a role for SOSTDC1 as a potential tumor suppressor.
To investigate this hypothesis, we interrogated the Oncomine database to examine the SOSTDC1 levels in adult renal clear cell tumors and pediatric Wilms tumors. We then performed single nucleotide polymorphism (SNP) and sequencing analyses of SOSTDC1 in 25 pediatric and 36 adult renal tumors. Immunohistochemical staining of patient samples was utilized to examine the impact of SOSTDC1 genetic aberrations on SOSTDC1 protein levels and signaling.
Within the Oncomine database, we found that SOSTDC1 levels were reduced in adult renal clear cell tumors and pediatric Wilms tumors. Through SNP and sequencing analyses of 25 Wilms tumors, we identified four with loss of heterozygosity (LOH) at 7p and three that affected SOSTDC1. Of 36 adult renal cancers, we found five with LOH at 7p, two of which affected SOSTDC1. Immunohistochemical analysis of SOSTDC1 protein levels within these tumors did not reveal a relationship between these instances of SOSTDC1 LOH and SOSTDC1 protein levels. Moreover, we could not discern any impact of these genetic alterations on Wnt signaling as measured by altered beta-catenin levels or localization.
This study shows that genetic aberrations near SOSTDC1 are not uncommon in renal cancer, and occur in adult as well as pediatric renal tumors. These observations of SOSTDC1 LOH, however, did not correspond with changes in SOSTDC1 protein levels or signaling regulation. Although our conclusions are limited by sample size, we suggest that an alternative mechanism such as epigenetic silencing of SOSTDC1 may be a key contributor to the reduced SOSTDC1 mRNA and protein levels observed in renal cancer.
Journal of Experimental & Clinical Cancer Research 11/2010; 29:147. · 2.15 Impact Factor
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Roula Albadine,
Wenle Wang,
Noel A Brownlee,
Antoun Toubaji,
Athanase Billis,
Perdram Argani,
Jonathan I Epstein, A Julian Garvin,
Rima Cousi,
Edward M Schaeffer,
Christian Pavlovich,
George J Netto
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ABSTRACT: Renal medullary carcinoma is an aggressive renal neoplasm without currently available effective therapy to our knowledge. Topoisomerase II alpha is a gyrase involved in cell proliferation, and DNA maintenance and repair. Topoisomerase II alpha is a target of inhibiting agents such as anthracyclines. Triggered by a recent response to topoisomerase II alpha inhibitors in a patient with renal medullary carcinoma, we evaluated topoisomerase II alpha expression in relation to the proliferation index and topoisomerase II alpha gene copy number status in a larger series of patients with renal medullary carcinoma.
Archival tissues from 14 renal medullary carcinomas were retrieved from our 3 institutions. Immunohistochemistry was performed using monoclonal antibodies for topoisomerase II alpha and Ki67. The percent of cells with positive nuclear staining was assessed in the highest area of expression for each marker. A previously suggested greater than 5% cutoff was used for topoisomerase II alpha over expression. The topoisomerase II alpha gene copy number was evaluated using fluorescence in situ hybridization. Locus specific topoisomerase II alpha gene and chromosome 17 centromere probes were used. The total number of topoisomerase II alpha and chromosome 17 centromere signals was counted in 150 cells per tumor and a topoisomerase II alpha-to-chromosome 17 centromere signal ratio was calculated in each tumor. A topoisomerase II alpha-to-chromosome 17 centromere ratio of 2.0 or greater and less than 0.8 was used as a cutoff for amplification and deletion, respectively. The percent of tumor cells with polysomic, eusomic or monosomic chromosome 17 status was also determined.
On immuno-expression analysis topoisomerase II alpha immunohistochemistry was technically inconclusive in 1 renal medullary carcinoma. Topoisomerase II alpha was over expressed in 11 of 13 renal medullary carcinomas (85%) (median 50%, range 1% to 80%). As expected, a high Ki67 proliferation index was noted in 13 of 14 tumors (median 87.5%, range 2% to 100%). Ki67 expression was greater than topoisomerase II alpha expression in all 13 informative tumors. A strong, statistically significant correlation was found for topoisomerase II alpha and Ki67 expression (pairwise CC 0.9, p = 0.0000). Topoisomerase II alpha over expression was associated with shorter survival (p = 0.000). On fluorescence in situ hybridization no topoisomerase II alpha amplification was detected in any of the 14 renal medullary carcinomas, including the 11 with topoisomerase II alpha over expression. Topoisomerase II alpha gene deletions were noted in 4 tumors. Two of 4 deletions were associated with chromosome 17 monosomy and 2 were in eusomic chromosome 17 tumors.
Topoisomerase II alpha is over expressed in 85% of renal medullary carcinomas, potentially supporting the use of topoisomerase II alpha inhibitor agents to treat this aggressive renal tumor. Our findings suggest that topoisomerase II alpha over expression in our renal medullary carcinoma cohort was not due to gene amplification, but rather to transcriptional or post-transcriptional modifications. The significance of the incidentally found topoisomerase II alpha deletions in 28% of renal medullary carcinomas requires further evaluation.
The Journal of urology 07/2009; 182(2):735-40. · 4.02 Impact Factor
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Kimberly Rose Blish,
Wei Wang,
Mark C Willingham,
Wei Du,
Charles E Birse,
Surekha R Krishnan,
Julie C Brown,
Gregory A Hawkins, A Julian Garvin,
Ralph B D'Agostino,
Frank M Torti,
Suzy V Torti
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ABSTRACT: We analyzed expression of candidate genes encoding cell surface or secreted proteins in normal kidney and kidney cancer. This screen identified a bone morphogenetic protein (BMP) antagonist, SOSTDC1 (sclerostin domain-containing-1) as down-regulated in kidney tumors. To confirm screening results, we probed cDNA dot blots with SOSTDC1. The SOSTDC1 message was decreased in 20/20 kidney tumors compared with normal kidney tissue. Immunohistochemistry confirmed significant decrease of SOSTDC1 protein in clear cell renal carcinomas relative to normal proximal renal tubule cells (p < 0.001). Expression of SOSTDC1 was not decreased in papillary and chromophobe kidney tumors. SOSTDC1 was abundantly expressed in podocytes, distal tubules, and transitional epithelia of the normal kidney. Transfection experiments demonstrated that SOSTDC1 is secreted and binds to neighboring cells and/or the extracellular matrix. SOSTDC1 suppresses both BMP-7-induced phosphorylation of R-Smads-1, -5, and -8 and Wnt-3a signaling. Restoration of SOSTDC1 in renal clear carcinoma cells profoundly suppresses proliferation. Collectively, these results demonstrate that SOSTDC1 is expressed in the human kidney and decreased in renal clear cell carcinoma. Because SOSTDC1 suppresses proliferation of renal carcinoma cells, restoration of SOSTDC1 signaling may represent a novel target in treatment of renal clear cell carcinoma.
Molecular biology of the cell 02/2008; 19(2):457-64. · 5.98 Impact Factor
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ABSTRACT: We studied interobserver variability in the proportions of human papillomavirus (HPV)-positive results for atypical squamous cells of undetermined significance (ASCUS) and atypical squamous cells, cannot exclude high-grade squamous intraepithelial lesion (ASC-H) diagnoses among 5 pathologists from the me laboratory during a 2-year period. These proportions were compared with individual pathologist's ASCUS/squamous intraepithelial lesion (SIL) ratios. Of 1,299 ASCUS diagnoses, 32.3% had HPV testing; 49.4% were HPV+. Positive findings by individual pathologists ranged from 38% to 67% (P = .057). There was a difference in the proportions of high risk HPV results for individual pathologists (P < .001). For the pathologist who diagnosed 38% (23/61) of samples as HPV+, the ASCUS/SIL was 0.58; the pathologist who diagnosed 67% (28/42) as HPV+ had a ratio of 1.02. Of the ASC-H diagnoses, 32.9% were tested for HPV; 63% (46/73) were positive. Although the HPV+ proportion by pathologist ranged from 54% to 83%, no significant differences were identified. Within the me laboratory, interobserver variability exists in the proportions of HPV positivity for ASCUS and ASC-H interpretations.
American Journal of Clinical Pathology 12/2007; 128(6):1010-4. · 2.60 Impact Factor
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ABSTRACT: OBJECTIVE: Percutaneous thermal ablation is an emerging technique in the management of renal cell carcinoma (RCC), with greatest efficacy in tumors < or = 3 cm. The purpose of this retrospective study was to evaluate the role and utility of pretreatment CT-guided biopsy in patients referred for percutaneous thermal ablation of renal tumors. CONCLUSION: Less than 5% of samples in our study were benign, and 11.8% were nondiagnostic. Biopsy in smaller lesions was less accurate; therefore biopsy is less useful for these renal lesions. Because fine-needle aspiration (FNA) has higher sensitivity than core biopsy, an appropriate algorithm may be to begin with FNA and reserve core biopsy for cases in which an onsite cytotechnologist is unavailable or deems the sample of inadequate cellularity.
American Journal of Roentgenology 06/2007; 188(6):1500-5. · 2.78 Impact Factor
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ABSTRACT: Clear cell sarcoma of the kidney (CCSK) is a prognostically unfavorable renal neoplasm of childhood. Previous cytogenetic studies of CCSK have reported balanced translocations t(10;17)(q22;p13) and t(10;17)(q11;p12). Although the tumor suppressor gene p53 is located at the chromosome 17p13 breakpoint, p53 abnormalities are rarely present in these tumors.
To identify cytogenetic abnormalities in CCSK and correlate these findings with other clinicopathologic parameters.
A retrospective review of CCSK patients from 1990 to 2005 was conducted at our medical center. We performed clinical and histologic review, p53 immunohistochemical and classic cytogenetics (or ploidy analysis), and p53 fluorescence in situ hybridization analyses.
Five male patients (age range, 6 months to 4 years) were identified with cytogenetic abnormalities. Of 3 cytogenetically informative cases, one revealed a clonal balanced translocation t(10;17)(q22;p13) and an interstitial deletion of chromosome 14, del(14)(q24.1q31.1), and the other 2 patients had normal karyotypes. Fluorescence in situ hybridization for p53 in the t(10;17) case revealed no deletion. Immunohistochemical evaluation of p53 demonstrated lack of nuclear protein accumulation in all cases.
Together with the published literature, our results indicate that translocation (10;17) and interstitial deletions of chromosome 14q are recurring cytogenetic lesions in CCSK. To date, 3 cases of CCSK or "sarcomatoid Wilms tumors" have been reported to exhibit t(10;17). One previously reported case of CCSK contained deletion 14q. Results of p53 immunohistochemistry and/or p53 fluorescence in situ hybridization in this report suggest lack of mutations or deletions of this tumor suppressor in these CCSK cases. The t(10;17) breakpoint and deletion of chromosome 14q24 suggest that other genes are involved in tumor pathogenesis.
Archives of pathology & laboratory medicine 04/2007; 131(3):446-51. · 2.58 Impact Factor
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Masayuki Takahashi,
Ximing J Yang,
Todd T Lavery,
Kyle A Furge,
Bart O Williams,
Maria Tretiakova,
Anthony Montag,
Nicholas J Vogelzang,
Gian G Re, A Julian Garvin,
Stefan Söderhäll,
Susumu Kagawa,
Debra Hazel-Martin,
Agneta Nordenskjold,
Bin Tean Teh
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ABSTRACT: The aims of this study were to understand the underlying molecular mechanisms of favorable histology Wilms tumors (WTs) and to classify them based on their molecular signatures. We studied a total of 15 favorable histology WTs using microarrays containing 19,968 cDNAs. First, we found commonly altered genes in WT. A total of 267 cDNAs were significantly overexpressed at least 3-fold in all of the tumors compared with noncancerous kidney and contained known WT-related genes such as IGF II and WT1. The gene with the highest expression change compared with noncancerous kidney was topoisomerase IIalpha. By hierarchical clustering, there was a clear distinction between high-stage and low-stage tumors. A total of 30 cDNAs were found differentially expressed between the high- and low-stage groups. One of them, Stathmin 1, which is involved in the microtubule system, was highly expressed in high-stage tumors compared with the low-stage tumors. The present chemotherapy regimens for WT consist mainly of topoisomerase II inhibitors (i.e., actinomycin D, doxorubicin, and etoposide) and antimicrotubule agents (i.e., vincristine and paclitaxel). Our data suggest that high expression of topoisomerase IIalpha and microtubule-related genes such as tubulin and stathmin 1 may be related to the high chemosensitivity of WT. In addition, retinol-related genes such as CRABP2 and retinol-binding protein 1 were overexpressed in WT, and CRABP2 was more highly expressed in the poor outcome patients, which suggests that retinoid acid may be a potential drug. In summary, our findings suggest that the integration of gene expression data and clinical parameters could aid in detecting aggressive tumors among favorable histology WT and lead to the discovery of new drugs for WT.
Cancer Research 12/2002; 62(22):6598-605. · 7.86 Impact Factor
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ABSTRACT: Mutation of p53 has been implicated in progression of classical Wilms tumor (WT) into the anaplastic variant (AWT), drug resistance, and poor prognosis. Because of prognostic similarities, clear cell sarcoma of the kidney (CCSK) has been classified with AWT and other aggressive pediatric renal tumors, apart from congenital mesoblastic nephroma (CMN), which is instead a relatively benign tumor of neonates. Initially, CCSK and CMN were assumed to be ontologically related, but the role of p53 in the pathogenesis of either disease has not been sufficiently evaluated as in AWT. We examined the status of p53 in CMN and CCSK in comparison to AWT by immunohistochemistry and mRNA analysis of p53, the downstream effector p21(WAF-1/CIP-1) ( p21), the multidrug resistance gene MDR-1, a putative target of p53, and the p53-antagonist Mdm-2. Surprisingly, strong p53 nuclear immunoreactivity was found in cultures from two CMN specimens, but not in frozen or fixed tumor tissue from five other CMN specimens, nor in cell lines or tumor tissue from CCSK. Sequence analysis excluded p53 mutations. The size of the p53 mRNA in CMN and CCSK primary tumors excluded gross deletions or rearrangements. Low levels of Mdm-2 mRNA in CCSK and CMN primary tumors and cultures did not support a role for Mdm-2. Absence of MDR-1 mRNA excluded MDR-1 in the drug-resistant phenotype of CCSK. Cisplatin-induced p21 transactivation assays and G(1) cell cycle arrest analyses showed that p21 transactivation and G(1) arrest occurred in both CCSK and CMN cultures, demonstrating integrity of the p53 signal transduction pathway. Absence of p53 functional abnormalities excluded relationships between CCSK and CMN as in AWT, supporting the association of cellular CMN with congenital fibrosarcomas as more recently proposed.
Pediatric and Developmental Pathology 5(3):257-68. · 0.99 Impact Factor
