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David Seligson

Publications and source records attributed to David Seligson.

At least 19 recordsLinked to original sources
PubMed2007

p21 is a prognostic marker for renal cell carcinoma: implications for novel therapeutic approaches.

PURPOSE: Kidney cancer, although relatively rare compared to other malignancies, is the most lethal of the common urological malignancies. Current treatments are inadequate as evidenced by a poor 5-year survival of patients with metastatic disease. Since there exists a significant disparity in the survival of patients with localized vs metastatic disease, efforts are under way to identify molecular markers of progression as well as targets for novel therapeutic approaches. The apoptosis and cell cycle regulatory protein, p21(waf1/cip1), has been investigated as a possible target in other cancers since it is involved in the repair and apoptotic response of normal and malignant cells to DNA damage. MATERIALS AND METHODS: We performed immunohistochemical analysis of a tissue array of 366 patients for which we have data on grade, stage and survival. We found that nuclear p21 is most highly expressed in collecting duct carcinoma and lowest in oncocytoma. Cytosolic p21 staining was highest in oncocytoma. RESULTS: In clear cell renal cell carcinoma p21 has prognostic value, which is a function of whether patients have localized or metastatic disease at diagnosis, suggesting the existence of 2 discrete classes of this disease. In localized disease higher levels of nuclear p21 were associated with a better prognosis, but in patients with metastatic disease at diagnosis higher levels of nuclear and cytosolic p21 were associated with worse survival. CONCLUSIONS: Based on our findings p21 may be useful in prognostication, and it may have a role in the differing biological behaviors of localized and metastatic renal cell carcinoma.

Biomarkers, Tumor↗
PubMed2006

Decreased expression of annexin A1 is correlated with breast cancer development and progression as determined by a tissue microarray analysis.

Annexin A1 (ANXA1) is a calcium- and phospholipid-binding protein and a known mediator of glucocorticoid-regulated inflammatory responses. Using a combined multiple high-throughput approach, we recently identified a reduced expression of ANXA1 in human breast cancer. The finding was confirmed at the gene level by quantitative reverse transcription-polymerase chain reaction and at the protein level by immunohistochemical staining of normal, benign, and malignant breast tissues. In this study, we constructed and used a high-density human breast cancer tissue microarray to characterize the expressional pattern of ANXA1 according to histopathologies. The tissue microarray contains 1,158 informative breast tissue cores of different histologies including normal tissues, hyperplasia, in situ and invasive tumors, and lymph node metastases. Our results showed that there was a significant decrease in glandular expression of ANXA1 in ductal carcinoma in situ and invasive ductal carcinoma compared with either normal breast tissue or hyperplasia (P < .0001). Moreover, in benign breast tissue, myoepithelial cells showed strong expression of ANXA1. There was a decrease of ANXA1 expression in myoepithelial cells in ductal carcinoma in situ lesions compared with the same cell population in either normal or hyperplastic lesions. These results suggest that suppressed ANXA1 expression in breast tissue is correlated with breast cancer development and progression.

Annexin A1↗
PubMed2005

A molecular classification of papillary renal cell carcinoma.

Despite the moderate incidence of papillary renal cell carcinoma (PRCC), there is a disproportionately limited understanding of its underlying genetic programs. There is no effective therapy for metastatic PRCC, and patients are often excluded from kidney cancer trials. A morphologic classification of PRCC into type 1 and 2 tumors has been recently proposed, but its biological relevance remains uncertain. We studied the gene expression profiles of 34 cases of PRCC using Affymetrix HGU133 Plus 2.0 arrays (54,675 probe sets) using both unsupervised and supervised analyses. Comparative genomic microarray analysis was used to infer cytogenetic aberrations, and pathways were ranked with a curated database. Expression of selected genes was validated by immunohistochemistry in 34 samples with 15 independent tumors. We identified two highly distinct molecular PRCC subclasses with morphologic correlation. The first class, with excellent survival, corresponded to three histologic subtypes: type 1, low-grade type 2, and mixed type 1/low-grade type 2 tumors. The second class, with poor survival, corresponded to high-grade type 2 tumors (n = 11). Dysregulation of G1-S and G2-M checkpoint genes were found in class 1 and 2 tumors, respectively, alongside characteristic chromosomal aberrations. We identified a seven-transcript predictor that classified samples on cross-validation with 97% accuracy. Immunohistochemistry confirmed high expression of cytokeratin 7 in class 1 tumors and of topoisomerase IIalpha in class 2 tumors. We report two molecular subclasses of PRCC, which are biologically and clinically distinct and may be readily distinguished in a clinical setting.

Adult↗
PubMed2005

Loss of annexin A1 expression in human breast cancer detected by multiple high-throughput analyses.

To test the efficacy of combined high-throughput analyses (HTA) in target gene identification, screening criteria were set using >fivefold difference by microarray and statistically significant changes (p<0.01) in SAGE and EST. Microarray analysis of two normal and seven breast cancer samples found 129 genes with >fivefold changes. Further SAGE and EST analyses of these genes identified four qualified genes, ERBB2, GATA3, AGR2, and ANXA1. Their expression pattern was validated by RT-PCR in both breast cell lines and tissue samples. Loss of ANXA1 in breast cancer was further confirmed at mRNA level by Human Breast Cancer Tissue Profiling Array and at protein level by immunohistochemical staining. This study demonstrated that combined HTA effectively narrowed the number of genes for further study, while retaining the sensitivity in identifying biologically important genes such as ERBB2 and ANXA1. A distinctive loss of ANXA1 in breast cancer suggests its involvement in maintaining normal breast biology.

Algorithms↗
PubMed2005

Tumor classification by tissue microarray profiling: random forest clustering applied to renal cell carcinoma.

We describe a novel strategy (random forest clustering) for tumor profiling based on tissue microarray data. Random forest clustering is attractive for tissue microarray and other immunohistochemistry data since it handles highly skewed tumor marker expressions well and weighs the contribution of each marker according to its relatedness with other tumor markers. This is the first tumor class discovery analysis of renal cell carcinoma patients based on protein expression profiles. The tissue array data contained at least three tumor samples from each of 366 renal cell carcinoma patients. The eight tumor markers explore tumor proliferation, cell cycle abnormalities, cell mobility, and the hypoxia pathway. Since the procedure is unsupervised, no clinicopathological data or traditional classifications are used a priori. To explore whether the tissue microarray data can be used to identify fundamental subtypes of renal cell carcinoma patients, we first carried out random forest clustering of all 366 patients. By analyzing the tumor markers simultaneously, the procedure automatically detected classes that correspond to clear- vs non-clear cell tumors (demonstration of proof-of-principle). The resulting molecular grouping provides better prediction of survival (logrank P=0.000090) than this classical pathological grouping (logrank P=0.023). We then sought to extend the class discovery by searching for finer subclasses of clear cell patients. The procedure automatically discovered: (a) two classes corresponding to low- and high-grade patients (demonstration of proof-of-principle); (b) a subgroup of long-surviving clear cell patients with a distinct molecular profile and (c) two novel tumor subclasses in low-grade clear cell patients that could not be explained by any clinicopathological variables (demonstration of discovery).

Biomarkers, Tumor↗
PubMed2005

p53 is an independent predictor of tumor recurrence and progression after nephrectomy in patients with localized renal cell carcinoma.

PURPOSE: We determined which clinical and molecular variables can predict cancer recurrence in patients following surgical management for localized renal cell carcinoma (RCC). MATERIALS AND METHODS: From a custom kidney cancer tissue microarray containing tumors specimens from 350 patients 193 undergoing nephrectomy for localized RCC at our institution between 1989 and 2000 were identified. The array was then analyzed by immunohistochemistry for certain molecular markers, namely CA9, CA12, Ki67, gelsolin, p53, EpCAM, pTEN and vimentin. The medical records of these patients were then reviewed for age, sex, TNM stage, tumor size, nuclear grade, Eastern Cooperative Oncology Group (ECOG) performance status, recurrence status and, when applicable, time to recurrence. Cox regression analyses were done to determine clinical and molecular predictors of time to tumor recurrence. RESULTS: Of the patients 15% demonstrated evidence of tumor recurrence following nephrectomy (29 of 193). Univariate Cox regression demonstrated that tumor size, T stage, grade, ECOG performance status, Ki67, EpCAM and p53 were significantly associated with recurrence (p <0.05). A multivariate Cox regression model showed that T stage (p = 0.018), ECOG (p = 0.004) and p53 (p = 0.003) were the 3 most significant predictors. p53 expression correlated significantly with nuclear grade (Pearson correlation 0.22, p = 0.023) but not with any other clinical factors. Patients with localized tumors demonstrating mean p53 staining values above and below 20% of cells had recurrence rates of 37.7% and 14.4%, respectively (RR = 3.28, p = 0.018). CONCLUSIONS: p53 is a significant molecular predictor of tumor recurrence, as identified in patients undergoing treatment for localized RCC.

Adult↗
PubMed2005

Using tumor markers to predict the survival of patients with metastatic renal cell carcinoma.

PURPOSE: Approximately 30% of renal cell carcinomas (RCCs) present as metastatic disease. Molecular markers have the potential to characterize accurately the biological behavior of tumors and they may be useful for determining prognosis. MATERIALS AND METHODS: A custom tissue array was constructed using clear cell RCC from 150 patients with metastatic RCC who underwent nephrectomy prior to immunotherapy. The tissue array was stained for 8 molecular markers, namely Ki67, p53, gelsolin, carbonic anhydrase (CA)9, CA12, PTEN (phosphatase and tensin homologue deleted on chromosome 10), epithelial cell adhesion molecule and vimentin. Marker status and established clinical predictors of prognosis were considered when developing a prognostic model for disease specific survival. RESULTS: On univariate Cox regression analysis certain markers were statistically significant predictors of survival, namely CA9 (p <0.00001), p53 (p = 0.0072), gelsolin (p = 0.030), Ki67 (p = 0.036) and CA12 (p = 0.043). On multivariate Cox regression analysis that included all markers and clinical variables CA9 (p = 0.00002), PTEN (p <0.0001), vimentin (p = 0.0032), p53 (p = 0.028), T category (p = 0.0025) and performance status (p = 0.0013) were significant independent predictors of disease specific survival and they were used to construct a combined molecular and clinical prognostic model. The bias corrected concordance index (C-index) of this combined prognostic model was C = 0.68, which was significantly higher (p = 0.0033) than that of a multivariate clinical predictor model (C = 0.62) based on the UCLA Integrated Staging System (T category, histological grade and performance status). CONCLUSIONS: In patients with clear cell RCC a prognostic model for survival that includes molecular and clinical predictors is significantly more accurate than a standard clinical model using the combination of stage, histological grade and performance status.

Adult↗
PubMed2005

Expression of transcription factor Yin Yang 1 in prostate cancer.

The transcription repressor Yin Yang 1 (YY1) is expressed in several human cancer cell lines and its expression correlates with resistance to immune-mediated apoptosis. This study used tissue microarrays to investigate the expression and localization of YY1 in 1364 representative tissue samples from 246 hormone naive prostate cancer patients who underwent radical prostatectomy. Staining intensity and frequency measures for both YY1 nuclear and cytoplasmic expression were higher in neoplastic tissues and in PIN samples compared to matched benign cells (p < 0.0001 for all comparisons). Expression of YY1 is predominantly elevated in early malignancy (PIN), as well as in tumors of intermediate to high morphologic grade (Gleason's grade 3-5). Using multivariate Cox proportional hazards analysis, we observed that low nuclear YY1 staining is an independent predictor of a shorter time to recurrence (p = 0.012). Based on these results, we hypothesize that YY1 may play a role in prostate cancer development; however, decreased YY1 may give metastatic cells a survival advantage. These results may also implicate YY1 as a useful diagnostic and prognostic marker.

Aged↗
PubMed2004

Trefoil factor 3 is overexpressed in human prostate cancer.

The trefoil factors are secreted peptides produced by normal intestinal mucosa. Members of the trefoil family are overexpressed in a variety of cancers and are associated with tumor invasion, resistance to apoptosis, and metastasis. Recent cDNA array analyses suggest that human intestinal trefoil factor 3 (TFF3) may be overexpressed in human prostate cancer. Immunohistochemistry was performed on a prostate cancer tissue microarray containing tumor tissue samples from 246 primary radical retropubic prostatectomy cases with antibodies specific for TFF3. Prostatic intraepithelial neoplasia (PIN), benign prostatic hyperplasia (BPH), and morphologically normal prostatic epithelium were represented on this array. Additionally, 18 metastatic lesions were also stained. Two independent pathologists scored the tissue arrays, with positive cases defined as those containing TFF3 staining in a majority of target cells within any spots representing the appropriate designated histology. Forty-two percent of 236 cases containing prostate cancer stained positive for TFF3, while only 10% of 145 cases containing normal tissue and 18% of 91 cases containing BPH, stained positive. Seven of 18 (39%) metastatic lesions analyzed stained positive. Although TFF3 expression correlates significantly with prostate cancer, TFF3 expression did not correlate with Gleason grade, tumor stage, or rate of recurrence. These studies validate that TFF3 is overexpressed in a subset of primary and metastic prostate cancers.

Aged↗
PubMed2004

Using protein expressions to predict survival in clear cell renal carcinoma.

PURPOSE: An accurate system for predicting survival for patients with solid tumors will allow for better patient selection for both established and novel therapies. We propose a staging system for clear cell variants of renal cell carcinoma (RCC) that includes molecular predictors and standard clinical predictors such as tumor-node-metastasis (TNM) stage, histological grade, and performance status (PS). EXPERIMENTAL DESIGN: A custom tissue array was constructed using clear cell RCC from 318 patients, representing all stages of localized and metastatic RCC, and immunohistochemically stained for molecular markers Ki67, p53, gelsolin, CA9, CA12, PTEN, EpCAM, and vimentin. We present a strategy for evaluating individual candidate markers for prognostic information and integrating informative markers into a multivariate prognostic system. RESULTS: The overall median follow-up and the median follow-up for surviving patients were 28 and 55 months, respectively. A prognostic model based primarily on molecular markers included metastasis status, p53, CA9, gelsolin, and vimentin as predictors and had high discriminatory power: its statistically validated concordance index (C-index) was found to be 0.75. A prognostic model based on a combination of clinical and molecular predictors included metastasis status, T stage, Eastern Cooperative Oncology Group PS, p53, CA9, and vimentin as predictors and had a C-index of 0.79, which was significantly higher (P < 0.05) than that of prognostic models based on grade alone (C = 0.65), TNM stage alone (C = 0.73), or the University of California Los Angeles integrated staging system (C = 0.76). CONCLUSIONS: Protein expressions obtained using widely available technology can complement standard clinical predictors such as TNM stage, histological grade, and PS.

Adenocarcinoma, Clear Cell↗
PubMed2004

Expression pattern of the novel gene EG-1 in cancer.

PURPOSE: We recently discovered a novel gene responsive to tumor-conditioned media: endothelial-derived gene 1 (EG-1). Its transcript has been shown to be present in epithelial cells, as well as in endothelial cells. In this study, we examined the levels of EG-1 protein expression in breast, colon, prostate, and lung cancers, which constitute the four most common solid malignancies in the United States. EXPERIMENTAL DESIGN: Polyclonal antibodies were generated that recognize the EG-1 peptide. These antibodies were used in immunoblot analysis, as well as immunohistochemistry of multiple human clinical specimens of cancer. RESULTS: In immunoblots of whole cell lysates, EG-1 antibodies revealed the presence of a 22-kDa peptide. Immunohistochemistry of breast, colon, and prostate specimens showed higher levels of EG-1 peptides in cancer tissues, in comparison with their benign counterparts. However, EG-1 expression was minimal in both benign and malignant lung tissues. CONCLUSIONS: Here, we demonstrated that the expression of EG-1 is elevated in cancerous in comparison to benign epithelial cells, as seen in immunohistochemistry of human pathological specimens. These observations collectively support the hypothesis that the novel gene EG-1 is associated with the malignant phenotype of the common epithelial-derived cancers of the breast, colon, and prostate.

Antibodies↗
PubMed2004

Prognostic value of carbonic anhydrase IX and KI67 as predictors of survival for renal clear cell carcinoma.

PURPOSE: The natural history of renal cell carcinoma (RCC) is complex and not entirely explained by conventional prognostic factors. In this study we evaluated the prognostic value of carbonic anhydrase IX (CAIX) and Ki67 to predict survival in RCC. MATERIALS AND METHODS: Immunohistochemical analysis using a CAIX and a Ki67 monoclonal antibody was performed on tissue microarrays constructed from paraffin embedded specimens from 224 patients treated with nephrectomy for clear cell renal carcinoma. CAIX and Ki67 staining were correlated with clinical factors, pathological features and survival. Median followup was 34 months (range 0.3 to 117) and disease specific survival was the primary end point assessed. RESULTS: Univariate statistical analysis showed that high Ki67 staining and low CAIX staining correlated significantly with poor median survival (21 months, p < 0.001 and 22 months, p = 0.011, respectively). Each marker was highly significant for stratifying patient groups defined by T stage, Fuhrman grade, nodal status, metastatic status and performance status. On multivariate analysis CAIX and Ki67 were significant predictors of survival with an HR of 1.78 (p = 0.014) and 1.75 (p = 0.009), respectively. Although CAIX and Ki67 staining were inversely correlated (p = 0.009), Ki67 significantly substratified patient subgroups defined by high or low CAIX staining (p = 0.001 and 0.003, respectively). When Ki67 and CAIX were combined into a single parameter, RCC tumors could be stratified into low, intermediate and high risk groups with a median survival of greater than 101, 31 and 9 months, respectively (p <0.001). On multivariate analysis the combined parameter consisting of Ki67 and CAIX was a significant predictor of survival (p <0.001) and it was able to displace histological grade. CONCLUSIONS: Ki67and CAIX are useful prognostic biomarkers for RCC that improve the survival prediction and classification of kidney cancer.

Adult↗