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Publication
Journal: Nature Genetics
January/4/2010
Abstract
Ulcerative colitis is a common form of inflammatory bowel disease with a complex etiology. As part of the Wellcome Trust Case Control Consortium 2, we performed a genome-wide association scan for ulcerative colitis in 2,361 cases and 5,417 controls. Loci showing evidence of association at P < 1 x 10(-5) were followed up by genotyping in an independent set of 2,321 cases and 4,818 controls. We find genome-wide significant evidence of association at three new loci, each containing at least one biologically relevant candidate gene, on chromosomes 20q13 (HNF4A; P = 3.2 x 10(-17)), 16q22 (CDH1 and CDH3; P = 2.8 x 10(-8)) and 7q31 (LAMB1; P = 3.0 x 10(-8)). Of note, CDH1 has recently been associated with susceptibility to colorectal cancer, an established complication of longstanding ulcerative colitis. The new associations suggest that changes in the integrity of the intestinal epithelial barrier may contribute to the pathogenesis of ulcerative colitis.
Publication
Journal: Cancer Research
August/24/2003
Abstract
To identify potential targets for aberrant methylation in pancreatic cancer, we analyzed global changes in gene expression profiles of four pancreatic cancer cell lines after treatment with the demethylating agent 5-aza-2'-deoxycytidine (5Aza-dC) and/or the histone deacetylase inhibitor trichostatin A. A substantial number of genes were induced 5-fold or greater by 5Aza-dC alone (631 transcripts), trichostatin A alone (1196 transcripts), and by treatment with both agents (857 transcripts). Four hundred and seventy-five genes were markedly (>5-fold) induced after 5Aza-dC treatment in pancreatic cancer cell lines but not in a nonneoplastic pancreatic epithelial cell line. The methylation status of 11 of these 475 genes was examined in a panel of 42 pancreatic cancers, and all 11 of these genes were aberrantly methylated in pancreatic cancer but rarely, if any, methylated in 10 normal pancreatic ductal epithelia. These genes include UCHL1 (methylated in 100% of 42 pancreatic cancers), NPTX2 (98%), SARP2 (95%), CLDN5 (93%), reprimo (86%), LHX1 (76%), WNT7A (71%), FOXE1 (69%), TJP2 (64%), CDH3 (19%), and ST14 (10%). Three of these 11 genes (NPTX2, SARP2, and CLDN5) were selected for further analysis in a larger panel of specimens, and aberrant methylation of at least one of these three genes was detectable in 100% of 43 primary pancreatic cancers and in 18 of 24 (75%) pancreatic juice samples obtained from patients with pancreatic cancer. Thus, a substantial number of genes are induced by 5Aza-dC treatment of pancreatic cancer cells, and many of them may represent novel targets for aberrant methylation in pancreatic carcinoma.
Publication
Journal: PLoS ONE
April/22/2010
Abstract
BACKGROUND
Gene expression profiling has revolutionized our ability to molecularly classify primary human tumors and significantly enhanced the development of novel tumor markers and therapies; however, progress in the diagnosis and treatment of melanoma over the past 3 decades has been limited, and there is currently no approved therapy that significantly extends lifespan in patients with advanced disease. Profiling studies of melanoma to date have been inconsistent due to the heterogeneous nature of this malignancy and the limited availability of informative tissue specimens from early stages of disease.
RESULTS
In order to gain an improved understanding of the molecular basis of melanoma progression, we have compared gene expression profiles from a series of melanoma cell lines representing discrete stages of malignant progression that recapitulate critical characteristics of the primary lesions from which they were derived. Here we describe the unsupervised hierarchical clustering of profiling data from melanoma cell lines and melanocytes. This clustering identifies two distinctive molecular subclasses of melanoma segregating aggressive metastatic tumor cell lines from less-aggressive primary tumor cell lines. Further analysis of expression signatures associated with melanoma progression using functional annotations categorized these transcripts into three classes of genes: 1) Upregulation of activators of cell cycle progression, DNA replication and repair (CDCA2, NCAPH, NCAPG, NCAPG2, PBK, NUSAP1, BIRC5, ESCO2, HELLS, MELK, GINS1, GINS4, RAD54L, TYMS, and DHFR), 2) Loss of genes associated with cellular adhesion and melanocyte differentiation (CDH3, CDH1, c-KIT, PAX3, CITED1/MSG-1, TYR, MELANA, MC1R, and OCA2), 3) Upregulation of genes associated with resistance to apoptosis (BIRC5/survivin). While these broad classes of transcripts have previously been implicated in the progression of melanoma and other malignancies, the specific genes identified within each class of transcripts are novel. In addition, the transcription factor NF-KB was specifically identified as being a potential "master regulator" of melanoma invasion since NF-KB binding sites were identified as consistent consensus sequences within promoters of progression-associated genes.
CONCLUSIONS
We conclude that tumor cell lines are a valuable resource for the early identification of gene signatures associated with malignant progression in tumors with significant heterogeneity like melanoma. We further conclude that the development of novel data reduction algorithms for analysis of microarray studies is critical to allow for optimized mining of important, clinically-relevant datasets. It is expected that subsequent validation studies in primary human tissues using such an approach will lead to more rapid translation of such studies to the identification of novel tumor biomarkers and therapeutic targets.
Publication
Journal: Biochimica et Biophysica Acta - General Subjects
January/9/2013
Abstract
E-cadherin and P-cadherin are major contributors to cell-cell adhesion in epithelial tissues, playing pivotal roles in important morphogenetic and differentiation processes during development, and in maintaining integrity and homeostasis in adult tissues. It is now generally accepted that alterations in these two molecules are observed during tumour progression of most carcinomas. Genetic or epigenetic alterations in E- and P-cadherin-encoding genes (CDH1 and CDH3, respectively), or alterations in their proteins expression, often result in tissue disorder, cellular de-differentiation, increased invasiveness of tumour cells and ultimately in metastasis. In this review, we will discuss the major properties of E- and P-cadherin molecules, its regulation in normal tissue, and their alterations and role in cancer, with a specific focus on gastric and breast cancer models.
Publication
Journal: Cancer Research
April/3/2005
Abstract
The study looked for an optimal set of genes differentiating between papillary thyroid cancer (PTC) and normal thyroid tissue and assessed the sources of variability in gene expression profiles. The analysis was done by oligonucleotide microarrays (GeneChip HG-U133A) in 50 tissue samples taken intraoperatively from 33 patients (23 PTC patients and 10 patients with other thyroid disease). In the initial group of 16 PTC and 16 normal samples, we assessed the sources of variability in the gene expression profile by singular value decomposition which specified three major patterns of variability. The first and the most distinct mode grouped transcripts differentiating between tumor and normal tissues. Two consecutive modes contained a large proportion of immunity-related genes. To generate a multigene classifier for tumor-normal difference, we used support vector machines-based technique (recursive feature replacement). It included the following 19 genes: DPP4, GJB3, ST14, SERPINA1, LRP4, MET, EVA1, SPUVE, LGALS3, HBB, MKRN2, MRC2, IGSF1, KIAA0830, RXRG, P4HA2, CDH3, IL13RA1, and MTMR4, and correctly discriminated 17 of 18 additional PTC/normal thyroid samples and all 16 samples published in a previous microarray study. Selected novel genes (LRP4, EVA1, TMPRSS4, QPCT, and SLC34A2) were confirmed by Q-PCR. Our results prove that the gene expression signal of PTC is easily detectable even when cancer cells do not prevail over tumor stroma. We indicate and separate the confounding variability related to the immune response. Finally, we propose a potent molecular classifier able to discriminate between PTC and nonmalignant thyroid in more than 90% of investigated samples.
Publication
Journal: Clinical Cancer Research
December/20/2005
Abstract
OBJECTIVE
P-cadherin overexpression has been reported in breast carcinomas, where it was associated with proliferative high-grade histological tumors. This study aimed to analyze P-cadherin expression in invasive breast cancer and to correlate it with tumor markers, pathologic features, and patient survival. Another purpose was to evaluate the P-cadherin promoter methylation pattern as the molecular mechanism underlying this gene regulation.
METHODS
Using a series of invasive breast carcinomas, P-cadherin expression was evaluated and correlated with histologic grade, estrogen receptor, MIB-1, and p53 and c-erbB-2 expression. In order to assess whether P-cadherin expression was associated with changes in CDH3 promoter methylation, we studied the methylation status of a gene 5'-flanking region in these same carcinomas. This analysis was also done for normal tissue and for a breast cancer cell line treated with a demethylating agent.
RESULTS
P-cadherin expression showed a strong correlation with high histologic grade, increased proliferation, c-erbB-2 and p53 expression, lack of estrogen receptor, and poor patient survival. This overexpression can be regulated by gene promoter methylation because the 5-Aza-2'-deoxycytidine treatment of MCF-7/AZ cells increased P-cadherin mRNA and protein levels. Additionally, we found that 71% of P-cadherin-negative cases showed promoter methylation, whereas 65% of positive ones were unmethylated (P = 0.005). The normal P-cadherin-negative breast epithelial cells showed consistent CDH3 promoter methylation.
CONCLUSIONS
P-cadherin expression was strongly associated with tumor aggressiveness, being a good indicator of clinical outcome. Moreover, the aberrant expression of P-cadherin in breast cancer might be regulated by gene promoter hypomethylation.
Publication
Journal: Nucleic Acids Research
December/11/2008
Abstract
Alternative processing of pre-mRNA transcripts is a major source of protein diversity in eukaryotes and has been implicated in several disease processes including cancer. In this study we have performed a genome wide analysis of alternative splicing events in lung adenocarcinoma. We found that 2369 of the 17 800 core Refseq genes appear to have alternative transcripts that are differentially expressed in lung adenocarcinoma versus normal. According to their known functions the largest subset of these genes (30.8%) is believed to be cancer related. Detailed analysis was performed for several genes using PCR, quantitative RT-PCR and DNA sequencing. We found overexpression of ERG variant 2 but not variant 1 in lung tumors and overexpression of CEACAM1 variant 1 but not variant 2 in lung tumors but not in breast or colon tumors. We also identified a novel, overexpressed variant of CDH3 and verified the existence and overexpression of a novel variant of P16 transcribed from the CDKN2A locus. These findings demonstrate how analysis of alternative pre-mRNA processing can shed additional light on differences between tumors and normal tissues as well as between different tumor types. Such studies may lead to the development of additional tools for tumor diagnosis, prognosis and therapy.
Publication
Journal: Cancer Research
June/2/2005
Abstract
P-Cadherin/CDH3 belongs to the family of classic cadherins that are engaged in various cellular activities including motility, invasion, and signaling of tumor cells, in addition to cell adhesion. However, the biological roles of P-cadherin itself are not fully characterized. Based on information derived from a previous genome-wide cDNA microarray analysis of microdissected pancreatic ductal adenocarcinoma (PDAC), we focused on P-cadherin as one of the genes most strongly overexpressed in the great majority of PDACs. To investigate the consequences of overexpression of P-cadherin in terms of pancreatic carcinogenesis and tumor progression, we used a P-cadherin-deficient PDAC cell line, Panc-1, to construct a cell line (Panc1-CDH3) that stably overexpressed P-cadherin. Induction of P-cadherin in Panc1-CDH3 increased the motility of the cancer cells, but a blocking antibody against P-cadherin suppressed the motility in vitro. Overexpression of P-cadherin was strongly associated with cytoplasmic accumulation of one of the catenins, p120ctn, and cadherin switching in PDAC cells. Moreover, P-cadherin-dependent activation of cell motility was associated with activation of Rho GTPases, Rac1 and Cdc42, through accumulation of p120ctn in cytoplasm and cadherin switching. These findings suggest that overexpression of P-cadherin is likely to be related to the biological aggressiveness of PDACs; blocking of P-cadherin activity or its associated signaling could be a novel therapeutic approach for treatment of aggressive pancreatic cancers.