Biomedical subjects

Dennis A Faith

Publications and source records attributed to Dennis A Faith.

7 recordsLinked to original sources

PubMed2006

A novel role of myosin VI in human prostate cancer.

Myosin VI is an actin motor that moves to the minus end of the polarized actin filament, a direction opposite to all other characterized myosins. Using expression microarrays, we identified myosin VI as one of the top genes that demonstrated cancer-specific overexpression in clinical prostate specimens. Protein expression of myosin VI was subsequently analyzed in arrayed prostate tissues from 240 patients. Notably, medium-grade prostate cancers demonstrated the most consistent cancer-specific myosin VI protein overexpression, whereas prostate cancers associated with more aggressive histological features continued to overexpress myosin VI but to a lesser extent. Myosin VI protein expression in cell lines positively correlated with the presence of androgen receptor. Small interference RNA-mediated myosin VI knockdown in the LNCaP human prostate cancer cell line resulted in impaired in vitro migration and soft-agar colony formation. Depletion of myosin VI expression was also accompanied by global gene expression changes reflective of attenuated tumorigenic potential, as marked by a nearly 10-fold induction of TXNIP (VDUP1), a tumor suppressor with decreased expression in prostate cancer specimens. These results support that myosin VI is critical in maintaining the malignant properties of the majority of human prostate cancers diagnosed today.

Biomarkers, Tumor↗

PubMed2004

Trefoil factor 3 overexpression in prostatic carcinoma: prognostic importance using tissue microarrays.

BACKGROUND: Human intestinal trefoil factor 3 (TFF3) is a member of a family of polypeptides encoded by a cluster of genes on chromosome 21. Through gene expression profiling studies TFF3 mRNA has been found to be overexpressed in prostate cancer. METHODS: We used immunochemistry on tissue microarrays and software tools, collectively referred to as TMAJ, for online assessment of staining to analyze samples from 294 primary tumors and 61 metastatic lesions. RESULTS: Applying a cutoff of 20% of cells staining as positive, the frequency of staining was 18.8% in normal (51 of 272) and 47.0% in primary tumors (126 of 268), P < 0.0001, Wilcoxon rank sum). Expression of TFF3 in metastatic prostate cancer was similar to that in primary tumors. TFF3 expression was not associated with time to biochemical recurrence, development of distant metastasis, or death due to prostate cancer. Scoring data derived from visual estimation of expression correlated highly with semi-automated image analysis using the Automated Cellular Imaging System (ACIS) from Chromavision, Inc. CONCLUSIONS: These studies validate that TFF3 is overexpressed at the protein level in a subset of primary and metastatic prostate cancers, show the first use of the TMAJ database, and demonstrate the ability to semi-automatically scan and score immunohistochemically stained tissue microarray slides.

Biomarkers, Tumor↗

PubMed2003

Xq27-28 deletions in prostate carcinoma.

Linkage studies have implicated a prostate cancer susceptibility locus at Xq27-28 (termed HPCX), estimated to be responsible for approximately 16% of hereditary prostate cancer cases. To date, this region has not been investigated in sporadic disease. In this study, we examined tumor DNA samples prepared from patients with sporadic prostate cancer, prostate cancer cell lines, and prostate cancer xenografts for evidence of genomic alterations within the Xq27-28 region. To facilitate the detection of nullizygosity, we examined a unique series of highly tumor-enriched DNA samples prepared from men with multi-sampled metastatic prostate cancer, as well as a series of prostate cancer xenografts and cell lines. PCR amplification of carcinoma and normal DNA templates was performed for 11 loci spanning an Xq27-28 interval of approximately 16 cM. Among 19 patients studied, somatic deletions in this region were found in two cases. Within these two cases, each independent metastatic tumor sample available from an individual (n = 4 sites and 8 sites, respectively) showed the same reduction to nullizygosity, suggesting a pre-metastatic origin for the deletion events in both. Mapping of the deletion boundaries with eight additional sets of markers indicated that both deletions had breakpoints within an approximately 500- to 800-kb interval containing FMR1; however, the deletions were non-overlapping. The lack of a common region of deletion suggests one of three possibilities: (1) that these two deletions are unrelated, (2) that the deletions affect the opposite ends of an as yet unknown gene, or (3) that each deletion has inactivated a single copy of an unknown gene arranged in cis in the region of interest. These data clearly indicate that deletions do occur within the HPCX locus in a subset of sporadic prostate cancers and therefore raises the possibility that the gene at this locus may prove to play a role in sporadic disease.

Animals↗

PubMed2002

Sequence variants of alpha-methylacyl-CoA racemase are associated with prostate cancer risk.

The enzyme alpha-methylacyl-CoA racemase (AMACR) plays an important role in peroxisomal beta-oxidation of branched-chain fatty acid and therefore is relevant to carcinogenesis. The involvement of AMACR in prostate cancer (CaP) is implicated by the recent observation that expression of AMACR is consistently and extensively up-regulated in CaP. This observation is of particular interest, given previous findings from epidemiological studies that red meat and dairy products, major sources of branched-chain fatty acid, are associated with CaP risk and from linkage studies that the AMACR gene region at 5p13 is linked to a CaP susceptibility gene. In this study, we hypothesize that sequence variants in AMACR may alter the risk for CaP. To test this hypothesis, we sequenced all five exons, exon-intron junctions, the promoter region, and 3'-untranslated region of AMACR in germ-line DNA samples of 96 probands from hereditary CaP (HPC) families. Seventeen sequence variants, including five novel (R118Q, V185A, P238S, Q239H, and L250R) and five known (M9V, S52P, D175G, S201L, and K277E) missense changes, were identified. Six of these variants are at conserved residues among the rat and mouse AMACR. Eleven of these single nucleotide polymorphisms were genotyped in a total of 159 HPC probands, 245 sporadic cases, and 211 unaffected controls to assess their association with CaP risk. Significantly different genotype frequencies between HPC probands and unaffected controls were found for several missense changes, including M9V (P = 0.03), G1175D (P = 0.02), S291L (P = 0.02), and K277E (P = 0.02). Haplotype analysis provided stronger evidence for association (P = 0.001). Furthermore, the AMACR sequence variants strongly cosegregate with CaP in HPC families (log of odds = 3.78; P = 0.00006), especially in the subset of families whose probands carry the "A-A" haplotype of M9V and D175G (log of odds = 4.34; P = 0.000008). These results suggest that sequence variants in AMACR may be associated with CaP risk.

3' Untranslated Regions↗

PubMed2002

Germline mutations and sequence variants of the macrophage scavenger receptor 1 gene are associated with prostate cancer risk.

Deletions on human chromosome 8p22-23 in prostate cancer cells and linkage studies in families affected with hereditary prostate cancer (HPC) have implicated this region in the development of prostate cancer. The macrophage scavenger receptor 1 gene (MSR1, also known as SR-A) is located at 8p22 and functions in several processes proposed to be relevant to prostate carcinogenesis. Here we report the results of genetic analyses that indicate that mutations in MSR1 may be associated with risk of prostate cancer. Among families affected with HPC, we identified six rare missense mutations and one nonsense mutation in MSR1. A family-based linkage and association test indicated that these mutations co-segregate with prostate cancer (P = 0.0007). In addition, among men of European descent, MSR1 mutations were detected in 4.4% of individuals affected with non-HPC as compared with 0.8% of unaffected men (P = 0.009). Among African American men, these values were 12.5% and 1.8%, respectively (P = 0.01). These results show that MSR1 may be important in susceptibility to prostate cancer in men of both African American and European descent.

Aged↗

PubMed2002

Mutational analysis of ETV6 in prostate carcinoma.

BACKGROUND: In an effort to better understand the molecular events responsible for progression of prostate carcinoma to metastatic disease, we have recently identified a homozygous deletion at 12p12-13 involving ETV6 (tel). Although mutational analysis of ETV6 has not been examined previously in prostate carcinoma, it is an attractive candidate prostate cancer tumor suppressor gene since as it previously has been implicated in malignancy. Therefore, we decided to analyze 43 prostate cell lines, xenografts, and metastatic foci for inactivating mutations. METHODS: DNA was isolated from 7 cell lines, 18 xenografts, and 18 metastatic deposits. Single-strand conformational polymorphism (SSCP) analysis of ETV6, was performed by polymerase chain reaction (PCR) amplification of each exon by using intron specific primers. PCR products were then resolved by gel electrophoresis, and aberrantly migrating PCR products were then sequenced. RESULTS: Two previously described polymorphisms and four novel sequence changes were identified. Polymorphisms at nucleotide 258 (G --> A, Thr --> Thr) and 602 (T --> C, Leu --> Pro) were identified in eight and one specimen(s), respectively. Analysis of noncancerous DNA confirmed the presence of the polymorphisms in the germ-line. Four possible mutations were identified at nucleotides 24 (T --> G, Cys --> Trp), 380 (G --> A, Arg --> Glu), 776 (G --> T, Arg --> Leu), and 876 (C --> T, Leu --> Leu). Three were in xenografts or cell lines. Because normal DNA was not available, these could represent rare polymorphisms. The sole mutation in a clinical specimen, at nucleotide 876, did not result in an amino acid change. CONCLUSION: Our data suggest that mutational inactivation ETV6 may occur in prostate carcinoma. The functional significance of these potential inactivating mutations remains to be determined.

Carcinoma↗

PubMed2002

Germline sequence variants of the LZTS1 gene are associated with prostate cancer risk.

The 8p22 through p23 region has been identified as a potential site for genes associated with prostate cancer. The gene LZTS1 has been mapped to the 8p22 through p23 region and identified as a potential tumor suppressor based on loss of heterozygosity studies using primary esophageal tumors. Sequence analysis of mRNA from various tumors has revealed multiple mutations and aberrant mRNA transcripts. The most recent report associates LZTS1 function with stabilization of p34(cdc2) during the late S-G2/M stage of mitosis, affecting normal cell growth. In this study, a detailed DNA sequence analysis of LZTS1 was performed in a screening panel consisting of sporadic and hereditary prostate cancer (HPC) cases and unaffected controls. Twenty-four SNP, 15 of which were novel, were identified in germline DNA. Four coding SNP were identified. Eleven informative SNP were genotyped in 159 HPC probands, 245 sporadic prostate cancer cases, and 222 unaffected controls. Four of these SNP were statistically significant for association with prostate cancer (P < or = 0.04). These results add evidence supporting a role of LZTS1 in prostate cancer risk.

Base Sequence↗