Genome-wide analysis of allelic imbalance in prostate cancer using the Affymetrix 50K SNP mapping array

Tørring, Niels; Borre, Michael; Sørensen, Karina Dalsgaard; Andersen, Claus Lindbjerg; Wiuf, Carsten; Ørntoft, Torben F.

doi:10.1038/sj.bjc.6603476

Cited by 51 publications

(26 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Laser microdissection was done as described in ref. 31. DNA was bisulfite converted using the MethylEasy DNA Bisulfite Modification Kit (Human Molecular Signaling).…”

Section: Translational Relevancementioning

confidence: 99%

Genetic and Epigenetic SLC18A2 Silencing in Prostate Cancer Is an Independent Adverse Predictor of Biochemical Recurrence after Radical Prostatectomy

Sørensen¹,

Wild

Mortezavi

et al. 2009

Clinical Cancer Research

View full text Add to dashboard Cite

Purpose: This study investigates SLC18A2 (vesicular monoamine transporter 2) expression in prostate adenocarcinoma and examines its potential as a predictive marker for prostate cancer patient outcome after radical prostatectomy. Experimental Design: Expression and single nucleotide polymorphism microarray analyses identified SLC18A2 as both down-regulated and subject to common loss-of-heterozygosity in prostate cancer. Down-regulated SLC18A2 expression was validated on tissue microarrays containing benign and malignant prostate specimens from an independent patient group (n = 738). Furthermore, SLC18A2 immunoreactivity in radical prostatectomy tumor specimens (n = 506) was correlated to clinicopathologic characteristics and recurrence-free survival. The possibility of SLC18A2 silencing by aberrant DNA methylation in prostate cancer cells was investigated by bisulfite sequencing. Results: Tissue microarray analysis revealed markedly lower cytoplasmic SLC18A2 staining in cancer compared with nonmalignant prostate tissue samples, confirming RNA expression profiling results. Furthermore, multivariate analysis identified cytoplasmic SLC18A2 immunoreactivity as a novel predictor of biochemical recurrence following prostatectomy (hazard ratio, 0.485; 95% confidence interval, 0.333-0.709; P < 0.001) independent of prostate-specific antigen, Gleason score, tumor stage, and surgical margin status. SLC18A2 showed loss-of-heterozygosity in 23% of the tumors and was densely hypermethylated in 15 of 17 (88%) prostate cancer samples plus 6 of 6 prostate cancer cell lines. In contrast, SLC18A2 was unmethylated in 4 of 4 adjacent nonmalignant prostate and 3 of 5 benign prostatic hyperplasia tissue samples, whereas 2 of 5 benign prostatic hyperplasia samples had monoallelic hypermethylation. Methylation and histone deacetylase inhibitory agents rescued SLC18A2 expression in three prostate cancer cell lines. Conclusions: SLC18A2 silencing by DNA hypermethylation and/or allelic loss is a frequent event inprostate cancerandanovelindependent predictorofbiochemicalrecurrenceafterprostatectomy.

show abstract

“…Laser microdissection was done as described in ref. 31. DNA was bisulfite converted using the MethylEasy DNA Bisulfite Modification Kit (Human Molecular Signaling).…”

Section: Translational Relevancementioning

confidence: 99%

Genetic and Epigenetic SLC18A2 Silencing in Prostate Cancer Is an Independent Adverse Predictor of Biochemical Recurrence after Radical Prostatectomy

Sørensen¹,

Wild

Mortezavi

et al. 2009

Clinical Cancer Research

View full text Add to dashboard Cite

show abstract

“…2 In short, adenocarcinoma cells were microdissected from 5-lm hematoxylin-stained sections of fresh frozen or Tissue Tek-embedded prostate cancer specimens using the PALM Microbeam System (PALM Microlaser Technologies AG, Bernried, Germany). Genomic DNA was isolated from 40 microdissected prostate cancer specimens and matching blood samples (normal DNA) using the PUREGENE DNA Purification Kit (Gentra Systems, Minneapolis, MN), and analyzed on SNP microarrays covering 58,960 SNPs (GeneChip Human Mapping 50K Array Xba 240; Affymetrix, Santa Clara, CA).…”

Section: Laser-microdissection and Snp Microarray Analysismentioning

confidence: 99%

“…1 Recently, we identified common allelic imbalance at 6q14-6q22 in prostate cancer by a genome-wide loss of heterozygosity (LOH) analysis using high-density single nucleotide polymorphism (SNP) microarrays. 2 Other groups have earlier reported similar regions of deletion/LOH at 6q in prostate cancer (Ref. 3 and references therein); however, a possible target tumor suppressor gene (TSG) remains to be identified from this region.…”

mentioning

confidence: 99%

Chromosomal deletion, promoter hypermethylation and downregulation of FYN in prostate cancer

Sørensen¹,

Borre²,

Ørntoft³

et al. 2007

Intl Journal of Cancer

View full text Add to dashboard Cite

Loss of heterozygosity (LOH) at 6q is a frequent chromosomal aberration in prostate adenocarcinoma; however, a possible target gene remains to be identified. Key words: prostate cancer; FYN tyrosine kinase; tumor suppressor gene; hypermethylation; loss of heterozygosity Development and progression of prostate cancer is associated with the accumulation of complex genetic and epigenetic aberrations.1 Recently, we identified common allelic imbalance at 6q14-6q22 in prostate cancer by a genome-wide loss of heterozygosity (LOH) analysis using high-density single nucleotide polymorphism (SNP) microarrays.2 Other groups have earlier reported similar regions of deletion/LOH at 6q in prostate cancer (Ref. 3 and references therein); however, a possible target tumor suppressor gene (TSG) remains to be identified from this region. Interestingly, several cancer types, including breast, 4 gastric 5 and cervical cancer 6 as well as a variety of hematopoietic malignancies 7,8 have common regions of deletion at 6q that coincide with that identified in prostate cancer, suggesting that a putative target TSG at 6q may be shared by at least some of these malignancies.Retroviral tagging has proved to be a powerful cancer gene discovery tool, with many genes identified as common integration sites in retrovirus-induced murine leukemia/lymphoma models, playing critical roles also in human cancers, including solid tumors.9,10 On the basis of this and substantiated by the overlapping deletions at 6q found in both prostate cancer and various types of human hematopoietic malignancies, we envisaged that retroviral tags from murine leukemia/lymphoma models might help the search for a candidate TSG at 6q. Hence, in this study, to identify a new possible TSG in prostate cancer, we hypothesized that a gene in the main LOH region at 6q14-6q22 that is both (i) transcriptionally downregulated in prostate cancer compared to nonmalignant prostate tissues and (ii) disrupted by retroviral insertion in murine hematopoietic cancer models, would provide a good candidate for further analysis. Accordingly, the SRC family tyrosine kinase gene FYN at 6q21 was selected for further investigation.FYN contains an N-terminal SH4 myristoylation and palmitoylation domain, which targets the protein to the inner plasma membrane. It is followed by a unique sequence, distinguishing FYN from other SRC family members, 2 protein-protein interaction domains (SH3 and SH2), a kinase domain (SH1) and a C-terminal negative regulatory domain.11 The 2 known major splice forms, FYN(B) (aka P59FynB) using exon 7A and FYN(T) (aka P59FynT) using exon 7B, 11 differ in a linker region between SH2 and SH1 that extends into the kinase domain, causing moderate regulatory differences between these isoforms.12 FYN(B) is highly expressed in brain, and hematopoietic cells express mainly FYN(T), while most other tissues express both isoforms.11 A variant mRNA lacking exon 7 (FYN(D7)) exists in blood cells, but the corresponding endogenous protein has not been documented. 13The biological fun...

show abstract

“…CSMD1 is located on chromosome 8p23, a region that is frequently deleted in different types of cancer (1,(6)(7)(8)(9)(10). In addition, reduced CSMD1 mRNA and protein expression has been observed in different cancers (11)(12)(13)(14)(15)(16)(17).…”

Section: Introductionmentioning

confidence: 99%

Loss of CSMD1 expression disrupts mammary duct formation while enhancing proliferation, migration and invasion

et al. 2017

View full text Add to dashboard Cite

Abstract. The CUB and sushi multiple domains 1 (CSMD1) gene maps to chromosome 8p23, a region deleted in many cancers. Loss of CSMD1 expression is associated with poor prognosis in breast cancer suggesting that it acts as a tumour suppressor in this cancer. However, the function of CSMD1 is largely unknown. Herein, we investigated CSMD1 functions in cell line models. CSMD1 expression was suppressed in MCF10A and LNCaP cells using short hairpin RNA. Functional assays were performed focusing on the 'normal' MCF10A cell line. Suppression of CSMD1 significantly increased the proliferation, cell migration and invasiveness of MCF10A cells compared to shcontrols. shCSMD1 cells also showed significantly reduced adhesion to Matrigel and fibronectin. In a three-dimensional Matrigel model of MCF10A cells, reduced CSMD1 expression resulted in the development of larger and more poorly differentiated breast acini-like structures that displayed impaired lumen formation. Loss of CSMD1 expression disrupts a model of mammary duct formation while enhancing proliferation, migration and invasion. Our data suggest that CSMD1 is involved in the suppression of a transformed phenotype. IntroductionCUB and sushi multiple domains-1 (CSMD1) is a very large gene which contains 71 exons that span over 2 Mb of genomic DNA on chromosome 8p23 (1). Multiple splice variants exist for CSMD1 and these encode proteins of varying length. The largest transcript is 14.3 kb long and this encodes a 3,565 amino acid protein (1). The full-length protein is a membrane protein with an extracellular region containing 14 CUB and 28 sushi domains, a single transmembrane domain and a short cytoplasmic domain that contains a putative tyrosine phosphorylation site. CSMD1 belongs to the CSMD gene family whose members also include the structurally similar proteins CSMD2 and CSMD3 (1-3). The function of CSMD1 is largely unknown. Although CSMD1 has been shown to inhibit C3 deposition onto the surface of cells leading to the inhibition of the classical complement pathway (4,5). The structure of CSMD1 predicts that CSMD1 is a receptor for unknown ligand(s) and is involved in signal transduction (1).CSMD1 is believed to act as a tumour suppressor based on a number of observations. CSMD1 is located on chromosome 8p23, a region that is frequently deleted in different types of cancer (1,6-10). In addition, reduced CSMD1 mRNA and protein expression has been observed in different cancers (11-17). An array comparative genomic hybridization study revealed a high rate of loss of 8p23.2 containing the CSMD1 gene in advanced prostrate cancer samples. A further small real-time PCR study identified a decrease in CSMD1 mRNA levels in higher stage prostrate cancer samples (11). Similarly reduced CSMD1 expression at the mRNA level has been identified in colorectal cancer associated with reduced patient survival (12). Furthermore, somatic mutations were detected in CSMD1 in 11% (6/54) of colorectal cancer patients along side DNA methylation and allele loss, predominantly in early onset ...

show abstract

Genome-wide analysis of allelic imbalance in prostate cancer using the Affymetrix 50K SNP mapping array

Cited by 51 publications

References 35 publications

Genetic and Epigenetic SLC18A2 Silencing in Prostate Cancer Is an Independent Adverse Predictor of Biochemical Recurrence after Radical Prostatectomy

Genetic and Epigenetic SLC18A2 Silencing in Prostate Cancer Is an Independent Adverse Predictor of Biochemical Recurrence after Radical Prostatectomy

Chromosomal deletion, promoter hypermethylation and downregulation of FYN in prostate cancer

Loss of CSMD1 expression disrupts mammary duct formation while enhancing proliferation, migration and invasion

Contact Info

Product

Resources

About