Biomedical subjects

Torben F Orntoft

Publications and source records attributed to Torben F Orntoft.

21 records · Page 2Linked to original sources

PubMed2002

Allelic imbalances in human bladder cancer: genome-wide detection with high-density single-nucleotide polymorphism arrays.

BACKGROUND: Bladder cancer is characterized by genomic instability. In this study, we investigated whether genome-wide screening using single-nucleotide polymorphism (SNP) arrays could detect allelic imbalance (loss or gain of at least one allele) in bladder cancers. METHODS: For microarray analysis, DNA was isolated from microdissected bladder tumors and leukocytes from 11 patients. The stage T1 tumor (connective tissue invasive) and the subsequent stage T2-4 tumor (muscle invasive) were available from eight of these patients, and only the first muscle-invasive stage T2-4 tumor was available from three of the 11 patients. The microarray contained 1494 biallelic polymorphic sequences. For microsatellite analyses, DNA was isolated from tumors and leukocytes of nine patients with primary T2-4 tumors and 13 patients with Ta (noninvasive) tumors. All statistical tests were two-sided. RESULTS: We assigned a genotype to 1204 loci, 343 of which were heterozygous. Allelic imbalance was detected in known areas of imbalance on chromosomes 6, 8, 9, 11, and 17, and a new area of imbalance was detected on the p arm of chromosome 6. Microsatellite analysis of nine other T2-4 tumors and 13 Ta tumors showed that allelic imbalance was more frequent in T2-4 tumors than in Ta tumors (P<.001). We detected 8.5 allelic imbalances (median) in 348 informative loci in T1 tumors and 28 allelic imbalances (median) in 329 informative loci in T2-4 tumors. When pairs of T1 and T2-4 tumors were analyzed from eight patients, 68% of imbalances detected in T1 tumors (146 imbalances) occurred in the subsequent T2-4 tumors (99 imbalances). Homozygous TP53 mutations were more often associated (P =.005) with high allelic imbalance than with low allelic imbalance. CONCLUSION: SNP arrays are feasible for high-throughput, genome-wide scanning for allelic imbalances in bladder cancer.

Allelic Imbalance↗

PubMed2002

Expression profiling confirms the role of endocytic receptor megalin in renal vitamin D3 metabolism.

BACKGROUND: The endocytic receptor megalin constitutes the major pathway for clearance of low-molecular weight plasma proteins from the glomerular filtrate into the renal proximal tubules. Furthermore, the receptor has been implicated in a number of other functions in the kidney including uptake and activation of 25-(OH) vitamin D3, calcium and sodium reabsorption as well as signal transduction. METHODS: We used genome-wide expression profiling by microarray technology to detect changes in the gene expression pattern in megalin knockout mouse kidneys and to uncover some of the renal pathways affected by megalin deficiency. RESULTS: Alterations were identified in several (patho)physiologic processes in megalin-deficient kidneys including the renal vitamin D metabolism, transforming growth factor (TGF)-beta1 signal transduction, lipid transport and heavy metal detoxification. Most importantly, changes were detected in the mRNA levels of 25-(OH) vitamin D-24-hydroxylase and 25-(OH) vitamin D-1alpha-hydroxylase as well as strong up-regulation of TGF-beta1 target genes. Both findings indicate plasma vitamin D deficiency and lack of vitamin D signaling in renal tissues. CONCLUSIONS: Expression profiling confirms a crucial role for megalin in renal vitamin D metabolism.

Animals↗

PubMed2002

Impact of alterations affecting the p53 pathway in bladder cancer on clinical outcome, assessed by conventional and array-based methods.

This study was designed to define the potential clinical relevance of identifying alterations affecting p53 pathway in bladder cancer and to test a new, low-cost, high-throughput, and array-based TP53 sequencing technology. Tumor samples from 140 evaluable patients with bladder cancer were analyzed with two methods to detect TP53 gene mutations, including single-stranded conformational polymorphism followed by direct sequencing and an oligonucleotide array-based sequencing method. Immunohistochemistry was used to assess patterns of expression of p53, p21/WAF1, and mdm2. Median follow-up time was 27.6 months. Results from the above analyses were correlated with clinicopathological parameters and outcome. Combining the mutation-detection assays, 79 cases (56.4%) were found to harbor TP53 gene mutations. Direct sequencing identified 66 point mutations and five frameshift mutations. The p53 oligonucleotide array detected 65 point mutations and four splice site mutations in different exons but missed all five frameshift mutations. p53 nuclear overexpression was observed in 71 cases (50.7%), lack of p21 nuclear expression was found in 81 cases (57.9%), and mdm2 nuclear overexpression was seen in 64 cases (45.7%). In multivariate analysis, 17 patients (12.1%) had an altered p53 pathway, defined by the detection of mutant TP53 and/or p53 nuclear overexpression, loss of p21 nuclear expression, and mdm2 nuclear overexpression, and exhibited the worst clinical outcome in the observation period (P = 0.015), and it appears to be a significant prognostic factor associated with patient survival.

Cyclin-Dependent Kinase Inhibitor p21↗