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Detection of bladder cancer in urine by a tumor suppressor gene hypermethylation panel.
| Content Provider | Semantic Scholar |
|---|---|
| Author | Dulaimi, Essel A. Uzzo, Robert G. Greenberg, Richard Evan Al-Saleem, T. Cairns, Paul |
| Copyright Year | 2004 |
| Abstract | PURPOSE Bladder cancer is potentially curable in the majority of cases; however, the prognosis for patients with advanced disease at presentation remains poor. Current noninvasive tests such as cytology lack sufficient sensitivity to detect low-grade, low-stage tumors. Silencing of tumor suppressor genes, such as p16(INK4a), VHL, and the mismatch repair gene hMLH1, has established promoter hypermethylation as a common mechanism for tumor suppressor inactivation in human cancers. It is also a promising new target for molecular detection in bodily fluids including urine, a readily accessible fluid known to contain bladder cancer cells. Methylation-specific PCR (MSP) can determine the presence or absence of methylation of a gene locus at a sensitivity level of up to 1 methylated allele in 1000 unmethylated alleles, appropriate for identifying cancer cell DNA in a bodily fluid. EXPERIMENTAL DESIGN We first determined the frequency of hypermethylation of the Rb tumor suppressor gene by bisulfite sequencing and of the p16(INK4a), p14(ARF), APC, and RASSF1A tumor suppressor genes by MSP in 45 bladder cancers. We then designed a panel optimal for diagnostic coverage composed of the APC, RASSF1A, and p14(ARF) tumor suppressor genes. This panel was tested for detection of hypermethylation in matched sediment DNA from urine specimens obtained before surgery from the same 45 bladder cancer patients (2 Tis, 16 Ta, 10 T1, and 17 T2-4) as well as normal and benign control DNAs. RESULTS Hypermethylation of at least one of three suppressor genes (APC, RASSF1A, and p14(ARF)) was found in all 45 tumor DNAs (100% diagnostic coverage). We detected gene hypermethylation in the matched urine DNA from 39 of 45 patients (87% sensitivity), including 16 cases that had negative cytology. No hypermethylation of APC, RASSF1A, or p14(ARF) was observed in normal transitional cell DNAs or in urine DNAs from normal healthy individuals and patients with inflammatory urinary disease (cystitis). Furthermore, an unmethylated gene in the tumor DNA was always found to be unmethylated in the matched urine DNA (100% specificity). CONCLUSIONS Promoter hypermethylation of tumor suppressor genes is common in bladder cancer and was found in all grades and stages of tumors examined. Hypermethylation was detected in the urine DNA from 39 of 45 (87%) patients, including cases of early-stage disease amenable to cure. MSP may enhance early detection of bladder cancer using a noninvasive urine test. |
| Starting Page | 371 |
| Ending Page | 401 |
| Page Count | 31 |
| File Format | PDF HTM / HTML |
| Alternate Webpage(s) | http://clincancerres.aacrjournals.org/content/clincanres/10/6/1887.full.pdf |
| PubMed reference number | 15041703v1 |
| Volume Number | 10 |
| Issue Number | 6 |
| Journal | Clinical cancer research : an official journal of the American Association for Cancer Research |
| Language | English |
| Access Restriction | Open |
| Subject Keyword | Alleles Bisulfite Sequencing Bladder Neoplasm CDKN2A gene Cyclin-Dependent Kinase Inhibitor 2A, human Cystitis Early Diagnosis Genes, Suppressor Genes, vif Grade Hypermethylation Kidney Failure, Chronic Liquid substance Malignant Neoplasms Malignant neoplasm of urinary bladder Methylation Mismatch Repair Nephroblastoma One Thousand Patients RASSF1 gene RASSF1 wt Allele Specimen Transitional Epithelial Cells Tumor Suppressor Genes Urinalysis Von Hippel-Lindau Syndrome cancer cell hydrogen sulfite p14ARF Protein pediatric intracranial germ cell brain tumor |
| Content Type | Text |
| Resource Type | Article |
