Bladder Cancer

What's New?

TERT-Promoter Mutations Urine Assay for Early Detection and Monitoring of Bladder Cancer
~ July 2014

Urothelial (transitional cell) bladder carcinoma is the 4th most common malignancy in American males with 72,570 new cases diagnosed in the US in 2013 leading to 15,210 deaths. Muscle invasive BC is responsible for most bladder cancer death. It arises from histologically well-defined papillary and flat non-invasive precursor lesions, providing a potential opportunity for early detection and treatment prior to the development of the frequently fatal muscle invasive stage of the disease. Although urine cytology has a reasonable sensitivity and specificity for detecting high-grade neoplasms of the bladder, its performance in detecting precursor tumors is poor. Several U.S. Food and Drug Administration-approved urine-based markers have been developed in an attempt to improve the accuracy of noninvasive screening and surveillance in BC patients. Their performance inconsistencies have impeded their widespread clinical use. Currently, cystoscopy and transurethral biopsy (TURB) remain the gold standard for bladder cancer detection, diagnosis and surveillance. Because of the high rate of tumor recurrence, frequent follow up cystoscopy procedures are required, resulting in an unacceptable rate of invasive procedures and ballooning healthcare costs. In the US, bladder cancer management incurs the largest cost burden per patient among all tumor types with an estimated $3 billion per year total cost to the healthcare system.

Initially described in melanoma, activating mutations in the promoter of the telomerase reverse transcriptase (TERT) gene lead to increased telomerase expression allowing neoplasms to avoid senescence and thus extending cancer cell longevity. Recently, a Johns Hopkins University research team, led by Dr. Vogelstein, Dr. Nickolas Papadopolous, Dr Luis Diaz and Dr. Ken Kinzler from the Ludwig Cancer Research Centre and Dr. George Netto from the division of Urologic Pathology and Dr. Trinity Bivalacqua at the Brady Urologic Institute demonstrated a very high prevalence of TERT promoter mutation in a wide range of bladder cancer precursors lesions making TERT promoter mutations the most common genetic alterations identified to date in such lesions. In order to determine whether urine TERT status was an indicator of bladder cancer recurrence, the group evaluated the mutation status in a series of early tumors and matched collected follow-up urine samples. Among patients whose tumors harbored TERT promoter mutations, identical mutations were present in follow-up urines in almost all patients that recurred, but no mutations were found in the urine of bladder cancer patients did not recur on follow up.

These exciting results, strongly suggest a potential utility for the analysis of TERT promoter mutations as a novel DNA based urine test that can facilitate the early diagnosis of bladder cancer in patients at high risk for the disease. The test will also provide a non-invasive method that will limit the number of repeated endoscopic procedures currently needed to monitor bladder cancer patients for cancer recurrence. By diagnosing the cancer before it spreads deep into the bladder wall, the test could improve survival in patients diagnosed and treated at an early stage of cancer.

Kinde I, Munari E, Faraj SF, Hruban RH, Schoenberg M, Bivalacqua T, Allaf M, Springer S, Wang Y, Diaz LA Jr, Kinzler KW, Vogelstein B, Papadopoulos N, Netto GJ. TERT promoter mutations occur early in urothelial neoplasia and are biomarkers of early disease and disease recurrence in urine. Cancer Res. 2013 Dec 15;73(24):7162-7. doi: 10.1158/0008-5472.CAN-13-2498. Epub 2013 Oct 11.

PubMed PMID: 24121487
PubMed Central PMCID: PMC3966102

Creation of Cystectomy Bladder Cancer Progression Tissue Microarrays
~ April 2008

Through the use of high throughput genetic technologies, such as cDNA microarrays and serial analysis of gene expression (SAGE), numerous new markers of cancer have been identified. With the discovery of so many novel markers of disease and targets for potential therapy, there needs to be a way to quickly screen a large number of cancers for their expression of these new markers. Tissue microarray technology allows for such high-volume screening. In tissue microarrays, numerous cores (spots) of a large number of different tumors are placed into a single paraffin tissue block. This block can yield up to 300 or so slides, each containing samples of multiple (up to 300) tumors, which can be analyzed using a variety of technologies including immunohistochemistry for protein expression, in situ hybridization for RNA expression, and florescence in situ hybridization for DNA copy number. The pathology department of The Johns Hopkins Hospital has created a tissue microarray facility, which allows for construction of microarrays from tumors of any organ system. Such arrays have been constructed for prostatic, pancreatic and bile duct adenocarcinomas, and preliminary results with these arrays have shown that tissue arrays can greatly speed the analysis of new cancer markers.

We have previously completed the construction of a bladder carcinoma tissue microarray (TMA , See Figure). This microarray contains spots of 20 different bladder carcinomas, along with normal bladder specimens and normal unrelated tissues as controls. We have also constructed tissue microarrays from non-invasive papillary tumors. There is an urgent need to be able to predict which papillary tumors are destined to recur and progress, as well as to identify, which will run a benign course. Identification of benign lesions would allow the urologist to minimize follow-up, with its associated patient discomfort and expense, and to eliminate the morbidity of unnecessary therapy. In addition, the ability to identify tumors destined to progress would permit intensified surveillance and potentially early intervention therapy in order to diminish the risk of tumor death. These microarray blocks allow us to rapidly screen bladder carcinomas for novel tumor markers.

We have just completed the construction of a new set of TMAs from over 140 invasive bladder cancers obtained from cystectomy patients at Johns Hopkins University with extended well characterized clinical follow up. The case control design and the well characterized clinical data make this new TMA set of great utility to our ongoing research interest in identifying new markers that will help predict clinical outcome of invasive bladder cancer. Several exciting studies are already ongoing utilizing the new set of TMAs.