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A Noninvasive Test Can Help Predict Bladder Cancer Recurrence

April 1, 2014
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PHILADELPHIA — A DNA methylation marker test done on urine samples collected from patients with non-muscle-invasive bladder cancer (NMIBC) can predict tumor recurrence with high sensitivity and specificity, according to a study published in Clinical Cancer Research, a journal of the American Association for Cancer Research.

Gangning Liang, Ph.D.

Gangning Liang, Ph.D.

The test measures three DNA methylation markers in urine, and it was able to detect tumor recurrence with 80 percent sensitivity and 97 percent specificity in NMIBC patients. The test predicted tumor recurrence in 80 percent of the patients who subsequently had a recurrence, while current standard methods of monitoring, cytology and cystoscopy, were able to detect tumor recurrence in only 35 percent and 15 percent of these patients, respectively.

“NMIBC accounts for 80 percent of all bladder cancer cases and is characterized by a high rate of recurrence, which leads to a high cost in treatment and management,” said Gangning Liang, Ph.D., an associate professor in the Department of Urology at USC Norris Comprehensive Cancer Center in Los Angeles. “The current standards for monitoring of bladder cancer recurrence are either unreliable or invasive. We wanted to find reliable biomarkers to monitor recurrence of NMIBC using a noninvasive assay.”

DNA methylation is a process by which genes can be silenced or activated. “In some cancers, patterns of DNA methylation are disturbed, and DNA methylation markers can be early indicators of tumorigenesis and tumor recurrence; they are stable not only in tissues, but also in biological fluids,” explained Liang. “The technology we developed can detect DNA methylation changes in a small amount of DNA in patients’ urine.

“Our test can help detect bladder cancer at an early stage of recurrence using noninvasive methods. By routine testing methods, we hope to identify recurrence before the appearance of symptoms, because by the time symptoms appear, the cancer may have already begun to spread,” he added.

Liang and colleagues collected 368 urine samples over a period of seven years from 90 NMIBC patients who were under surveillance for tumor recurrence. They isolated DNA from the samples and performed DNA methylation analyses and initially identified six methylation markers.

Using stepwise validation and testing, they shortlisted a three-marker combination that yielded the highest sensitivity and specificity, with an area under the curve (AUC) of 0.95. An AUC score of one means the test is perfect in predicting the outcome, and values near 0.5 mean the test is poor and unreliable.

The researchers found that 80 percent of the patients whose urine tests were positive for the markers subsequently developed recurrence, and 74 percent whose urine tests were negative for the markers did not experience tumor recurrence.

The three markers whose DNA methylation status is assessed in the test are SOX1, IRAK3, and L1-MET.

“Our findings can be used not only to monitor the recurrence of bladder cancer, but also to monitor response to chemotherapy, and this approach may also be adopted in monitoring recurrent prostate, kidney, and lung cancers by noninvasive means,” said Liang. “However, the test needs to be further validated in larger clinical trials before it can be used as a standard test in clinics.”

This study was funded by the National Cancer Institute. Liang declares no conflicts of interest.

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