Chromosomal alterations in exfoliated urothelial cells from bladder cancer cases and healthy men: a prospective screening study

Abstract

BackgroundChromosomal instability in exfoliated urothelial cells has been associated with the development of bladder cancer. Here, we analyzed the accumulation of copy number variations (CNVs) using fluorescence in situ hybridization in cancer cases and explored factors associated with the detection of CNVs in tumor-free men.MethodsThe prospective UroScreen study was designed to investigate the performance of UroVysion™ and other tumor tests for the early detection of bladder cancer in chemical workers from 2003–2010. We analyzed a database compiling CNVs of chromosomes 3, 7, and 17 and at 9p21 that were detected in 191,434 exfoliated urothelial cells from 1,595 men. We assessed the accumulation of CNVs in 1,400 cells isolated from serial samples that were collected from 18 cancer cases up to the time of diagnosis. A generalized estimating equation model was applied to evaluate the influence of age, smoking, and urine status on CNVs in cells from tumor-free men.ResultsTetrasomy of chromosomes 3, 7 and 17, and DNA loss at 9p21 were the most frequently observed forms of CNV. In bladder cancer cases, we observed an accumulation of CNVs that started approximately three years before diagnosis. During the year prior to diagnosis, cells from men with high-grade bladder cancer accumulated more CNVs than those obtained from cases with low-grade cancer (CNV < 2: 7.5% vs. 1.1%, CNV > 2: 16-17% vs. 9-11%). About 1% of cells from tumor-free men showed polysomy of chromosomes 3, 7, or 17 or DNA loss at 9p21. Men aged ≥50 years had 1.3-fold more cells with CNVs than younger men; however, we observed no further age-related accumulation of CNVs in tumor-free men. Significantly more cells with CNVs were detected in samples with low creatinine concentrations.ConclusionsWe found an accumulation of CNVs during the development of bladder cancer starting three years before diagnosis, with more altered cells identified in high-grade tumors. Also, a small fraction of cells with CNVs were exfoliated into urine of tumor-free men, mainly exhibiting tetraploidy or DNA loss at 9p21. Whether these cells are preferentially cleared from the urothelium or are artifacts needs further exploration.

Assessment of potential predictors of calretinin and mesothelin to improve the diagnostic performance to detect malignant mesothelioma: results from a population-based cohort study

“…A sensitivity analysis revealed that cancer closer to blood collection had a stronger impact on calretinin concentrations than cancers detected later than 1-year past blood collection (data not shown). This is in agreement with a study on bladder cancer 32 and on ovarian cancer, 33 where cancer-related biomarkers showed more frequently elevated concentrations exceeding cut-offs 1 year prior to diagnosis. Four participants with cancer past blood collection showed increased calretinin concentrations above the cut-off at time of blood collection.…”

Gastric cancer and gene copy number variation: emerging cancer drivers for targeted therapy

“…12 DNA CNVs include gene amplification, gain, loss and deletion. In addition to gene mutation, CNV has a significant role in tumorigenesis in many cancers, such as GC, 13 ovarian cancer, 14 hepatocellular carcinoma, 15 testicular germ cell tumors, 16 colorectal carcinoma, 17 bladder cancer 18 and so on. The accumulation of CNVs during gastric oncogenesis may be a result of preferential selection by which transforming cells gain evolutionary advantage.…”

Prognostic microRNAs in upper tract urothelial carcinoma: multicenter and international validation study

“…The miRNA-31-5p gene is located on 9p21.3. DNA lost at 9p21 has been frequently observed in bladder and UTUC patients [ 39 , 40 ]. Across differing cancer types, genetic variants of the 9p21 region have been associated with the development of multiple cancers which suggests this region's importance [ 41 ].…”