Detection of mitochondrial deoxyribonucleic acid alterations in urine from urothelial cell carcinoma patients

Our study aims at understanding the timing and nature of mitochondrial deoxyribonucleic acid (mtDNA) alterations in urothelial cell carcinoma (UCC) and their detection in urine sediments. The entire 16.5 kb mitochondrial genome was sequenced in matched normal lymphocytes, tumor and urine sediments from 31 UCC patients and compared to different clinical stages and histological grades. The mtDNA content index was examined in all the specimens. Sixty‐five percent (20/31) of the patients harbored at least 1 somatic mtDNA mutation. A total of 25 somatic mtDNA mutations were detected, which were more frequent in the respiratory complex coding regions (Complex I, III, IV and V) of the mtDNA and significantly affected respiratory Complex III compared to the other complexes (p = 0.021–0.039). Compared to Stage Ta, mtDNA mutation was higher in Stage T1 and significantly higher in Stage T2 (p = 0.01) patients. MtDNA mutation was also significantly higher (p = 0.04) in Stage T2 compared to Stage T1 patients. Ninety percent (18/20) of the patients harboring mtDNA mutation in the tumor also had mutation in their urine sediments. Eighty percent (20/25) of the tumor‐associated mtDNA mutations was detectable in the urine sediments. Compared to the normal lymphocytes, the mtDNA content increased significantly in the tumor (p = 0.0013) and corresponding urine sediments (p = 0.0025) in 19/25 (76%) patients analyzed. Our results indicate that mtDNA alterations occur frequently in progressive stages of UCC patients and are readily detectable in the urine sediments. MtDNA mutations appear to provide a promising tool for developing early detection and monitoring strategies for UCC patients.

[1]  A. Chatterjee,et al.  Mitochondrial Subversion in Cancer , 2011, Cancer Prevention Research.

[2]  J. Califano,et al.  Mitochondrial DNA Mutation in Normal Margins and Tumors of Recurrent Head and Neck Squamous Cell Carcinoma Patients , 2010, Cancer Prevention Research.

[3]  J. Choi,et al.  Analysis of fluorescence in situ hybridization, mtDNA quantification, and mtDNA sequence for the detection of early bladder cancer. , 2010, Cancer genetics and cytogenetics.

[4]  D. Dressman,et al.  Heteroplasmic mitochondrial DNA mutations in normal and tumor cells , 2010, Nature.

[5]  R. Yung,et al.  Following Mitochondrial Footprints through a Long Mucosal Path to Lung Cancer , 2009, PloS one.

[6]  L. Kiemeney,et al.  The present and future burden of urinary bladder cancer in the world , 2009, World Journal of Urology.

[7]  M. Hoque,et al.  Mitochondrial cytochrome B gene mutation promotes tumor growth in bladder cancer. , 2008, Cancer research.

[8]  E. Messing,et al.  Current state of screening for bladder cancer , 2007, Expert review of anticancer therapy.

[9]  A. Maitra,et al.  Frequency and phenotypic implications of mitochondrial DNA mutations in human squamous cell cancers of the head and neck , 2007, Proceedings of the National Academy of Sciences.

[10]  D. Cutler,et al.  An oligonucleotide microarray for high-throughput sequencing of the mitochondrial genome. , 2006, The Journal of molecular diagnostics : JMD.

[11]  A. Chatterjee,et al.  Mitochondrial DNA mutations in human cancer , 2006, Oncogene.

[12]  D. Wallace.  A Mitochondrial Paradigm of Metabolic and Degenerative Diseases, Aging, and Cancer: A Dawn for Evolutionary Medicine , 2005, Annual review of genetics.

[13]  S. Sukumar,et al.  Tumor‐specific changes in mtDNA content in human cancer , 2005, International journal of cancer.

[14]  A. Carvalho,et al.  Increased Mitochondrial DNA Content in Saliva Associated with Head and Neck Cancer , 2005, Clinical Cancer Research.

[15]  Mukesh Verma,et al.  Proteomic analysis of cancer-cell mitochondria , 2003, Nature Reviews Cancer.

[16]  J. Jen,et al.  Facile detection of mitochondrial DNA mutations in tumors and bodily fluids. , 2000, Science.

[17]  Bert Vogelstein,et al.  Somatic mutations of the mitochondrial genome in human colorectal tumours , 1998, Nature Genetics.

[18]  R H Hruban,et al.  Molecular assessment of histopathological staging in squamous-cell carcinoma of the head and neck. , 1995, The New England journal of medicine.