Ekkehard Schütz1, Mohammad R Akbari2, Julia Beck1, Howard Urnovitz1, William W Zhang3, Kirsten Bornemann-Kolatzki1, William M Mitchell4, Robert K Nam3, Steven A Narod2. 1. Chronix Biomedical, Göttingen, Germany; 2. Women's College Research Institute, Women's College Hospital, University of Toronto, Toronto, Canada; Dalla Lana School of Public Health, University of Toronto, Toronto, Canada. 3. Division of Urology, Sunnybrook Research Institute, University of Toronto, Toronto, Canada; 4. Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, TN; bill.mitchell@vanderbilt.edu.
Abstract
BACKGROUND: Genomic instability resulting in copy number variation is a hallmark of malignant transformation and may be identified through massive parallel sequencing. Tumor-specific cell free DNA (cfDNA) present in serum and plasma provides a real-time, easily accessible surrogate. METHODS: DNA was extracted from serum of 204 patients with prostate cancer (Gleason score 2-10), 207 male controls, and patients with benign hyperplasia (n = 10) and prostatitis (n = 10). DNA was amplified by use of random primers, tagged with molecular identifiers, sequenced on a SOLID system, and aligned to the human genome. We evaluated the number of sequence reads of cfDNA in sliding 100-kbp intervals for variation from controls. We used chromosomal regions with significant variations in alignment hits for their ability to segregate patients and matched controls. RESULTS: Using ROC curves to assess diagnostic performance, we evaluated the number of regions in a first subset (n = 177), with variations in alignment hits alone, provided an area under the curve (AUC) of 0.81 (95% CI 0.7-0.9, P < 0.001). Using 5 rounds of 10-fold cross-validation with the full data set, we established a final model that discriminated prostate cancer from controls with an AUC of 0.92 (0.87-0.95), reaching a diagnostic accuracy of 83%. Both benign prostatic hypertrophy and prostatitis could be distinguished from prostate cancer by use of cfDNA, with an accuracy of 90%. CONCLUSIONS: Assessment of a limited number of chromosomal structural instabilities by use of massive parallel sequencing of cfDNA was sufficient to distinguish between prostate cancer and controls. This large cohort demonstrates the utility of cfDNA in prostate cancer recently established in other malignant neoplasms.
BACKGROUND: Genomic instability resulting in copy number variation is a hallmark of malignant transformation and may be identified through massive parallel sequencing. Tumor-specific cell free DNA (cfDNA) present in serum and plasma provides a real-time, easily accessible surrogate. METHODS: DNA was extracted from serum of 204 patients with prostate cancer (Gleason score 2-10), 207 male controls, and patients with benign hyperplasia (n = 10) and prostatitis (n = 10). DNA was amplified by use of random primers, tagged with molecular identifiers, sequenced on a SOLID system, and aligned to the human genome. We evaluated the number of sequence reads of cfDNA in sliding 100-kbp intervals for variation from controls. We used chromosomal regions with significant variations in alignment hits for their ability to segregate patients and matched controls. RESULTS: Using ROC curves to assess diagnostic performance, we evaluated the number of regions in a first subset (n = 177), with variations in alignment hits alone, provided an area under the curve (AUC) of 0.81 (95% CI 0.7-0.9, P < 0.001). Using 5 rounds of 10-fold cross-validation with the full data set, we established a final model that discriminated prostate cancer from controls with an AUC of 0.92 (0.87-0.95), reaching a diagnostic accuracy of 83%. Both benign prostatic hypertrophy and prostatitis could be distinguished from prostate cancer by use of cfDNA, with an accuracy of 90%. CONCLUSIONS: Assessment of a limited number of chromosomal structural instabilities by use of massive parallel sequencing of cfDNA was sufficient to distinguish between prostate cancer and controls. This large cohort demonstrates the utility of cfDNA in prostate cancer recently established in other malignant neoplasms.
Authors: Esther Campos-Fernández; Letícia S Barcelos; Aline Gomes de Souza; Luiz R Goulart; Vivian Alonso-Goulart Journal: Am J Cancer Res Date: 2019-07-01 Impact factor: 6.166
Authors: Faye R Harris; Irina V Kovtun; James Smadbeck; Francesco Multinu; Aminah Jatoi; Farhad Kosari; Kimberly R Kalli; Stephen J Murphy; Geoffrey C Halling; Sarah H Johnson; Minetta C Liu; Andrea Mariani; George Vasmatzis Journal: Sci Rep Date: 2016-07-20 Impact factor: 4.379
Authors: Yu-Hsiang Chen; Bradley A Hancock; Jeffrey P Solzak; Dumitru Brinza; Charles Scafe; Kathy D Miller; Milan Radovich Journal: NPJ Breast Cancer Date: 2017-07-03
Authors: Shu Xia; Manish Kohli; Meijun Du; Rachel L Dittmar; Adam Lee; Debashis Nandy; Tiezheng Yuan; Yongchen Guo; Yuan Wang; Michael R Tschannen; Elizabeth Worthey; Howard Jacob; William See; Deepak Kilari; Xuexia Wang; Raymond L Hovey; Chiang-Ching Huang; Liang Wang Journal: Oncotarget Date: 2015-06-30