Epigenetic markers of prostate cancer in plasma circulating DNA

Rene Cortese, Andrew Kwan, Emilie Lalonde, Olga Bryzgunova, Anna Bondar, Ying Wu, Juozas Gordevicius, Mina Park, Gabriel Oh, Zachary Kaminsky, Justina Tverkuviene, Arvydas Laurinavicius, Feliksas Jankevicius, Dorota H.S. Sendorek, Syed Haider, Sun Chong Wang, Sonata Jarmalaite, Pavel Laktionov, Paul C. Boutros, Arturas Petronis

研究成果: 雜誌貢獻期刊論文同行評審

45 引文 斯高帕斯(Scopus)

摘要

Epigenetic differences are a common feature of many diseases, including cancer, and disease-associated changes have even been detected in bodily fluids. DNA modification studies in circulating DNA (cirDNA) may lead to the development of specific non-invasive biomarkers. To test this hypothesis, we investigated cirDNA modifications in prostate cancer patients with locally confined disease (n = 19), in patients with benign prostate hyperplasias (n = 20) and in men without any known prostate disease (n = 20). This initial discovery screen identified 39 disease-associated changes in cirDNA modification, and seven of these were validated using the sodium bisulfite-based mapping of modified cytosines in both the discovery cohort and an independent 38-patient validation cohort. In particular, we showed that the DNA modification of regions adjacent to the gene encoding ring finger protein 219 distinguished prostate cancer from benign hyperplasias with good sensitivity (61%) and specificity (71%). We also showed that repetitive sequences detected in this study were meaningful, as they indicated a highly statistically significant loss of DNA at the pericentromeric region of chromosome 10 in prostate cancer patients (p = 1.8 × 10-6). Based on these strong univariate results, we applied machine-learning techniques to develop a multi-locus biomarker that correctly distinguished prostate cancer samples from unaffected controls with 72% accuracy. Lastly, we used systems biology techniques to integrate our data with publicly available DNA modification and transcriptomic data from primary prostate tumors, thereby prioritizing genes for further studies. These data suggest that cirDNA epigenomics are promising source for non-invasive biomarkers.

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文章編號dds192
頁(從 - 到)3619-3631
頁數13
期刊Human Molecular Genetics
21
發行號16
DOIs
出版狀態已出版 - 8月 2012

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