Unique somatic variants in DNA from urine exosomes of individuals with bladder cancer

Molecular Therapy: Methods & Clinical Development

David J. McConkey¹  Sara P.Y. Che²  Shanna M. Pretzsch²  Kathleen M. McAndrews²  Valerie S. LeBleu²  Kerri Wolf-Dennen²  Paul Kurywchak²  Xunian Zhou²  Chia-Chin Wu³  Mark D’Souza⁴  T. Conrad Gilliam⁴  Natalia Maltsev⁴  Bingqing Xie⁴  Dinanath Sulakhe⁴  Colin P. Dinney⁵  Bogdan A. Czerniak⁶  Raghu Kalluri⁶  Olga V. Volpert⁷ 

[1] Feinberg School of Medicine, Northwestern University, Chicago, IL, USA;Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, TX, USA;Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA;Department of Human Genetics, University of Chicago, Chicago, IL, USA;Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, TX, USA;Department of Urology, University of Texas MD Anderson Cancer Center, Houston, TX, USA;Johns Hopkins Greenberg Bladder Cancer Institute, Baltimore, MD, USA;

关键词: bladder cancer;    biomarker;    cancer;    exosomes;    extracellular vesicles;    size exclusion chromatography;   

DOI  :  

来源: DOAJ

【 摘 要 】

Bladder cancer (BC), a heterogeneous disease characterized by high recurrence rates, is diagnosed and monitored by cystoscopy. Accurate clinical staging based on biopsy remains a challenge, and additional, objective diagnostic tools are needed urgently. We used exosomal DNA (exoDNA) as an analyte to examine cancer-associated mutations and compared the diagnostic utility of exoDNA from urine and serum of individuals with BC. In contrast to urine exosomes from healthy individuals, urine exosomes from individuals with BC contained significant amounts of DNA. Whole-exome sequencing of DNA from matched urine and serum exosomes, bladder tumors, and normal tissue (peripheral blood mononuclear cells) identified exonic and 3′ UTR variants in frequently mutated genes in BC, detectable in urine exoDNA and matched tumor samples. Further analyses identified somatic variants in driver genes, unique to urine exoDNA, possibly because of the inherent intra-tumoral heterogeneity of BC, which is not fully represented in random small biopsies. Multiple variants were also found in untranslated portions of the genome, such as microRNA (miRNA)-binding regions of the KRAS gene. Gene network analyses revealed that exoDNA is associated with cancer, inflammation, and immunity in BC exosomes. Our findings show utility of exoDNA as an objective, non-invasive strategy to identify novel biomarkers and targets for BC.

【 授权许可】

Unknown