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Tumor DNA contains specific somatic alterations that are crucial for the diagnosis and treatment of cancer. Due to the spatial and temporal intra-tumor heterogeneity, multi-sampling is needed to adequately characterize the somatic alterations. Tissue biopsy, however, is limited by the restricted access to sample and the challenges to recapitulate the tumor clonal diversity. Non-blood circulating tumor DNA are tumor DNA fragments presents in non-blood body fluids, such as urine, saliva, sputum, stool, pleural fluid, and cerebrospinal fluid (CSF). Recent studies have demonstrated the presence of tumor DNA in these non-blood body fluids and their application to the diagnosis, screening, and monitoring of cancers. Non-blood circulating tumor DNA has an enormous potential for large-scale screening of local neoplasms because of its non-invasive nature, close proximity to the tumors, easiness and it is an economically viable option. It permits longitudinal assessments and allows sequential monitoring of response and progression. Enrichment of tumor DNA of local cancers in non-blood body fluids may help to archive a higher sensitivity than in plasma ctDNA. The direct contact of cancerous cells and body fluid may facilitate the detection of tumor DNA. Furthermore, normal DNA always dilutes the plasma ctDNA, which may be aggravated by inflammation and injury when very high amounts of normal DNA are released into the circulation. Altogether, our review indicate that non-blood circulating tumor DNA presents an option where the disease can be tracked in a simple and less-invasive manner, allowing for serial sampling informing of the tumor heterogeneity and response to treatment.

Non-blood circulating tumor DNA detection in cancer