Fragmentation of cell-free DNA is induced by upper tract urothelial carcinoma-associated systemic inflammation.

Reliable biomarkers for upper tract urothelial carcinoma (UTUC) have yet to be found. Plasma cell-free DNA (cfDNA) has been clinically applied as a minimally invasive blood biomarker for various types of cancer. We investigated the utility of plasma cfDNA as a blood biomarker in UTUC patients. The fragment size of plasma cfDNA was shorter and the concentration of plasma cfDNA was higher in UTUC patients than in healthy controls. The fragment size of plasma cfDNA had a moderate accuracy of diagnosing UTUC (AUC = 0.72), and multivariate analysis indicated that the fragment size of plasma cfDNA was significantly associated with the presence of UTUC (Odds ratio = 0.807, 95% CI 0.653 - 0.955, p = 0.024). Furthermore, we found that the size of plasma cfDNA shortens alongside disease progression (p < 0.001). The fragment size of plasma cfDNA in UTUC patients may be an auxiliary tool for the diagnosis of UTUC patients. We also found a high correlation between the fragmentation of plasma cfDNA and serum levels of three inflammatory cytokines (TNFα [r = -0.837], IL-6 [r = -0.964], IL-1ra [r = -0.911]) which were reported to associate with poor prognosis. Also, we found that the proportion of short fragments of cfDNA was significantly increased in the supernatant of peripheral blood mononuclear cells (PBMCs) from healthy controls cultured in media containing TNFα. These results supposed that cancer associated-systemic inflammation, especially TNFα, may contribute to the fragmentation of plasma cfDNA in UTUC patients.

Cancer science. 2020 Oct 07 [Epub ahead of print]

Kosuke Nakano, Yoshiyuki Yamamoto, Gaku Yamamichi, Satoru Yumiba, Eisuke Tomiyama, Makoto Matsushita, Yoko Koh, Yujiro Hayashi, Cong Wang, Yu Ishizuya, Taigo Kato, Koji Hatano, Atsunari Kawashima, Takeshi Ujike, Kazutoshi Fujita, Norio Nonomura, Motohide Uemura

Department of Urology, Osaka University Graduate School of Medicine, Suita, Japan.