Fragmentation of cell‐free DNA is induced by upper‐tract urothelial carcinoma–associated systemic inflammation

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

doi:10.1111/cas.14679

Cited by 8 publications

(6 citation statements)

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“…Upper tract urothelial carcinoma is uncommon cancer that accounts for ~5%–10% of all urothelial carcinomas 1,2 . In total, ~60% of UTUCs are invasive at diagnosis (compared with 15%–25% of bladder cancers), 3 while ~7% are metastases 4 .…”

Section: Introductionmentioning

confidence: 99%

“…Upper tract urothelial carcinoma is uncommon cancer that accounts for ~5%–10% of all urothelial carcinomas. 1 , 2 In total, ~60% of UTUCs are invasive at diagnosis (compared with 15%–25% of bladder cancers), 3 while ~7% are metastases. 4 Standard treatment for patients with nonmetastatic UTUC is radical nephroureterectomy, while systemic treatment with platinum‐based chemotherapy or immune checkpoint inhibitors is administered for metastatic UTUC.…”

Section: Introductionmentioning

confidence: 99%

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Perioperative circulating tumor DNA enables the identification of patients with poor prognosis in upper tract urothelial carcinoma

et al. 2022

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Perioperative systemic chemotherapy improves the prognosis of upper tract urothelial carcinoma (UTUC). The first objective of this study was to verify whether perioperative circulating tumor DNA (ctDNA) analysis using a pan‐cancer gene panel and next‐generation sequencing could identify patients with poor prognosis who require perioperative chemotherapy. Second, we investigated whether ctDNA is useful for minimal residual disease (MRD) detection and treatment monitoring in UTUC. This study included 50 patients with untreated UTUC, including 43 cases of localized UTUC. We performed targeted ultradeep sequencing of plasma cell‐free DNA (cfDNA) and buffy coat DNA and whole‐exome sequencing of cancer tissues, allowing exclusion of possible false positives. We attempted to stratify the prognosis according to the perioperative ctDNA levels in patients with localized UTUC. In patients with metastatic UTUC, ctDNA was evaluated before, during, and after systemic treatment. In total, 23 (46%) of 50 patients with untreated UTUC were ctDNA positive, and 17 (40%) of 43 patients with localized UTUC were ctDNA positive. Of the detected TP53 mutations, 19% were false positives due to clonal hematopoiesis of indeterminate potential. Among preoperative risk factors, only the preoperative ctDNA fraction>2% was a significant and independent risk factor associated with worse recurrence‐free survival (RFS). Furthermore, the existence of ctDNA early points after the operation was significantly associated with worse RFS, suggesting the presence of MRD. ctDNA also showed a potential as a real‐time marker for systemic therapy in patients with metastatic UTUC. Detection of ctDNA may indicate potential metastasis and guide decisions on perioperative chemotherapy.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Perioperative circulating tumor DNA enables the identification of patients with poor prognosis in upper tract urothelial carcinoma

et al. 2022

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“…Liquid biopsy is becoming an essential resource to provide information on the biological characteristics of cancer with minimum invasiveness, which enables longitudinal and real‐time monitoring when compared to cancer tissue‐based tests in oncology 7–10 . In particular, with the advancement of NGS technology, ctDNA receives plenty of attention, which detects cancer‐related genomic alterations in peripheral blood.…”

Section: Introductionmentioning

confidence: 99%

Early dynamics of circulating tumor DNA predict clinical response to immune checkpoint inhibitors in metastatic renal cell carcinoma

et al. 2022

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Objectives Detection of genomic alterations in circulating tumor deoxyribonucleic acid of peripheral blood can guide the selection of systemic therapy in cancer patients. The predictive significance of circulating tumor deoxyribonucleic acid in metastatic renal cell carcinoma remains unclear, especially for patients treated with immune checkpoint inhibitors. Methods In this study, we collected plasma samples before and 1 month after commencing nivolumab monotherapy or nivolumab plus ipilimumab therapy from 14 metastatic renal cell carcinoma patients. We performed circulating tumor deoxyribonucleic acid genomic profiling in plasma cell‐free deoxyribonucleic acid by next‐generation sequencing using a commercially available pan‐cancer panel (Guardant360 CDx). Additionally, we also performed whole exome sequencing of tumor tissues and compared the concordance of genomic profiles with circulating tumor deoxyribonucleic acid. Results Nine patients had circulating tumor deoxyribonucleic acid in pretreatment plasma samples with a total of 20 mutations (15 single nucleotide variants, three insertions/deletions, and two copy number amplification). VHL (30.0%) was the most frequently mutated gene, followed by TP53 (20.0%), and 45.0% of circulating tumor deoxyribonucleic acid mutations were concordant with somatic mutations in tumor tissues. Patients with decreasing circulating tumor deoxyribonucleic acid mutant allele frequency had better progression free survival when compared to those with increasing mutant allele frequency (P = 0.0441). Conclusions Our findings revealed that early circulating tumor deoxyribonucleic acid dynamics can serve as a predictive biomarker for response to immune checkpoint inhibitors in metastatic renal cell carcinoma patients.

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“…This ctDNA has a unique genetic and epigenetic pattern that mirrors that of the tumor source [21][22][23][24], and the load of this DNA seems to correlate with tumor staging and prognosis [25]. In such conditions of tissue stress, the amount of cfDNA found in biofluids increases, both as small fragments and large fragments [26][27][28][29]. These are thought to be mainly originated from cell apoptosis and necrosis, respectively, and partially by other mechanisms such as autophagy or mitotic catastrophe, although additional studies are needed to ascertain their role [26,27,[29][30][31].…”

Section: Introductionmentioning

confidence: 99%

“…In such conditions of tissue stress, the amount of cfDNA found in biofluids increases, both as small fragments and large fragments [26][27][28][29]. These are thought to be mainly originated from cell apoptosis and necrosis, respectively, and partially by other mechanisms such as autophagy or mitotic catastrophe, although additional studies are needed to ascertain their role [26,27,[29][30][31]. In addition, another type of DNA may also be valuable when assessing a disorder with liquid biopsy.…”

Section: Introductionmentioning

confidence: 99%

Circulating Cell-Free DNA in Liquid Biopsies as Potential Biomarker for Bladder Cancer: A Systematic Review

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Plana

et al. 2021

Cancers

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Bladder cancer (BC) is among the most frequent cancer types in the world and is the most lethal urological malignancy. Presently, diagnostic and follow-up methods for BC are expensive and invasive. Thus, the identification of novel predictive biomarkers for diagnosis, progression, and prognosis of BC is of paramount importance. To date, several studies have evidenced that cell-free DNA (cfDNA) found in liquid biopsies such as blood and urine may play a role in the particular scenario of urologic tumors, and its analysis may improve BC diagnosis report about cancer progression or even evaluate the effectiveness of a specific treatment or anticipate whether a treatment would be useful for a specific patient depending on the tumor characteristics. In the present review, we have summarized the up-to-date studies evaluating the value of cfDNA as potential diagnostic, prognostic, or monitoring biomarker for BC in several biofluids.

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Fragmentation of cell‐free DNA is induced by upper‐tract urothelial carcinoma–associated systemic inflammation

Abstract: This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

Cited by 8 publications

References 30 publications

Perioperative circulating tumor DNA enables the identification of patients with poor prognosis in upper tract urothelial carcinoma

Perioperative circulating tumor DNA enables the identification of patients with poor prognosis in upper tract urothelial carcinoma

Early dynamics of circulating tumor DNA predict clinical response to immune checkpoint inhibitors in metastatic renal cell carcinoma

Circulating Cell-Free DNA in Liquid Biopsies as Potential Biomarker for Bladder Cancer: A Systematic Review

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