Clinical significance of the mutational landscape and fragmentation of circulating tumor DNA in renal cell carcinoma
Open Access
- 10 December 2018
- journal article
- research article
- Published by Wiley in Cancer Science
- Vol. 110 (2), 617-628
- https://doi.org/10.1111/cas.13906
Abstract
Reliable biomarkers for renal cell carcinoma (RCC) have yet to be determined. Circulating tumor DNA (ctDNA) is an emerging resource to detect and monitor molecular characteristics of various tumors. The present study aims to clarify the clinical utility of ctDNA for RCC. Fifty‐three patients histologically diagnosed with clear cell RCC were enrolled. Targeted sequencing was carried out using plasma cell‐free DNA (cfDNA) and tumor DNA. We applied droplet digital PCR (ddPCR) to validate detected mutations. cfDNA fragment size was also evaluated using a microfluidics‐based platform and sequencing. Proportion of cfDNA fragments was defined as the ratio of small (50‐166 bp) to large (167‐250 bp) cfDNA fragments. Association of mutant allele frequency of ctDNA with clinical course was analyzed. Prognostic potential was evaluated using log‐rank test. A total of 38 mutations across 16 (30%) patients were identified from cfDNA, including mutations in TP53 (n = 6) and VHL (n = 5), and median mutant allele frequency of ctDNA was 10%. We designed specific ddPCR probes for 11 mutations and detected the same mutations in both cfDNA and tumor DNA. Positive ctDNA was significantly associated with a higher proportion of cfDNA fragments (P = .033), indicating RCC patients with ctDNA had shorter fragment sizes of cfDNA. Interestingly, the changes of mutant allele frequency in ctDNA concurrently correlated with clinical course. Positive ctDNA and fragmentation of cfDNA were significantly associated with poor cancer‐specific survival (P < .001, P = .011). In conclusion, our study shows the clinical utility of ctDNA status and cfDNA fragment size as biomarkers for prognosis and disease monitoring in RCC.Keywords
Funding Information
- Japan Society for the Promotion of Science (16K20139, 18K16692)
This publication has 42 references indexed in Scilit:
- Prognostic Role and HER2 Expression of Circulating Tumor Cells in Peripheral Blood of Patients Prior to Radical Cystectomy: A Prospective StudyEuropean Urology, 2012
- RECIST rulesCancer Imaging, 2012
- Cell-free nucleic acids as biomarkers in cancer patientsNature Reviews Cancer, 2011
- Integrative genomics viewerNature Biotechnology, 2011
- Maternal Plasma DNA Sequencing Reveals the Genome-Wide Genetic and Mutational Profile of the FetusScience Translational Medicine, 2010
- The Sequence Alignment/Map format and SAMtoolsBioinformatics, 2009
- Fast and accurate short read alignment with Burrows–Wheeler transformBioinformatics, 2009
- Epidemiologic and socioeconomic burden of metastatic renal cell carcinoma (mRCC): A literature reviewCancer Treatment Reviews, 2008
- The role of macrophages in the in vitro generation of extracellular DNA from apoptotic and necrotic cellsImmunology, 2005
- DNA fragments in the blood plasma of cancer patients: quantitations and evidence for their origin from apoptotic and necrotic cells.2001