Methylated Cell-Free DNA Sequencing (MeD-seq) of LpnPI Digested Fragments to Identify Early Progression in Metastatic Renal Cell Carcinoma Patients on Watchful Waiting

• Published in: Cancers Vol. 15; no. 5; p. 1374
• Main Authors: Bos, Manouk K, Verhoeff, Sarah R, Oosting, Sjoukje F, Menke-van der Houven van Oordt, Willemien C, Boers, Ruben G, Boers, Joachim B, Gribnau, Joost, Martens, John W M, Sleijfer, Stefan, van Herpen, Carla M L, Wilting, Saskia M
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 21.02.2023; MDPI
• Subjects: Blood & organ donations; Carcinoma, Renal cell; Clinical medicine; Data processing; Development and progression; Diagnosis; DNA; DNA methylation; DNA sequencing; Genomes; Health aspects; Kidney cancer; Metastases; Metastasis; Methods; Methylation; Nucleotide sequencing; Patients; Prognosis; Renal cell carcinoma; Netherlands; United States > US; DNA methylation; metastatic renal cell carcinoma; cfDNA; watchful waiting
• ISSN: 2072-6694; 2072-6694
• DOI: 10.3390/cancers15051374

According to the current guidelines, watchful waiting (WW) is a feasible option for patients with good or intermediate prognosis renal-cell carcinoma (RCC). However, some patients rapidly progress during WW, requiring the initiation of treatment. Here, we explore whether we can identify those patients using circulating cell-free DNA (cfDNA) methylation. We first defined a panel of RCC-specific circulating methylation markers by intersecting differentially methylated regions from a publicly available dataset with known RCC methylation markers from the literature. The resulting RCC-specific methylation marker panel of 22 markers was subsequently evaluated for an association with rapid progression by methylated DNA sequencing (MeD-seq) in serum from 10 HBDs and 34 RCC patients with a good or intermediate prognosis starting WW in the IMPACT-RCC study. Patients with an elevated RCC-specific methylation score compared to HBDs had a shorter progression-free survival (PFS, = 0.018), but not a shorter WW-time ( = 0.15). Cox proportional hazards regression showed that only the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) criteria were significantly associated with WW time (HR 2.01, = 0.01), whereas only our RCC-specific methylation score (HR 4.45, = 0.02) was significantly associated with PFS. The results of this study suggest that cfDNA methylation is predictive of PFS but not WW.