In summary, this is the first large‐scale study to demonstrate PC‐specific hypermethylation of ST6GALNAC3 and ZNF660 and prognostic value of ZNF660 hypermethylation for BCR, OS, and CSS, as well as to demonstrate biomarker potential of ST6GALNAC3, ZNF660, CCDC181, and HAPLN3 ctDNA hypermethylation for PC. Here, CCDC181 is linked to pachyonychia congenita.