In summary, our findings reveal novel aspects of the molecular pathogenesis of PC, particularly the importance of mutational processes reflected in the APOBEC signatures SBS2 and SBS13, heterozygous germline mutations in MUTYH as potential predisposing factors, and recurrent overexpression of FGFR1 and RET. Here, FGFR1 is linked to pachyonychia congenita.