This hypothesis is quite plausible because the formation of ecDNA is associated with the loss of function of TP53. 7,69 A longitudinal study in BE and associated EAC shows that TP53 deficiency precedes the formation of ecDNA.7 A TCGA pan-cancer analysis further shows that TP53 is the only gene whose mutations are significantly higher in ecDNA-containing tumors.69 Therefore, when the compromised TP53 primes genomic instability, such as whole-genome doubling,81 scar-less ecDNA formation is possible under the cut-and-re-ligation context. The gene discussed is TP53; the disease is cancer.