TP53 R249S Mutation Detected in Circulating Tumor DNA is associated with Prognosis of Hepatocellular Carcinoma Patients with or without Hepatectomy.

BACKGROUND & AIMS Somatic mutation R249S in TP53 is highly common in hepatocellular carcinoma (HCC). We aim to investigate the effects of R249S in ctDNA on the prognosis of HCC. METHODS We analyzed three cohorts including 895 HCC patients. TP53 mutation spectrum was examined by direct sequencing of genomic DNA from tissue specimens in HCC patients with hepatectomy (Cohort 1, N=260). R249S and other recurrent missense mutations were assessed for their biological functions and associations with overall survival (OS) and progression free survival (PFS) of HCC patients in Cohort 1. R249S within circulating tumor DNA (ctDNA) was detected through droplet digital polymerase chain reaction (ddPCR) and its association with OS and PRS was analyzed in HCC patients with (Cohort 2, N=275) or without (Cohort 3, N=360) hepatectomy. RESULTS In Cohort 1, R249S occupied 60.28% of all TP53 mutations. Overexpression of R249S induced more serious malignant phenotypes than those of the other three identified TP53 recurrent missense mutations. Additionally, R249S, but not other missense mutations, was significantly associated with worse OS (P=0.006) and PFS (P=0.01) of HCC patients. Consistent with the results in Cohort 1, HCC patients in Cohort 2 and 3 with R249S had worse OS (P=8.291 × 10-7 and 2.608 × 10-7 in Cohort 2 and 3, respectively) and PFS (P=5.115 × 10-7 and 5.900 × 10-13 in Cohort 2 and 3, respectively) compared to those without this mutation. CONCLUSIONS TP53 R249S mutation in ctDNA may serve as a promising prognosis biomarker for HCC patients with or without hepatectomy.