Tumor Mutational Concordance and Recurrence Timing in Hepatocellular Carcinoma

In hepatocellular carcinoma (HCC), intrahepatic recurrence includes true recurrence from clonal relapse and multicentric recurrence from de novo tumorigenesis. Recurrence timing is used to distinguish these types; however, its accuracy remains unclear. This study aimed to classify recurrent tumors based on somatic mutational concordance and assess the validity of recurrence timing.

Whole-exome sequencing was performed on paired primary and recurrent HCC tumors from 49 patients enrolled in a prospective institutional omics project. Tumors with ≥ 10 shared somatic mutations were classified as true recurrence. Clinicopathological features, recurrence timing, driver mutation patterns, and survival outcomes were compared between recurrence types. Mutational concordance was quantified using shared variant counts and the Jaccard similarity index.

Of the 49 patients, 22 (44.9%) showed true recurrence and 27 (55.1%) had multicentric recurrence. Multicentric recurrence tumors harbored no shared variants or only a single shared variant with the primary tumor. True recurrence was associated with significantly higher concordance in histological differentiation and Edmondson-Steiner grading and greater retention of CTNNB1, TP53, ARID1A, and KEAP1 mutations. The number of shared variants (median: 115 vs. 0, and p < 0.001) and the Jaccard index (median: 0.44 vs. 0.00 and p < 0.001) were significantly higher in the true recurrence group. Recurrence timing was inconsistently correlated with mutational concordance, although a 3-year cutoff yielded significant separation.

Recurrence timing alone insufficiently reflects clonal relationships. Genomic profiling offers a reliable framework for distinguishing between recurrence types and guiding HCC management.