Preoperative plasma cell-free DNA chromosomal instability predicts microvascular invasion in hepatocellular carcinoma: a prospective study.

Abstract

Background: Microvascular invasion (MVI) has been recognized as a risk factor for early recurrence after hepatectomy in patients with hepatocellular carcinoma (HCC). This study aimed to estimate the performance of an ultrasensitive chromosomal aneuploidy detector (UCAD) model for preoperative MVI prediction in operable HCC patients based on plasma cell-free DNA (cfDNA).

Methods: A prospective study included HCC patients who underwent surgery in 2021. Preoperative peripheral plasma samples of eligible patients were collected to extract cfDNA, which was then subject to next generation sequencing. Low-coverage whole-genome sequencing data were analyzed for chromosomal instability using different parameters, including Z-score, chromosomal instability score (CIN score), tumor fraction (TFx) and a UCAD model (UCAD = CIN score + TFx + Z-score of all chromosomes). Receiver operating characteristic (ROC) curve was used to evaluate the performance of these parameters in preoperative MVI prediction.

Results: Finally, a total of 74 patients with HCC who undergone hepatectomy were prospectively enrolled. Chromosomal instability was evaluated by copy number alterations and oncogenes MCL1 (located at 1q), MYC (located at 8q), TERT (located at 5p), EGFR (located at 7p), and VEGFA (located at 6p) were identified in plasma cfDNA. The UCAD model was a superior parameter in predicting preoperative MVI, with an area under curve (AUC) value 0.749 with a sensitivity of 0.938 specificity of 0.466. Univariate analysis revealed that tumor size (≥ 5 cm) and UCAD (> 0.199) significantly increased the risk of MVI, which were further demonstrated by multivariate analysis, with odd ratio of 1.338 (95%CI, 1.060-1.689) and 2.028 (95%CI, 1.053-3.908) (P < 0.05).

Conclusions: Our cfDNA-based UCAD model has shown a promising performance for preoperative MVI prediction in operable HCC patients.

Trial registration: This study was registered at https://clinicaltrials.gov/ on 16 May 2022, retrospectively registered, Registration number: NCT05371873.