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. 2020 Aug;40(8):1997-2007.
doi: 10.1111/liv.14463. Epub 2020 May 23.

Preoperative evaluation of microvascular invasion with circulating tumour DNA in operable hepatocellular carcinoma

Dong Wang  1 , Yaping Xu  2 , Jennifer B Goldstein  3 , Ke Ye  1 , Xi Hu  1 , Liang Xiao  1 , Lifeng Li  2 , Lianpeng Chang  2 , Yanfang Guan  2 , Guo Long  1 , Qiongzhi He  2 , Xin Yi  2 , Jianjun Zhang  4   5 , Zhiming Wang  1 , Xuefeng Xia  2 , Ledu Zhou  1
Affiliations

Preoperative evaluation of microvascular invasion with circulating tumour DNA in operable hepatocellular carcinoma

Dong Wang et al. Liver Int. 2020 Aug.

Abstract

Background & aims: Microvascular invasion (MVI) is a critical prognostic factor for operable hepatocellular carcinoma (HCC). This study aimed to explore the performance of circulating tumour DNA (ctDNA) in evaluating MVI status preoperatively.

Methods: Seventy-three HCC patients were enrolled and randomly divided into a training cohort and a validation cohort in a 2:1 ratio, and preoperative blood and surgical tissue samples were obtained. Genomic alterations were analysed using targeted deep sequencing with a 1021-gene panel.

Results: In training cohort, 260 somatic mutations were identified in 40 blood samples (81.6%). CtDNA mutation was verified in paired tissue sample in 39 patients (97.5%). In univariate analysis, ctDNA allele frequency (AF) and largest tumour diameter were associated with the presence of MVI, but ctDNA AF was the only independent risk factor in multivariate analysis. With the cut-off value of 0.83%, ctDNA AF determined the presence of MVI with the sensitivity of 89.7% and specificity of 80.0% in the training cohort, and the sensitivity of 78.6% and the specificity of 81.8% in the validation cohort. In preoperative evaluation, ctDNA AF, AFP level and BCLC staging were associated with recurrence-free survival in both univariate and multivariate analysis.

Conclusions: CtDNA can serve as an independent risk factor of MVI for operable HCC and help determining precise treatment strategies. The integration of ctDNA in the management of operable HCC may achieve better clinical outcomes.

Keywords: ctDNA; hepatectomy; hepatocellular carcinoma; microvascular invasion; surgical management.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

FIGURE 1
FIGURE 1
Genomic landscape of ctDNA in the training cohort. (A) Heatmap illustrating the common mutant genes of ctDNA. Only genes that mutated in over three patients were included. Each column represents a single patient. Different colours indicate diverse mutation types. The right bars represent the frequencies of each gene. The upper bars sum the total number of mutations only exhibited in the heatmap (not the overall mutation number) for each patient. (B) The distribution of AF for the overall ctDNA mutations. AF, allele frequency
FIGURE 2
FIGURE 2
Somatic mutations found in paired ctDNA and resected tumour tissue in the training cohort. Heatmaps indicate the AF of the somatic mutations (blue, see colour key) or their absence (grey) in the 49 pairs of tumour tissue and ctDNA. T, tissue; PL, plasma
FIGURE 3
FIGURE 3
Correlation between ctDNA parameters, nomogram model and MVI status in the training cohort. The upper column chart and broken line graph indicates the distribution of the maximal AF and blood TMB respectively. The horizontal black broken line indicates the cuf‐off value of ctDNA AF in distinguishing MVI high and low risk according to ROC analysis. The nomogram model encompass AFP, HBV‐DNA, platelet count and imaging parameters to evaluate the MVI risk for HCC patients who met the Milan criteria. Patients who are inconsistent with the Milan criteria are labelled as ‘Not applicable’. AF, allele frequency; TMB, tumour mutation burden
FIGURE 4
FIGURE 4
Significantly enriched mutant genes of ctDNA (A) and tumour tissue (B) in MVI positive and negative patients in the training cohort. Significantly enriched mutant genes is determined by χ2 or Fisher's exact test. Only genes that mutated in over three patients were included in the analysis. Genes on the right and left of y‐axis demonstrate superior population frequencies in MVI positive and negative patients respectively. Gene with P < .05 is identified with statistical significance and labelled as red box
FIGURE 5
FIGURE 5
Survival analysis for patients with different clinicopathological characteristics and ctDNA AF. The patients are grouped by MVI status (A) and maximal ctDNA AF (B). The results of both training and validation cohort, as well as the total cohort, are exhibited. (C) Multivariate COX regression analysis reveals the independent risk factors for postoperative recurrence. Only variables suggesting statistical significance in univariate Kaplan‐Meier analysis are included in the COX model, and the analysis is based on the data from the total cohort. HR, hazard ratios
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