Abstract
Patients with hepatocellular carcinoma (HCC) have poor long-term survival following curative resection because of the high rate of tumor early recurrence. Little is known about the trajectory of genomic evolution from primary to early-recurrent HCC. In this study, we performed whole-genome sequencing (WGS) on 40 pairs of primary and early-recurrent hepatitis B virus (HBV)-related HCC tumors from patients who received curative resection, and from four patients whose primary and recurrent tumor were extensively sampled. We identified two recurrence patterns: de novo recurrence (18/40), which developed genetically independently of the primary tumor and carried different HCC drivers, and ancestral recurrence (22/40), which was clonally related to the primary tumor and progressed more rapidly than de novo recurrence. We found that the recurrence location was predictive of the recurrence pattern: distant recurrence tended to display the de novo pattern, whereas local recurrence tended to display the ancestral pattern. We then uncovered the evolutionary trajectories based on the subclonal architecture, driver-gene mutations, and mutational processes observed in the primary and recurrent tumors. Multi-region WGS demonstrated spatiotemporal heterogeneity and polyclonal, monophyletic dissemination in HCC ancestral recurrence. In addition, we identified recurrence-specific mutations and copy-number gains in BCL9, leading to WNT/β-catenin signaling activation and an immune-excluded tumor microenvironment, which suggests that BCL9 might serve as a new therapeutic target for recurrent HCC. Collectively, our results allow us to view with unprecedented clarity the genomic evolution during HBV-related HCC early recurrence, providing an important molecular foundation for enhanced understanding of HCC with implications for personalized therapy to improve patient survival.
Highlights
The incidence and mortality rates of hepatocellular carcinoma (HCC), one of the most prevalent types of cancer, have increased in recent years.[1]
Among the 11 patients with hepatic segment interval (HSI) 0, two patients as independent events,[17] our findings suggest that the recurrent experienced de novo recurrence, suggesting that the tumors that shared a high rate of mutations with their respective recurrent tumors were located in the same hepatic segment as the primary tumors were probably derived from the original clones. primary tumors, they were still new primary tumors
We found that the proportions of nonsynonymous mutations that were shared between the primary and recurrent tumors were clearly different between the patients with de novo recurrence and those with ancestral recurrence
Summary
The genomic landscape of 40 matched pairs of primary and earlyrecurrent HCCs We performed WGS of 40 matched pairs of primary HCC and earlyrecurrent HCC and matched non-cancerous liver samples from the same patients (Fig. 1a). We detected abundant clonality indices of the tumors on the basis of nonsynonymous genomic structural variations (SVs), with averages of 43.8 SVs SNVs and indels, which showed the likelihood of two tumors (range: 0–224) per primary tumor and 47.8 SVs (range: 0–204) per sharing mutations that were not expected to have co-occurred by recurrent tumor. Those SVs comprised 839 deletions, 37 deletions chance. Some early recurrence patterns in HCC (Fig. 2g)
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