AI Article Synopsis
- The study investigates the genetic factors that contribute to the early recurrence of hepatocellular carcinoma (HCC) in Chinese patients after surgical removal of the tumor, using various sequencing techniques on 182 primary HCC samples.
- Researchers identified five genes, including WNK2, with mutations linked to early tumor recurrence, and found that alterations in WNK2 were associated with lower protein levels and poorer survival outcomes.
- The findings suggest that WNK2 has a tumor-suppressor function, and its inactivation promotes HCC growth and metastasis, highlighting its potential role in early recurrence of the disease.
Article Abstract
Background & Aims: Early recurrence of hepatocellular carcinoma (HCC) after curative resection is common. However, the association between genetic mechanisms and early HCC recurrence, especially in Chinese patients, remains largely unknown.
Methods: We performed whole-genome sequencing (49 cases), whole-exome sequencing (18 cases), and deep targeted sequencing (115 cases) on 182 primary HCC samples. Focusing on WNK2, we used Sanger sequencing and qPCR to evaluate all the coding exons and copy numbers of that gene in an additional 554 HCC samples. We also explored the functional effect and mechanism of WNK2 on tumor growth and metastasis.
Results: We identified 5 genes (WNK2, RUNX1T1, CTNNB1, TSC1, and TP53) harboring somatic mutations that correlated with early tumor recurrence after curative resection in 182 primary HCC samples. Focusing on WNK2, the overall somatic mutation and copy number loss occurred in 5.3% (39/736) and 27.2% (200/736), respectively, of the total 736 HCC samples. Both types of variation were associated with lower WNK2 protein levels, higher rates of early tumor recurrence, and shorter overall survival. Biofunctional investigations revealed a tumor-suppressor role of WNK2: its inactivation led to ERK1/2 signaling activation in HCC cells, tumor-associated macrophage infiltration, and tumor growth and metastasis.
Conclusions: Our results delineate genomic events that characterize Chinese HCCs and identify WNK2 as a driver of early HCC recurrence after curative resection.
Lay Summary: We applied next-generation sequencing and conducted an in-depth genomic analysis of hepatocellular carcinomas from a Chinese patient cohort. The results delineate the genomic events that characterize hepatocellular carcinomas in Chinese patients and identify WNK2 as a driver associated with early tumor recurrence after curative resection.
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| http://dx.doi.org/10.1016/j.jhep.2019.07.014 | DOI Listing |
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