Citations

Abstract Background: Multifocal hepatocellular carcinoma (MF-HCC) accounts for >40% of HCCs, demonstrating a poor prognosis than single primary HCCs. Characterizing the dynamic changes of mutation signature along with clonal evolution, quantifying intrahepatic metastatic timing, and investigating the genetic structure in the preneoplastic stage underlying different subtypes of MF-HCC are important for understanding their molecular evolution and developing a precision management strategy. Methods: We conducted whole-exome sequencing in 74 tumor samples from spatially distinct regions in 35 resected tumor lesions and adjacent non-cancerous tissues in 11 patients with synchronous MF-HCCs, 15 histologically confirmed preneoplastic lesions and six samples from peripheral blood mononuclear cell. We also used the previously published MF-HCC cohorts (n=9) as an independent validation dataset. Results: We classified MF-HCCs into three subtypes, including intrahepatic metastasis, multicentric occurrence, and mixed intrahepatic metastasis and multicentric occurrence. The dynamic changes in mutation signatures between tumor subclonal expansions demonstrated varied etiologies underlying the clonal progression in different MF-HCC subtypes, especially the contribution of aristolochic acid exposure decreased along with subclonal expansions. The clonal evolution in intrahepatic metastasis exhibited an early metastatic seeding that occurred at 10-4–0.01 cm3 in primary tumor volume, below the limitation in clinical detection. These findings were validated in another independent cohort. In addition, for multicentric occurrence MF-HCC, mutational footprints in the preneoplastic lesions revealed common preneoplastic arising clones, evidently being ancestors of different tumor sites. Conclusion: Our study comprehensively characterized the dynamic mutational signature, early metastatic timing, and common preneoplastic clones in multicentric occurrence that characterized the varied tumor clonal evolutionary history underlying different subtypes of MF-HCC, and provided important implications for optimizing personalized clinical management for MF-HCC.

Abstract1q21 gain is a common cytogenetic abnormality featuring high‐risk multiple myeloma (HRMM). However, the molecular mechanism underlying the adverse prognostic effect of 1q21 gain remains largely unclear. Here, we report that ARNT/HIF‐1β, a 1q21 gene, is highly expressed in HRMM and induced by microenvironmental hypoxia, which confers drug resistance and correlates with inferior outcome. Analysis of the gene expression profile database revealed that ARNT expression was upregulated in MM and increased with disease progression or in HRMM subtypes (particularly 1q21 gain), while correlated to shorter overall survival. In a cohort of 40 MM patients, qPCR further validated that ARNT expression was higher in MM patients than normal donors. MM cells carrying 1q21 gain or acquired drug resistance displayed a robust increase in HIF‐1β protein level. Hypoxia induced HIF‐1β expression via a NF‐κB‐dependent process. Notably, HIF‐1β overexpression impaired bortezomib sensitivity, whereas shRNA knockdown of ARNT reversed hypoxia‐mediated drug resistance. Together, these findings suggest that ARNT/HIF‐1β might represent a novel biomarker for risk stratification and prognosis of HRMM patients, as well as a potential therapeutic target for overcoming 1q21 gain‐ or microenvironment‐mediated and acquired drug resistance in MM.