BACKGROUND
Hepatocellular carcinoma (HCC) often presents with multiple nodules within the liver, with limited effective interventions. The high genetic heterogeneity of HCC might be the major cause of treatment failure. We aimed to characterize genomic heterogeneity, infer clonal evolution, investigate RNA expression pattern and explore tumour immune microenvironment profile of multifocal HCC.


PATIENTS AND METHODS
Whole-exome sequencing and RNA sequencing were carried out in 34 tumours and six adjacent normal liver tissue samples from six multifocal HCC patients. Protein expression of Ki67, AFP, P53, Survivin and CD8 were detected by immunohistochemistry. Fluorescence in-situ hybridization was performed to validate the amplification status of sorafenib-targeted genes.


RESULTS
We deciphered genomic and transcriptional heterogeneity among tumours in each multifocal HCC patient including mutational profiles, copy number alterations, tumour evolutionary trajectory and tumour immune microenvironment profiles. Of note, sorafenib-targeted alterations were identified in the trunk of phylogenetic tree in only one out of six patients, which may explain the relative low treatment response rate to sorafenib in clinical practice. Moreover, we demonstrated RNA expression patterns and tumour immune microenvironment profiles of all nodules. We found that RNA expression pattern was associated with Edmonson-Steiner grading. Based on the differential expression of 66 reported immune markers, unsupervised hierarchical clustering analysis of 34 nodules identified immune subsets: one low expression cluster with seven nodules and one high expression cluster with 11 nodules. CD8+ T cells were more enriched in nodules of the high expression cluster.


CONCLUSIONS
Our study provided a detailed view of genomic and transcriptional heterogeneity, clonal evolution and immune infiltration of multifocal HCC. The heterogeneity of druggable targets and immune landscape might help interpret the clinical responsiveness to targeted drugs and immunotherapy for multifocal HCC patients.

L.X. Xu

M.H. He

Z.H. Dai

J. Yu

J.G. Wang

X.C. Li

B.B. Jiang

Z.F. Ke

T.H. Su

Z.W. Peng

Y. Guo

Z.B. Chen

S.L. Chen

S. Peng

M. Kuang

Annals of Oncology

ANNALS OF ONCOLOGY 是欧洲医学肿瘤学会和日本医学肿瘤学会的期刊，提供关于创新癌症治疗或与肿瘤学和精准医学相关的转化工作的快速有效的同行评审出版物。主要关注点包括：系统性抗癌治疗（特别关注分子靶向药物和新的免疫疗法）、随机试验（包括阴性试验）、顶级指南以及目前正在成为个性化医疗关键组成部分的新领域，如分子病理学、生物信息学、现代统计学, 和生物技术。如果放射治疗、外科手术和儿科手稿与上述领域之一有明显的相互作用或范式转换，则可以考虑。

The Annals of Oncology is the official journal of the European Society for Medical Oncology and the Japanese Society of Medical Oncology, focusing on innovative cancer treatments and translational research related to oncology and precision medicine. The journal primarily addresses several key areas: systemic cancer therapies, with a particular emphasis on molecular targeted drugs and new immunotherapies; randomized trials, including negative trials; top-tier guidelines; and emerging fields such as molecular pathology, bioinformatics, modern statistics, and biotechnology, which are becoming essential components of personalized medicine. Manuscripts related to radiation therapy, surgery, or pediatric studies will also be considered if they demonstrate significant interaction or paradigm shifts with the aforementioned areas.

《Annals of Oncology》是欧洲医学肿瘤学会和日本医学肿瘤学会的官方期刊，专注于创新癌症治疗及与肿瘤学和精准医学相关的转化研究。期刊主要关注以下几个方面：系统性抗癌治疗，特别是分子靶向药物和新型免疫疗法；随机试验，包括阴性试验；顶级指南；以及分子病理学、生物信息学、现代统计学和生物技术等新兴领域，这些领域正逐渐成为个性化医疗的重要组成部分。如果放射治疗、外科手术或儿科研究与上述领域有显著的相互作用或范式转变，也会被考虑发表。

Genomic and transcriptional heterogeneity of multifocal hepatocellular carcinoma

多灶性肝细胞癌的基因组和转录组异质性

Category	Quartile
医学	1
医学, 肿瘤学	1

Genomic and transcriptional heterogeneity of multifocal hepatocellular carcinoma

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