Genomic and transcriptional heterogeneity of multifocal hepatocellular carcinoma
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Officially Accepted for Publication

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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.

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.

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.
Acceptance Date27/03/2019
All Author(s) ListL 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
Journal nameAnnals of Oncology
LanguagesEnglish-United Kingdom
KeywordsHepatocellular carcinoma, Multifocal, Genomic heterogeneity, Transcriptional heterogeneity, Clonal evolution, Immune microenvironment

Last updated on 2020-06-07 at 02:08