Multi-omics characterization reveals the pathogenesis of liver focal nodular hyperplasia

Yuming Liu; Jinmai Zhang; Zhuo Wang; Jiaqiang Ma; Ke Wang; Dongning Rao; Mao Zhang; Youpei Lin; Yingcheng Wu; Zijian Yang; Liangqing Dong; Zhenbin Ding; Xiaoming Zhang; Jia Fan; Yongyong Shi; Qiang Gao

doi:10.1016/j.isci.2022.104921

Multi-omics characterization reveals the pathogenesis of liver focal nodular hyperplasia

iScience. 2022 Aug 11;25(9):104921. doi: 10.1016/j.isci.2022.104921. eCollection 2022 Sep 16.

Authors

Yuming Liu¹, Jinmai Zhang², Zhuo Wang², Jiaqiang Ma¹, Ke Wang², Dongning Rao¹, Mao Zhang¹, Youpei Lin¹, Yingcheng Wu¹, Zijian Yang¹, Liangqing Dong¹, Zhenbin Ding¹, Xiaoming Zhang³, Jia Fan^{1

4}, Yongyong Shi², Qiang Gao^{1

4

5}

Affiliations

¹ Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai 200032, China.
² Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Collaborative Innovation Center for Brain Science, Shanghai Jiao Tong University, Shanghai 200030, China.
³ Key Laboratory of Molecular Virology & Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai 200031, China.
⁴ Key Laboratory of Medical Epigenetics and Metabolism, Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China.
⁵ State Key Laboratory of Genetic Engineering, Fudan University, Shanghai 200433, China.

Abstract

The molecular landscape and pathogenesis of focal nodular hyperplasia (FNH) have yet to be elucidated. We performed multi-omics approaches on FNH and paired normal liver tissues from 22 patients, followed by multi-level bioinformatic analyses and experimental validations. Generally, FNH had low mutation burden with low variant allele frequencies, and the mutation frequency significantly correlated with proliferation rate. Although no recurrently deleterious genomic events were found, some putative tumor suppressors or oncogenes were involved. Mutational signatures indicated potential impaired mismatch function and possible poison contact. Integrated analyses unveiled a group of FNH specific endothelial cells that uniquely expressed SOST and probably had strong interaction with fibroblasts through PDGFB/PDGFRB pathway to promote fibrosis. Notably, in one atypical FNH (patient No.11) with pronounced copy number variations, we observed a unique immune module. Most FNH are benign, but molecularly atypical FNH still exist; endothelial cell derived PDGFB probably promotes the fibrogenic process in FNH.

Keywords: Genetics; Hepatology; Molecular biology; Omics; Transcriptomics.