Comprehensive molecular and immunological characterization of hepatocellular carcinomaResearch in context
Shu Shimada,
Kaoru Mogushi,
Yoshimitsu Akiyama,
Takaki Furuyama,
Shuichi Watanabe,
Toshiro Ogura,
Kosuke Ogawa,
Hiroaki Ono,
Yusuke Mitsunori,
Daisuke Ban,
Atsushi Kudo,
Shigeki Arii,
Minoru Tanabe,
Jack R. Wands,
Shinji Tanaka
Affiliations
Shu Shimada
Department of Molecular Oncology Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan
Kaoru Mogushi
Department of Molecular Oncology Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan
Yoshimitsu Akiyama
Department of Molecular Oncology Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan
Takaki Furuyama
Department of Hepato-Biliary-Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan
Shuichi Watanabe
Department of Hepato-Biliary-Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan
Toshiro Ogura
Department of Hepato-Biliary-Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan
Kosuke Ogawa
Department of Hepato-Biliary-Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan
Hiroaki Ono
Department of Hepato-Biliary-Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan
Yusuke Mitsunori
Department of Hepato-Biliary-Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan
Daisuke Ban
Department of Hepato-Biliary-Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan
Atsushi Kudo
Department of Hepato-Biliary-Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan
Shigeki Arii
Department of Hepato-Biliary-Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan
Minoru Tanabe
Department of Hepato-Biliary-Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan
Jack R. Wands
Liver Research Center, Warren Alpert Medical School of Brown University, Providence, RI, USA
Shinji Tanaka
Department of Molecular Oncology Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan; Department of Hepato-Biliary-Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan; Corresponding author at: Department of Molecular Oncology, Graduate School of Medicine, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan.
Background: Hepatocellular carcinoma (HCC) is a heterogeneous disease with various etiological factors, and ranks as the second leading cause of cancer-related mortality worldwide due to multi-focal recurrence. We herein identified three major subtypes of HCC by performing integrative analysis of two omics data sets, and clarified that this classification was closely correlated with clinicopathological factors, immune profiles and recurrence patterns. Methods: In the test study, 183 tumor specimens surgically resected from HCC patients were collected for unsupervised clustering analysis of gene expression signatures and comparative analysis of gene mutations. These results were validated by using genome, methylome and transcriptome data of 373 HCC patients provided from the Cancer Genome Atlas Network. In addition, omics data were obtained from pairs of primary and recurrent HCC. Findings: Comprehensive molecular evaluation of HCC by multi-platform analysis defined three major subtypes: (1) mitogenic and stem cell-like tumors with chromosomal instability; (2) CTNNB1-mutated tumors displaying immune suppression; and (3) metabolic disease-associated tumors, which included an immunogenic subgroup characterized by macrophage infiltration and favorable prognosis. Although genomic and epigenomic analysis explicitly distinguished between HCC with intrahepatic metastasis (IM) and multi-centric HCC (MC), the phenotypic similarity between the primary and recurrent tumors was not correlated to the IM/MC origin, but to the classification. Interpretation: Identification of these HCC subtypes provides further insights into patient stratification as well as presents opportunities for therapeutic development. Fund: Ministry of Education, Culture, Sports, Science and Technology of Japan (16H02670 and 18K19575), Japan Agency for Medical Research and Development (JP15cm0106064, JP17cm0106518, JP18cm0106540 and JP18fk0210040). Keywords: Hepatocellular carcinoma, Integrative analysis, Molecular classification, CTNNB1 mutation, Metabolic disease associated cancer, Immunogenic cancer, Hepatocellular carcinoma with intrahepatic metastasis, Multi-centric hepatocellular carcinoma
