title: HERC5 is a prognostic biomarker for post-liver transplant recurrent human hepatocellular carcinoma.
abstract: OBJECTIVE
  Orthotopic liver transplantation (OLT) can be an effective treatment option for certain patients with early stage hepatocellular carcinoma (HCC) meeting Milan, UCSF, or Hangzhou criteria. However, HCC recurrence rates post-OLT range from 20 to 40 %, with limited follow-up options. Elucidating genetic drivers common to primary and post-OLT recurrent tumors may further our understanding and help identify predictive biomarkers of recurrence-both to ultimately help manage clinical decisions for patients undergoing OLT.
  
  
  METHODS
  Whole exome and RNA sequencing in matched primary and recurrent tumors, normal adjacent tissues, and blood from four Chinese HCC patients was conducted. SiRNA knockdown and both qRT-PCR and Western assays were performed on PLCPRF5, SNU449 and HEPG2 cell lines; immunohistochemistry and RNA Sequencing were conducted on the primary tumors of Chinese HCC patients who experienced tumor recurrence post-OLT (n = 9) or did not experience tumor recurrence (n = 12).
  
  
  RESULTS
  In three independent HCC studies of patients undergoing transplantation (n = 21) or surgical resection (n = 242, n = 44) of primary tumors (total n = 307), HERC5 mRNA under-expression correlated with shorter: time to tumor recurrence (p = 0.007 and 0.02) and overall survival (p = 0.0063 and 0.023), even after adjustment for relevant clinical variables. HERC5 loss drives CCL20 mRNA and protein over-expression and associates with regulatory T cell infiltration as measured by FOXP3 expression. Further, matched primary and recurrent tumors from the 4 HCC patients indicated clonal selection advantage of Wnt signaling activation and CDKN2A inactivation.
  
  
  CONCLUSIONS
  HERC5 plays a crucial role in HCC immune evasion and has clinical relevance as a reproducible prognostic marker for risk of tumor recurrence and survival in patients.
authors.affiliation: Department of Liver Surgery and Liver Transplantation, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 201203, China. fengxue6879@163.com.
authors.forename: Feng
authors.initials: F
authors.lastname: Xue
authors.affiliation: Translational Bioinformatics, MedImmune, Gaithersburg, MD, 20878, USA. higgsb@medimmune.com.
authors.forename: Brandon W
authors.initials: BW
authors.lastname: Higgs
authors.affiliation: Translational Bioinformatics, MedImmune, Gaithersburg, MD, 20878, USA. jiaqihuang94041@yahoo.com.
authors.forename: Jiaqi
authors.initials: J
authors.lastname: Huang
authors.affiliation: Translational Bioinformatics, MedImmune, Gaithersburg, MD, 20878, USA. morehousec@medimmune.com.
authors.forename: Chris
authors.initials: C
authors.lastname: Morehouse
authors.affiliation: Translational Bioinformatics, MedImmune, Gaithersburg, MD, 20878, USA. weizhu365@gmail.com.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhu
authors.affiliation: Translational Bioinformatics, MedImmune, Gaithersburg, MD, 20878, USA. yaox@medimmune.com.
authors.forename: Xin
authors.initials: X
authors.lastname: Yao
authors.affiliation: Translational Bioinformatics, MedImmune, Gaithersburg, MD, 20878, USA. brohawnp@medimmune.com.
authors.forename: Philip
authors.initials: P
authors.lastname: Brohawn
authors.affiliation: Translational Bioinformatics, MedImmune, Gaithersburg, MD, 20878, USA. xiaoz@medimmune.com.
authors.forename: Zhan
authors.initials: Z
authors.lastname: Xiao
authors.affiliation: Translational Bioinformatics, MedImmune, Gaithersburg, MD, 20878, USA. sebastiany@medimmune.com.
authors.forename: Yinong
authors.initials: Y
authors.lastname: Sebastian
authors.affiliation: Translational Bioinformatics, MedImmune, Gaithersburg, MD, 20878, USA. zheng.r.liu@gmail.com.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Department of Liver Surgery and Liver Transplantation, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 201203, China. yunxia@163.com.
authors.forename: Yun
authors.initials: Y
authors.lastname: Xia
authors.affiliation: Translational Bioinformatics, MedImmune, Gaithersburg, MD, 20878, USA. shend@medimmune.com.
authors.forename: Dong
authors.initials: D
authors.lastname: Shen
authors.affiliation: Translational Bioinformatics, MedImmune, Gaithersburg, MD, 20878, USA. kuzioram@medimmune.com.
authors.forename: Mike
authors.initials: M
authors.lastname: Kuziora
authors.affiliation: Asia and Emerging Markets iMed, AstraZeneca R&D, 199 Liangjing Road, Shanghai, 201203, China. Harvey.Dong@astrazeneca.com.
authors.forename: Zhengwei
authors.initials: Z
authors.lastname: Dong
authors.affiliation: Asia and Emerging Markets iMed, AstraZeneca R&D, 199 Liangjing Road, Shanghai, 201203, China. Hulin.Han@astrazeneca.com.
authors.forename: Hulin
authors.initials: H
authors.lastname: Han
authors.affiliation: Asia and Emerging Markets iMed, AstraZeneca R&D, 199 Liangjing Road, Shanghai, 201203, China. Yi.Gu@astrazeneca.com.
authors.forename: Yi
authors.initials: Y
authors.lastname: Gu
authors.affiliation: Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 201203, China. nlorg@public.sta.net.cn.
authors.forename: Jianren
authors.initials: J
authors.lastname: Gu
authors.affiliation: Department of Liver Surgery and Liver Transplantation, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 201203, China. xiaqiang@medmail.com.cn.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Xia
authors.affiliation: Translational Bioinformatics, MedImmune, Gaithersburg, MD, 20878, USA. oliver_67@yahoo.com.
authors.forename: Yihong
authors.initials: Y
authors.lastname: Yao
mesh_terms: D014408:Biomarkers, Tumor / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000601:surgery*; D056915:DNA Copy Number Variations; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D008113:Liver Neoplasms / Q000601:surgery*; D016031:Liver Transplantation; D011379:Prognosis; D012008:Recurrence
chemical_list: D014408:Biomarkers, Tumor; C402395:HERC5 protein, human; D047908:Intracellular Signaling Peptides and Proteins