title: Imaging mass spectrometry reveals modified forms of histone H4 as new biomarkers of microvascular invasion in hepatocellular carcinomas.
abstract: Microvascular invasion (MiVI) is a major risk factor in postoperative tumor recurrence and mortality in hepatocellular carcinoma (HCC). Unfortunately, this histological feature is usually missed by liver biopsy because of limited sampling, and MiVI is commonly detected only after surgery and examination of the full resected specimen. To date, there exists no reliable tool for identifying MiVI prior to surgical procedures. This study aimed to compare the proteome of HCC with and without MiVI in order to identify surrogate biomarkers of MiVI. A training cohort comprising surgically resected primary HCC with MiVI (n = 30) and without MiVI (n = 26) was subjected to matrix-assisted laser desorption ionization imaging mass spectrometry (MALDI IMS). Comparative analysis of acquired mass spectra of the two groups yielded 30 differential protein peaks, among which 28 were more strongly expressed in HCC with MiVI. Among these, two peaks were identified as N-term acetylated histone H4 dimethylated at lysine (K) 20, and N-term acetylated histone H4 dimethylated at K20 and acetylated at K16. Both peaks were validated in the training cohort and in an independent validation cohort (n = 23) by immunohistochemistry and western blot.
  
  
  CONCLUSIONS
  These results demonstrate the potential of MALDI IMS for uncovering new relevant biomarkers of MiVI in HCC, and highlight the role of epigenetic modifications in the prognosis of HCC. Preoperative detection of modified forms of histone H4 expression in tumor biopsies would be helpful in management of patients with HCC.
authors.affiliation: Pathology Department, Beaujon Hospital, Assistance Publique-Hôpitaux de Paris, Clichy, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Poté
authors.forename: Theodore
authors.initials: T
authors.lastname: Alexandrov
authors.forename: Julie
authors.initials: J
authors.lastname: Le Faouder
authors.forename: Samira
authors.initials: S
authors.lastname: Laouirem
authors.forename: Thibaut
authors.initials: T
authors.lastname: Léger
authors.forename: Mouniya
authors.initials: M
authors.lastname: Mebarki
authors.forename: Jacques
authors.initials: J
authors.lastname: Belghiti
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Camadro
authors.forename: Pierre
authors.initials: P
authors.lastname: Bedossa
authors.forename: Valérie
authors.initials: V
authors.lastname: Paradis
mesh_terms: D000368:Aged; D014408:Biomarkers, Tumor / Q000378:metabolism*; D001706:Biopsy; D006528:Carcinoma, Hepatocellular / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology; D015331:Cohort Studies; D019468:Disease Management; D005260:Female; D006657:Histones / Q000378:metabolism*; D006801:Humans; D008113:Liver Neoplasms / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000453:epidemiology / Q000378:metabolism*; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D011379:Prognosis; D012307:Risk Factors; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization / Q000379:methods*
chemical_list: D014408:Biomarkers, Tumor; D006657:Histones