title: The chromatin remodelling component SMARCB1/INI1 influences the metastatic behavior of colorectal cancer through a gene signature mapping to chromosome 22.
abstract: BACKGROUND
  INI1 (Integrase interactor 1), also known as SMARCB1, is the most studied subunit of chromatin remodelling complexes. Its role in colorectal tumorigenesis is not known.
  
  
  METHODS
  We examined SMARCB1/INI1 protein expression in 134 cases of colorectal cancer (CRC) and 60 matched normal mucosa by using tissue microarrays and western blot and categorized the results according to mismatch repair status (MMR), CpG island methylator phenotype, biomarkers of tumor differentiation CDX2, CK20, vimentin and p53. We validated results in two independent data sets and in cultured CRC cell lines.
  
  
  RESULTS
  Herein, we show that negative SMARCB1/INI1 expression (11% of CRCs) associates with loss of CDX2, poor differentiation, liver metastasis and shorter patients' survival regardless of the MMR status or tumor stage. Unexpectedly, even CRCs displaying diffuse nuclear INI1 staining (33%) show an adverse prognosis and vimentin over-expression, in comparison with the low expressing group (56%). The negative association of SMARCB1/INI1-lack of expression with a metastatic behavior is enhanced by the TP53 status. By interrogating global gene expression from two independent cohorts of 226 and 146 patients, we confirm the prognostic results and identify a gene signature characterized by SMARCB1/INI1 deregulation. Notably, the top genes of the signature (BCR, COMT, MIF) map on the long arm of chromosome 22 and are closely associated with SMARCB1/INI1.
  
  
  CONCLUSIONS
  Our findings suggest that SMARCB1/INI1-dysregulation and genetic hot-spots on the long arm of chromosome 22 might play an important role in the CRC metastatic behavior and be clinically relevant as novel biomarkers.
authors.affiliation: Department of Sciences and Technologies, University of Sannio, Via Port'Arsa, 11 82100 Benevento, Italy. massimo.pancione@unisannio.it.
authors.forename: Massimo
authors.initials: M
authors.lastname: Pancione
authors.forename: Andrea
authors.initials: A
authors.lastname: Remo
authors.forename: Caterina
authors.initials: C
authors.lastname: Zanella
authors.forename: Lina
authors.initials: L
authors.lastname: Sabatino
authors.forename: Arturo
authors.initials: A
authors.lastname: Di Blasi
authors.forename: Carmelo
authors.initials: C
authors.lastname: Laudanna
authors.forename: Laura
authors.initials: L
authors.lastname: Astati
authors.forename: Michele
authors.initials: M
authors.lastname: Rocco
authors.forename: Delfina
authors.initials: D
authors.lastname: Bifano
authors.forename: Paolo
authors.initials: P
authors.lastname: Piacentini
authors.forename: Laura
authors.initials: L
authors.lastname: Pavan
authors.forename: Alberto
authors.initials: A
authors.lastname: Purgato
authors.forename: Filippo
authors.initials: F
authors.lastname: Greco
authors.forename: Alberto
authors.initials: A
authors.lastname: Talamini
authors.forename: Andrea
authors.initials: A
authors.lastname: Bonetti
authors.forename: Michele
authors.initials: M
authors.lastname: Ceccarelli
authors.forename: Roberto
authors.initials: R
authors.lastname: Vendraminelli
authors.forename: Erminia
authors.initials: E
authors.lastname: Manfrin
authors.forename: Vittorio
authors.initials: V
authors.lastname: Colantuoni
mesh_terms: D000368:Aged; D014408:Biomarkers, Tumor / Q000378:metabolism; D002454:Cell Differentiation; D042002:Chromatin Assembly and Disassembly / Q000235:genetics*; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics / Q000378:metabolism*; D002892:Chromosomes, Human, Pair 22 / Q000235:genetics*; D015331:Cohort Studies; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism / Q000473:pathology; D008113:Liver Neoplasms / Q000473:pathology / Q000556:secondary; D008297:Male; D011379:Prognosis; D000071796:SMARCB1 Protein; D016019:Survival Analysis; D046888:Tissue Array Analysis; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; D000071796:SMARCB1 Protein; C513266:SMARCB1 protein, human; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53