title: Aberrant methylation within RUNX3 CpG island associated with the nuclear and mitochondrial microsatellite instability in sporadic gastric cancers. Results of a GOIM (Gruppo Oncologico dell'Italia Meridionale) prospective study.
abstract: BACKGROUND
  Gastric cancer (GC) development is a multistep process, during which numerous alterations accumulate in nuclear and mitochondrial DNA. A deficiency of repair machinery brings about an accumulation of errors introduced within simple repetitive microsatellite sequences during replication of DNA. Aberrant methylation is related to microsatellite instability (MSI) by the silencing of the hMLH1 gene. The aim of this study is to investigate a possible relationship between the RUNX3 promoter methylation, nuclear microsatellite instability (nMSI) and mitochondrial microsatellite instability (mtMSI), in order to clarify its biological role in GC.
  
  
  METHODS
  nMSI and mtMSI were evaluated in a consecutive series of 100 GC patients. For the analysis of the nMSI, we followed the National Cancer Institute guidelines. mtMSI was assessed by analyzing a portion of the displacement-loop region. The aberrant methylation of RUNX3 was analyzed in 40 GC patients by methylation-specific PCR.
  
  
  RESULTS
  Overall, 55% of GC demonstrated methylation of the RUNX3 promoter; 82% of GC was classified as stable microsatellite instability, 5% as low-level microsatellite instability and 13% as high-level microsatellite instability (MSI-H); mtMSI was detected in 11% of GC. A significant association was found between mtMSI and tumor-node-metastasis staging, furthermore an interesting association between MSI-H status, mtMSI and RUNX3 methylation.
  
  
  CONCLUSIONS
  These data suggest that RUNX3 is an important target of methylation in the evolution of mtMSI and nMSI-H GC.
authors.affiliation: Section of Medical Oncology, Department of Oncology, Università di Palermo, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Gargano
authors.forename: D
authors.initials: D
authors.lastname: Calcara
authors.forename: S
authors.initials: S
authors.lastname: Corsale
authors.forename: V
authors.initials: V
authors.lastname: Agnese
authors.forename: C
authors.initials: C
authors.lastname: Intrivici
authors.forename: F
authors.initials: F
authors.lastname: Fulfaro
authors.forename: G
authors.initials: G
authors.lastname: Pantuso
authors.forename: M
authors.initials: M
authors.lastname: Cajozzo
authors.forename: V
authors.initials: V
authors.lastname: Morello
authors.forename: R M
authors.initials: RM
authors.lastname: Tomasino
authors.forename: L
authors.initials: L
authors.lastname: Ottini
authors.forename: G
authors.initials: G
authors.lastname: Colucci
authors.forename: V
authors.initials: V
authors.lastname: Bazan
authors.forename: A
authors.initials: A
authors.lastname: Russo
mesh_terms: D000368:Aged; D002467:Cell Nucleus / Q000235:genetics* / Q000378:metabolism; D050677:Core Binding Factor Alpha 3 Subunit / Q000235:genetics* / Q000378:metabolism; D018899:CpG Islands / Q000235:genetics*; D019175:DNA Methylation; D004272:DNA, Mitochondrial / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D053842:Microsatellite Instability; D018895:Microsatellite Repeats / Q000235:genetics; D008875:Middle Aged; D011446:Prospective Studies; D013274:Stomach Neoplasms / Q000235:genetics* / Q000378:metabolism
chemical_list: D050677:Core Binding Factor Alpha 3 Subunit; D004272:DNA, Mitochondrial; C493729:Runx3 protein, human