Mutant Cohesin Drives Chromosomal Instability in Early Colorectal Adenomas

Hum Mol Genet. 2014 Dec 20;23(25):6773-8. doi: 10.1093/hmg/ddu394. Epub 2014 Jul 30.

Abstract

Chromosome missegregation leads to chromosomal instability (CIN), thought to play a role in cancer development. As cohesin functions in guaranteeing correct chromosome segregation, increasing data suggest its involvement in tumorigenesis. In a screen of a large series of early colorectal adenomas, a precocious step during colorectal tumorigenesis, we identified 11 mutations in SMC1A core cohesin subunit. In addition, we sequenced the SMC1A gene in colorectal carcinomas and we found only one mutation. Finally, the transfection of the SMC1A mutations identified in early adenomas and wild-type SMC1A gene silencing in normal human fibroblasts led to CIN. Our findings that SMC1A mutations decrease from early adenomas to colorectal cancers and that mutations lead to CIN suggest that mutant cohesin could play a pivotal role during colorectal cancer development.

MeSH terms

  • Adenoma / genetics*
  • Adenoma / metabolism
  • Adenoma / pathology
  • Aneuploidy
  • Carcinogenesis / genetics*
  • Carcinogenesis / metabolism
  • Carcinogenesis / pathology
  • Cell Cycle Proteins / antagonists & inhibitors
  • Cell Cycle Proteins / genetics*
  • Cell Cycle Proteins / metabolism
  • Chromosomal Instability
  • Chromosomal Proteins, Non-Histone / antagonists & inhibitors
  • Chromosomal Proteins, Non-Histone / genetics*
  • Chromosomal Proteins, Non-Histone / metabolism
  • Chromosome Segregation
  • Colorectal Neoplasms / genetics*
  • Colorectal Neoplasms / metabolism
  • Colorectal Neoplasms / pathology
  • Female
  • Fibroblasts / cytology
  • Fibroblasts / metabolism
  • Gene Expression
  • Humans
  • Karyotyping
  • Male
  • Mutation*
  • Precancerous Conditions / genetics*
  • Precancerous Conditions / metabolism
  • Precancerous Conditions / pathology
  • Primary Cell Culture
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • Retrospective Studies

Substances

  • Cell Cycle Proteins
  • Chromosomal Proteins, Non-Histone
  • RNA, Small Interfering
  • structural maintenance of chromosome protein 1