Mutant cohesin drives chromosomal instability in early colorectal adenomas

Francesco Cucco; Adele Servadio; Veronica Gatti; Paolo Bianchi; Linda Mannini; Andrea Prodosmo; Elisa De Vitis; Gianluca Basso; Alessandro Friuli; Luigi Laghi; Silvia Soddu; Gabriella Fontanini; Antonio Musio

doi:10.1093/hmg/ddu394

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.

Authors

Affiliations

¹ Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche, Pisa, Italy Dipartimento di Biologia, Università degli Studi di Pisa, Pisa, Italy.
² Dipartimento di Patologia Chirurgica, Medica, Molecolare e di Area Critica, Università di Pisa, Pisa, Italy.
³ Oncologia Sperimentale, Istituto Nazionale Tumori Regina Elena, Roma, Italy.
⁴ Humanitas Clinical and Research Center, Rozzano (MI), Italy and.
⁵ Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche, Pisa, Italy.
⁶ Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche, Pisa, Italy Istituto Toscano Tumori, Firenze, Italy [email protected].

PMID: 25080505
DOI: 10.1093/hmg/ddu394

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