Mutant cohesin drives chromosomal instability in early colorectal adenomas

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.

Chromosomal Instability in Tumor Initiation and Development

“…Cohesin, best known for its function in chromosome segregation, has been found to play a role in cancer progression (48). Sequencing of cancer genomes has also revealed the presence of somatic mutations in cohesin in various cancers.…”

Big Bang Tumor Growth and Clonal Evolution

“…Indeed, Boveri proposed that chromosomal instability (CIN), resulting from whole or partial chromosomal gains and losses, was a critical event in tumorigenesis more than a century ago (Boveri and Boveri 1929). CIN may occur relatively early based on its prevalence in premalignancy (Rabinovitch et al 1989;Heaphy et al 2009;Cucco et al 2014). For example, genomic instability was shown to increase in atypical ductal hyperplasia (ADH) relative to normal tissue but to plateau in DCIS to invasive disease, suggesting that invasive carcinomas evolve from or in parallel to DCIS (Heaphy et al 2009).…”

Genome stability: What we have learned from cohesinopathies

“…In particular, alterations of genes belonging to the cohesin network have been reported in several types of cancer [Mannini et al, ; Mannini and Musio, ; Losada, ]. Moreover, mutations in cohesin factors have been associated with specific tumor stages and grades [Cucco et al, ; Taylor et al, ]. Interestingly, a recent report showed that genomic cohesin‐binding sites are frequently mutated in colorectal cancer samples [Katainen et al, ], corroborating the key role of cohesin dysfunctions in cancer development and progression.…”

“…In addition, in recent years mutations in core cohesin genes and auxiliary factors have been associated with carcinogenesis (Table , Fig. ) [Barber et al, ; Solomon et al, ; Welch et al, ; Balbas‐Martinez et al, ; Kon et al, ; Brohl et al, ; Cucco et al, ; Viny et al, ]. GIN is a well‐established hallmark of cancer cell phenotypes and for some cancers, such as colorectal carcinoma, it is predictive of a poor prognosis [Carter et al, ].…”

“…Experimental evidence indicates that cohesin pathway is a convergent hub for many biological processes intrinsically connected: sister chromatid cohesion, genome organization, gene expression regulation, DNA repair, and genome safeguarding [Michaelis et al, ; Parelho et al, ; Bauerschmidt et al, ; Kagey et al, ; Caron et al, ; Cipressa et al, ; Gelot et al, ]. The identification of both germinal and somatic mutations in cohesin genes in human developmental disorders, collectively termed cohesinopathies [Krantz et al, ; Tonkin et al, ; Schule et al, ; Vega et al, ; Musio et al, ; Deardorff et al, , ,; van der Lelij et al, ; Chetaille et al, ; Kaiser et al, ], and cancers including colon and bladder cancer and leukemia [Barber et al, ; Solomon et al, ; Welch et al, ; Kon et al, ; Cucco et al, ], all characterized by GIN, indicates that cohesin may be a pivotal actor in preserving genome stability. Taking this information as guide, we review the ways that the study of cohesinopathies can contribute to our understanding of GIN mechanisms.…”