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Mechanistic insight into chromosomal instability in colorectal cancer
▸ Burrell RA, McClelland SE, Endesfelder D, et al. Replication stress links structural and numerical cancer chromosomal instability. Nature 2013;494:492–6.
Chromosomal instability (CIN) results in the accumulation of numeric and structural chromosomal aberrations, and is a feature of a large proportion of colorectal cancers (CRCs). The mechanisms underlying CIN, however, remain obscure. A recent study by Burrell and colleagues has implicated replication stress as a driver of CIN in CRC. High-resolution images of anaphases of CIN positive CRC cells revealed that mitotic dysfunction was infrequent in CIN positive cells and that most chromosome segregation errors occurred through abnormal chromosome structure. The cause of these structural aberrations was postulated to be replication stress. Chemical induction of replication stress in CIN negative cells resulted in structural chromosome anomalies and segregation errors. DNA fibre assays revealed that CIN positive cell lines demonstrated impaired replication fork progression. The authors hypothesised that regions of frequent copy number loss may harbour genes that contribute to the CIN phenotype. Using comparative genomic hybridisation on CRC cell lines and tumours, copy number loss at chromosome 18q was most frequently associated with CIN positivity. Short interfering RNAs were used to silence 94 of the most frequently lost genes at 18q in CIN positive cell lines. Targeting PIGN, MEX3C and ZNF516 resulted in segregation errors, and was associated with an increase in markers of replication stress. When cells were supplemented with nucleosides, to overcome replication stress, CIN-suppressor gene silencing-induced segregation errors were attenuated. These data implicate specific genes in the pathogenesis of CIN, and demonstrate a key role for replication stress in the accumulation of chromosomal abnormalities. Replication stress may therefore represent a target for limiting tumour evolution and intra-tumoural heterogeneity.
Unexpected protective function of NOD2 against intestinal inflammation and tumourigenesis
▸ Couturier-Maillard A, Secher T, Rehman A, et al. NOD2-mediated dysbiosis predisposes mice to transmissible …