Replication stress links structural and numerical cancer chromosomal instability

Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3LY, UK.
Nature (Impact Factor: 41.46). 02/2013; 494(7438):492-6. DOI: 10.1038/nature11935
Source: PubMed


Cancer chromosomal instability (CIN) results in an increased rate of change of chromosome number and structure and generates intratumour heterogeneity. CIN is observed in most solid tumours and is associated with both poor prognosis and drug resistance. Understanding a mechanistic basis for CIN is therefore paramount. Here we find evidence for impaired replication fork progression and increased DNA replication stress in CIN+ colorectal cancer (CRC) cells relative to CIN- CRC cells, with structural chromosome abnormalities precipitating chromosome missegregation in mitosis. We identify three new CIN-suppressor genes (PIGN (also known as MCD4), MEX3C (RKHD2) and ZNF516 (KIAA0222)) encoded on chromosome 18q that are subject to frequent copy number loss in CIN+ CRC. Chromosome 18q loss was temporally associated with aneuploidy onset at the adenoma-carcinoma transition. CIN-suppressor gene silencing leads to DNA replication stress, structural chromosome abnormalities and chromosome missegregation. Supplementing cells with nucleosides, to alleviate replication-associated damage, reduces the frequency of chromosome segregation errors after CIN-suppressor gene silencing, and attenuates segregation errors and DNA damage in CIN+ cells. These data implicate a central role for replication stress in the generation of structural and numerical CIN, which may inform new therapeutic approaches to limit intratumour heterogeneity.

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Available from: Charles Swanton, Oct 12, 2014
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    • "Amplified or deleted regions that do not contain known drivers of tumorigenesis may direct the future detection of novel oncogenes or tumor suppressor genes, respectively. For example, a recent study has indicated that the loss of chromosome arm 18q is associated with the onset of aneuploidy during colorectal carcinogenesis and has identified three novel tumor suppressor genes in this region (Burrell et al., 2013). While our analysis showed that the frequency of chromosomal aberration was higher in carcinomas than adenomas, it was evident that on an individual sample basis, there were carcinomas with few aberrations and also a few adenomas with many aberrations. "
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    ABSTRACT: The progression of benign colorectal adenomas into cancer is associated with the accumulation of chromosomal aberrations. Even though patterns and frequencies of chromosomal aberrations have been well established in colorectal carcinomas, corresponding patterns of aberrations in adenomas are less well documented. The aim of this study was to profile chromosomal aberrations across colorectal adenomas and carcinomas to provide a better insight into key changes during tumor initiation and progression. Single nucleotide polymorphism array analysis was performed on 216 colorectal tumor/normal matched pairs, comprising 60 adenomas and 156 carcinomas. While many chromosomal aberrations were specific to carcinomas, those with the highest frequency in carcinomas (amplification of chromosome 7, 13q, and 20q; deletion of 17p and chromosome 18; LOH of 1p, chromosome 4, 5q, 8p, 17p, chromosome 18, and 20p) were also identified in adenomas. Hierarchical clustering using chromosomal aberrations revealed three distinct subtypes. Interestingly, these subtypes were only partially dependent on tumor staging. A cluster of colorectal cancer patients with frequent chromosomal deletions had the least favorable prognosis, and a number of adenomas (n = 9) were also present in the cluster suggesting that, at least in some tumors, the chromosomal aberration pattern is determined at a very early stage of tumor formation. Finally, analysis of LOH events revealed that copy-neutral/gain LOH (CN/G-LOH) is frequent (>10%) in carcinomas at 5q, 11q, 15q, 17p, chromosome 18, 20p, and 22q. Deletion of the corresponding region is sometimes present in adenomas, suggesting that LOH at these loci may play an important role in tumor initiation. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.
    Genes Chromosomes and Cancer 02/2015; 54(5). DOI:10.1002/gcc.22243 · 4.04 Impact Factor
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    • "MEX3C contributes to genetic susceptibility to hypertension , as shown by linkage analysis and association studies (Guzman et al. 2006). It is also a cancer chromosomal instability-repressor gene (Burrell et al. 2013). The mechanisms for both observations are unknown. "
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    ABSTRACT: MEX3C is an RNA-binding protein with unknown physiological function. We recently reported that a Mex3c mutation in mice causes growth retardation and reduced adiposity, but how adiposity is reduced remains unclear. Here we show that homozygous Mex3c gene trap mice have increased physical activity. The Mex3c mutation consistently conferred full protection from diet-induced obesity, hyperglycemia, insulin resistance, hyperlipidemia, and hepatic steatosis. In ob/ob mice with leptin deficiency, the Mex3c mutation also increased physical activity and improved glucose and lipid profiles. Expressing cre in neurons of Mex3c gene trap mice, an attempt to partially restoring neuronal Mex3c expression, significantly increased white adipose tissue deposition, but had no effects on body length. Our data suggest that one way in which Mex3c regulates adiposity is through controlling physical activity, and that neuronal Mex3c expression could play an important role in this process.
    Journal of Endocrinology 04/2014; DOI:10.1530/JOE-14-0071 · 3.72 Impact Factor
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    • "Since chromosome missegregation was shown to trigger oxidative stress [24,33], we analysed the transcriptional response to oxidative stress inducers nitric oxide and hydrogen dioxide. Aneuploidy was also recently linked to DNA damage and replication stress [34], therefore we analyzed the response to the replication inhibitor hydroxyurea and transcription inhibition by actinomycin D. Further, aneuploidy was shown to trigger proteotoxic stress and to activate autophagy [3,15,30,31]. Therefore, we compared the response to aneuploidy to the transcriptional changes elicited by cells grown under hypoxic conditions, which is known to result in energy and ER stress with subsequent proteotoxic stress. "
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    ABSTRACT: Aneuploidy, a karyotype deviating from multiples of a haploid chromosome set, affects the physiology of eukaryotes. In humans, aneuploidy is linked to pathological defects such as developmental abnormalities, mental retardation or cancer, but the underlying mechanisms remain elusive. There are many different types and origins of aneuploidy, but whether there is a uniform cellular response to aneuploidy in human cells has not been addressed so far. Here we evaluate the transcription profiles of eleven trisomic and tetrasomic cell lines and two cell lines with complex aneuploid karyotypes. We identify a characteristic aneuploidy response pattern defined by upregulation of genes linked to endoplasmic reticulum, Golgi apparatus and lysosomes, and downregulation of DNA replication, transcription as well as ribosomes. Strikingly, complex aneuploidy elicits the same transcriptional changes as trisomy. To uncover the triggers of the response, we compared the profiles with transcription changes in human cells subjected to stress conditions. Interestingly, we found an overlap only with the response to treatment with the autophagy inhibitor bafilomycin A1. Finally, we identified 23 genes whose expression is significantly altered in all aneuploids and which may thus serve as aneuploidy markers. Our analysis shows that despite the variability in chromosome content, aneuploidy triggers uniform transcriptional response in human cells. A common response independent of the type of aneuploidy might be exploited as a novel target for cancer therapy. Moreover, the potential aneuploidy markers identified in our analysis might represent novel biomarkers to assess the malignant potential of a tumor.
    BMC Genomics 02/2014; 15(1):139. DOI:10.1186/1471-2164-15-139 · 3.99 Impact Factor
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