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.

Cancer Research UK London Research Institute 44 Lincoln's Inn Fields London UK

Danish Cancer Society Research Center Strandboulevarden 49 Copenhagen Denmark

Department of Physics of Complex Systems Weizmann Institute of Science Rehovot Israel

Institute of Molecular and Translational Medicine Palacky University Olomouc Czech republic

Molecular and Population Genetics and NIHR Biomedical Research Centre The Wellcome Trust Centre for Human Genetics Oxford UK

Science for Life Laboratory Division of Translational Medicine and Chemical Biology Department of Medical Biochemistry and Biophysics Karolinska Institutet Stockholm Sweden

UCL Cancer Institute Paul O'Gorman Building Huntley St London UK

University of Applied Sciences Mathematics and Techniques Remagen Germany

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Nature. 2013 Aug 22;500(7463):490 PubMed

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Nature. 2013 Feb 28;494(7438):439-41. doi: 10.1038/494439a. PubMed

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