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Neoplasia. 2019 Jul;21(7):721-729. doi: 10.1016/j.neo.2019.04.009. Epub 2019 Jun 4.

Induced Chromosomal Aneuploidy Results in Global and Consistent Deregulation of the Transcriptome of Cancer Cells.

Author information

1
Section of Cancer Genomics, Genetics Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD.
2
Laboratory of Cellular and Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD.
3
Department of Chemistry and Biochemistry and the Comprehensive Cancer Center, The Ohio State University, Columbus, OH.
4
High Dimension Data Analysis Group, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD.
5
Laboratory of Gastrointestinal and Pancreatic Oncology, Institut D'Investigacions Biomèdiques August Pi i Sunyer, Hospital Clínic of Barcelona, CIBERehd, Barcelona, Spain.
6
Laboratory of Gastrointestinal and Pancreatic Oncology, Institut D'Investigacions Biomèdiques August Pi i Sunyer, Hospital Clínic of Barcelona, CIBERehd, Barcelona, Spain. Electronic address: jcamps@clinic.ub.es.
7
Section of Cancer Genomics, Genetics Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD. Electronic address: riedt@mail.nih.gov.

Abstract

Chromosomal aneuploidy is a defining feature of epithelial cancers. The pattern of aneuploidies is cancer-type specific. For instance, the gain of chromosome 13 occurs almost exclusively in colorectal cancer. We used microcell-mediated chromosome transfer to generate gains of chromosome 13 in the diploid human colorectal cancer cell line DLD-1. Extra copies of chromosome 13 resulted in a significant and reproducible up-regulation of transcript levels of genes on chromosome 13 (P = .0004, FDR = 0.01) and a genome-wide transcriptional deregulation in all 8 independent clones generated. Genes contained in two clusters were particularly affected: the first cluster on cytoband 13q13 contained 7 highly up-regulated genes (NBEA, MAB21L1, DCLK1, SOHLH2, CCDC169, SPG20 and CCNA1, P = .0003) in all clones. A second cluster was located on 13q32.1 and contained five upregulated genes (ABCC4, CLDN10, DZIP1, DNAJC3 and UGGT2, P = .003). One gene, RASL11A, localized on chromosome band 13q12.2, escaped the copy number-induced overexpression and was reproducibly and significantly down-regulated on the mRNA and protein level (P = .0001, FDR = 0.002). RASL11A expression levels were also lower in primary colorectal tumors as compared to matched normal mucosa (P = .0001, FDR = 0.0001. Overexpression of RASL11A increases cell proliferation and anchorage independent growth while decreasing cell migration in +13 clones. In summary, we observed a strict correlation of genomic copy number and resident gene expression levels, and aneuploidy dependent consistent genome-wide transcriptional deregulation.

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