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

Darawalee Wangsa; Rüdiger Braun; Christina H. Stuelten; Markus Brown; Kerry M. Bauer; Georg Emons; Leigh A. Weston; Yue Hu; Howard H. Yang; Maria Vila-Casadesús; Maxwell P. Lee; Philip Brauer; Lidia Warner; Madhvi Upender; Amanda B. Hummon; Jordi Camps; Thomas Ried

doi:10.1016/j.neo.2019.04.009

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

Darawalee Wangsa, Rüdiger Braun, Christina H. Stuelten, Markus Brown, Kerry M. Bauer, Georg Emons, Leigh A. Weston, Yue Hu, Howard H. Yang, Maria Vila-Casadesús, Maxwell P. Lee, Philip Brauer, Lidia Warner, Madhvi Upender, Amanda B. Hummon, Jordi Camps^*, Thomas Ried

^*Corresponding author for this work

Clinic of Surgery

19 Citations (Scopus)

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.

Original language	English
Journal	Neoplasia (United States)
Volume	21
Issue number	7
Pages (from-to)	721-729
Number of pages	9
ISSN	1522-8002
DOIs	https://doi.org/10.1016/j.neo.2019.04.009
Publication status	Published - 01.07.2019

Funding

The study was supported by the Intramural Research Program, National Cancer Institute/NIH. RB was supported by the Deutsche Krebshilfe, GE through the Deutsche Forschungsgemeinschaft. This work was supported by the Instituto de Salud Carlos III and co-funded by the European Regional Development Fund (ERDF) [CP13/00160, CPII18/00026, PI14/00783]; the CIBEREHD program; the CERCA Program (Generalitat de Catalunya); the Agència de Gestió d'Ajuts Universitaris i de Recerca, Generalitat de Catalunya [2017 SGR 1035]. R.B. was supported by a Mildred Scheel postdoctoral scholarship of the German Cancer Aid (Deutsche Krebshilfe).

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Research Areas and Centers

Research Area: Luebeck Integrated Oncology Network (LION)

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Cite this

Wangsa, D., Braun, R., Stuelten, C. H., Brown, M., Bauer, K. M., Emons, G., Weston, L. A., Hu, Y., Yang, H. H., Vila-Casadesús, M., Lee, M. P., Brauer, P., Warner, L., Upender, M., Hummon, A. B., Camps, J., & Ried, T. (2019). Induced Chromosomal Aneuploidy Results in Global and Consistent Deregulation of the Transcriptome of Cancer Cells. Neoplasia (United States), 21(7), 721-729. https://doi.org/10.1016/j.neo.2019.04.009

@article{075654d12f4046db924ee1b3c629f25c,

title = "Induced Chromosomal Aneuploidy Results in Global and Consistent Deregulation of the Transcriptome of Cancer Cells",

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.",

author = "Darawalee Wangsa and R{\"u}diger Braun and Stuelten, \{Christina H.\} and Markus Brown and Bauer, \{Kerry M.\} and Georg Emons and Weston, \{Leigh A.\} and Yue Hu and Yang, \{Howard H.\} and Maria Vila-Casades{\'u}s and Lee, \{Maxwell P.\} and Philip Brauer and Lidia Warner and Madhvi Upender and Hummon, \{Amanda B.\} and Jordi Camps and Thomas Ried",

note = "Copyright {\textcopyright} 2019. Published by Elsevier Inc.",

year = "2019",

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doi = "10.1016/j.neo.2019.04.009",

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Wangsa, D, Braun, R, Stuelten, CH, Brown, M, Bauer, KM, Emons, G, Weston, LA, Hu, Y, Yang, HH, Vila-Casadesús, M, Lee, MP, Brauer, P, Warner, L, Upender, M, Hummon, AB, Camps, J & Ried, T 2019, 'Induced Chromosomal Aneuploidy Results in Global and Consistent Deregulation of the Transcriptome of Cancer Cells', Neoplasia (United States), vol. 21, no. 7, pp. 721-729. https://doi.org/10.1016/j.neo.2019.04.009

TY - JOUR

T1 - Induced Chromosomal Aneuploidy Results in Global and Consistent Deregulation of the Transcriptome of Cancer Cells

AU - Wangsa, Darawalee

AU - Braun, Rüdiger

AU - Stuelten, Christina H.

AU - Brown, Markus

AU - Bauer, Kerry M.

AU - Emons, Georg

AU - Weston, Leigh A.

AU - Hu, Yue

AU - Yang, Howard H.

AU - Vila-Casadesús, Maria

AU - Lee, Maxwell P.

AU - Brauer, Philip

AU - Warner, Lidia

AU - Upender, Madhvi

AU - Hummon, Amanda B.

AU - Camps, Jordi

AU - Ried, Thomas

PY - 2019/7/1

Y1 - 2019/7/1

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/85066481076

U2 - 10.1016/j.neo.2019.04.009

DO - 10.1016/j.neo.2019.04.009

M3 - Journal articles

C2 - 31174021

AN - SCOPUS:85066481076

SN - 1522-8002

VL - 21

SP - 721

EP - 729

JO - Neoplasia (United States)

JF - Neoplasia (United States)

IS - 7

ER -

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

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