TPX2 and AURKA promote 20q amplicon-driven colorectal adenoma to carcinoma progression
- Anke H Sillars-Hardebol1,
- Beatriz Carvalho1,
- Marianne Tijssen1,
- Jeroen A M Beliën1,
- Meike de Wit1,
- Pien M Delis-van Diemen1,
- Fredrik Pontén2,
- Mark A van de Wiel3,4,
- Remond J A Fijneman1,
- Gerrit A Meijer1
- 1Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands
- 2Department of Genetics and Pathology, The Rudbeck Laboratory, Uppsala University, Uppsala, Sweden
- 3Department of Epidemiology and Biostatistics, VU University Medical Center, Amsterdam, The Netherlands
- 4Department of Mathematics, VU University, Amsterdam, The Netherlands
- Correspondence to Dr Remond J A Fijneman, VU University Medical Center, Department of Pathology, CCA 1.08, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands; rja.fijneman{at}vumc.nl
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Contributors 1. Study concept and design. 2. Acquisition of data. 3. Analysis and interpretation of data. 4. Drafting of the manuscript. 5. Critical revision of the manuscript for important intellectual content. 6. Statistical analysis. 7. Obtained funding. 8. Technical or material support. 9. Study supervision. AHS-H (1–6), BC (1, 3–6, 9), MT (2, 5, 8), JAMB (2, 3, 5), MdeW (2, 3, 5), PMD-vanD (2, 5, 8), FP (2, 3, 5, 8), MAvandeW (5, 6), RJAF (1, 3–6, 9), GAM (1, 3–7, 9).
- Revised 12 October 2011
- Accepted 14 October 2011
- Published Online First 29 December 2011
Abstract
Background and objective Progression of a colorectal adenoma to invasive cancer occurs in a minority of adenomas and is the most crucial step in colorectal cancer pathogenesis. In the majority of cases, this is associated with gain of a substantial part of chromosome 20q, indicating that multiple genes on the 20q amplicon may drive carcinogenesis. The aim of this study was to identify genes located on the 20q amplicon that promote progression of colorectal adenoma to carcinoma.
Design Functional assays were performed for 32 candidate driver genes for which a positive correlation between 20q DNA copy number and mRNA expression had been demonstrated. Effects of gene knockdown on cell viability, anchorage-independent growth, and invasion were analysed in colorectal cancer cell lines with 20q gain. Colorectal tumour protein expression was examined by immunohistochemical staining of tissue microarrays.
Results TPX2, AURKA, CSE1L, DIDO1, HM13, TCFL5, SLC17A9, RBM39 and PRPF6 affected cell viability and/or anchorage-independent growth. Chromosome 20q DNA copy number status correlated significantly with TPX2 and AURKA protein levels in a series of colorectal adenomas and carcinomas. Moreover, downmodulation of TPX2 and AURKA was shown to inhibit invasion.
Conclusion These data identify TPX2 (20q11) and AURKA (20q13.2) as two genes located on distinct regions of chromosome 20q that promote 20q amplicon-driven progression of colorectal adenoma to carcinoma. Therefore the selection advantage imposed by 20q gain in tumour progression is achieved by gain-of-function of multiple cancer-related genes—knowledge that can be translated into novel tests for early diagnosis of progressive adenomas.
- TPX2
- AURKA
- chromosome 20q gain
- colorectal adenoma to carcinoma progression
- colon carcinogenesis
- colorectal cancer
- colorectal cancer genes
- colorectal cancer screening
- colorectal carcinoma
- cancer
- adenoma
- molecular biology
- tumour markers
- gastric cancer
- genetic instability
- colonic adenomas
Footnotes
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Funding This work was supported by the Cancer Center Amsterdam and by the Aegon International Scholarship in Oncology.
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Competing interests None.
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Ethics approval This study was conducted with the approval of the medical ethics review board of the VU University Medical Center Amsterdam.
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Provenance and peer review Not commissioned; externally peer reviewed.
