Chromosome 20p11 gains are associated with liver-specific metastasis in patients with colorectal cancer
- Leonie J M Mekenkamp1,2,
- Josien C Haan3,
- Miriam Koopman4,
- M Elisa Vink-Börger1,
- Daniëlle Israeli3,
- Steven Teerenstra5,
- Bauke Ylstra3,
- Gerrit A Meijer3,
- Cornelis J A Punt2,6,
- Iris D Nagtegaal1
- 1Department of Pathology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
- 2Department of Medical Oncology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
- 3Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands
- 4Department of Medical Oncology, University Medical Center Utrecht, Utrecht, The Netherlands
- 5Department of Epidemiology, Biostatistics and Health Technology Assessment, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
- 6Department of Medical Oncology, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands
- Correspondence to Dr Iris D Nagtegaal, Department of Pathology, Radboud University Nijmegen Medical Centre, PO Box 9101, 6500 HB Nijmegen, The Netherlands;
Contributors LJMM, JCH, MEVK and DI carried out the experiments. LJMM, JCH, MEVK, MK, DI, ST, BY and IDN analysed and interpreted data. LJMM, JCH, GAM, CJAP and IDN were responsible for the study design and wrote the paper. JCH, MK, MEVK, DI, ST, BY, GAM, CJA and IDN revised the manuscript critically. All authors were involved in editing the paper and gave final approval of the submitted and published versions.
- Revised 6 December 2011
- Accepted 21 December 2011
- Published Online First 20 January 2012
Objective Metastatic colorectal cancer (CRC) cells have a selective preference for certain target organs that cannot be explained by circulatory patterns alone. This study aimed to identify clinicopathological features and chromosomal aberrations of primary tumours associated with organ-specific CRC metastasis.
Design Clinicopathological features were investigated in patients with CRC who had exclusively hepatic (n=182) versus exclusively extrahepatic (n=139) metastases. A total of 139 primary tumours of patients with hepatic (n=85) and extrahepatic metastases (n=54) were screened for chromosomal aberrations by microarray-based comparative genomic hybridisation, and the findings were validated in an independent set of 80 primary tumours. A publicly available database was used to correlate chromosomal aberrations with gene expression. Protein expression was evaluated by immunohistochemistry on tissue microarrays.
Results Patients with hepatic metastases were significantly more often male (71% vs 53% p=0.002), more often had abnormal lactate dehydrogenase activity (37% vs 14% p<0.0001), exhibited primary tumour localisation in the colon (52% vs 40% p=0.03) and had synchronous onset of metastases (70% vs 19% p<0.0001). Primary tumours of patients with hepatic metastases were more commonly T3 tumours (79% vs 63% p=0.006) and less commonly of mucinous histology (5% vs 16% p=0.02). Gain of 20p11 was more often observed in patients with hepatic metastases (p<0.05), which was confirmed in an independent dataset (p<0.05; false discovery rate <0.05). Twelve genes mapping at 20p11 were significantly overexpressed as a consequence of 20p11 copy number gain. C20orf3 showed the strongest correlation between RNA expression and DNA copy number. This was reflected in significantly higher protein expression in patients with hepatic metastases (59%; n=325) than in those with extrahepatic metastases (41%; n=256) (p=0.01).
Conclusion C20orf3 mapping at 20p11 is associated with hepatic-specific metastasis in patients with CRC. This gene is a candidate biomarker for liver metastases and may be of clinical value in early-stage CRC.
- Colorectal cancer
- hepatic metastasis
- extrahepatic metastasis
- genomic aberration
- colorectal metastases
- colorectal cancer genes
- liver metastases
- colorectal pathology
- tumour markers
- colon carcinogenesis
- gastric cancer
- genetic instability
- colonic adenomas
- surgical oncology
- small intestine cancer
- colorectal adenomas
Funding Dutch Colorectal Cancer Group. This funder had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests None.
Ethics approval The two randomised clinical trials were approved by the Committee on Human-Related Research Arnhem—Nijmegen and by the local institutional review boards. The written informed consent required for all patients before study entry also included translational research on tumour tissue.
Provenance and peer review Not commissioned; externally peer reviewed.