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Cellular Oncology

, Volume 39, Issue 6, pp 545–558 | Cite as

DNA copy number alterations, gene expression changes and disease-free survival in patients with colorectal cancer: a 10 year follow-up

  • Elisabetta BigagliEmail author
  • Carlotta De Filippo
  • Cinzia Castagnini
  • Simona Toti
  • Francesco Acquadro
  • Francesco Giudici
  • Marilena Fazi
  • Piero Dolara
  • Luca Messerini
  • Francesco Tonelli
  • Cristina Luceri
Original Paper

Abstract

Background

DNA copy number alterations (CNAs) and gene expression changes have amply been encountered in colorectal cancers (CRCs), but the extent at which CNAs affect gene expression, as well as their relevance for tumor development, are still poorly defined. Here we aimed at assessing the clinical relevance of these parameters in a 10 year follow-up study.

Methods

Tumors and normal adjacent colon mucosa, obtained at primary surgery from 21 CRC patients, were subjected to (i) high-resolution array CGH (a-CGH) for the detection of CNAs and (ii) microarray-based transcriptome profiling for the detection of gene expression (GE) changes. Correlations between these genomic and transcriptomic changes and their associations with clinical and histopathological parameters were assessed with the aim to identify molecular signatures associated with disease-free survival of the CRC patients during a 10 year follow-up.

Results

DNA copy number gains were frequently detected in chromosomes 7, 8q, 13, 19, 20q and X, whereas DNA copy number losses were frequently detected in chromosomes 1p, 4, 8p, 15, 17p, 18, 19 and 22q. None of these alterations were observed in all samples. In addition, we found that 2,498 genes were up- and that 1,094 genes were down-regulated in the tumor samples compared to their corresponding normal mucosa (p < 0.01). The expression of 65 genes was found to be significantly associated with prognosis (p < 0.01). Specifically, we found that up-regulation of the IL17RA, IGF2BP2 and ABCC2 genes, and of genes acting in the mTOR and cytokine receptor pathways, were strongly associated with a poor survival. Subsequent integrated analyses revealed that increased expression levels of the MMP9, BMP7, UBE2C, I-CAM, NOTCH3, NOTCH1, PTGES2, HMGB1 and ERBB3 genes were associated with copy number gains, whereas decreased expression levels of the MUC1, E2F2, HRAS and SIRT3 genes were associated with copy number losses. Pathways related to cell cycle progression, eicosanoid metabolism, and TGF-β and apoptosis signaling, were found to be most significantly affected.

Conclusions

Our results suggest that CNAs in CRC tumor tissues are associated with concomitant changes in the expression of cancer-related genes. In other genes epigenetic mechanism may be at work. Up-regulation of the IL17RA, IGF2BP2 and ABCC2 genes, and of genes acting in the mTOR and cytokine receptor pathways, appear to be associated with a poor survival. These alterations may, in addition to Dukes' staging, be employed as new prognostic biomarkers for the prediction of clinical outcome in CRC patients.

Keywords

Colorectal cancer DNA copy number alterations Comparative genomic hybridization (CGH) Gene expression alterations Disease-free survival 

Notes

Acknowledgements

This project was financially supported by the AIRC (Associazione Italiana per la Ricerca sul Cancro) REGIONAL GRANT 2005.

Authors’ contributions

CL, EB, CDF, PD, FT conceived and designed the experiments. EB and CL wrote the paper. The following authors performed the experiments: EB and CDF: a-CGH analysis, CL: GE analysis, FA: statistical analyses of a-CGH data, CC, ST and CL: a-CGH and GE data analyses, MF, FG and FT: patient recruitment, follow-up and samples collection, LM: histopathological evaluations.

Compliance with ethical standards

Ethical statements

This study was conducted in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. A written informed consent was obtained from all patients involved in the study.

Conflict of interest

The authors declare that they have no conflict of interest.

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Copyright information

© International Society for Cellular Oncology 2016

Authors and Affiliations

  • Elisabetta Bigagli
    • 1
    Email author
  • Carlotta De Filippo
    • 2
  • Cinzia Castagnini
    • 1
  • Simona Toti
    • 3
  • Francesco Acquadro
    • 4
  • Francesco Giudici
    • 5
  • Marilena Fazi
    • 5
  • Piero Dolara
    • 1
  • Luca Messerini
    • 6
  • Francesco Tonelli
    • 5
  • Cristina Luceri
    • 1
  1. 1.Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA)University of FlorenceFlorenceItaly
  2. 2.Institute of Biometeorology (IBIMET)National Research Council (CNR)FlorenceItaly
  3. 3.ISTATRomeItaly
  4. 4.Molecular Cytogenetics Group, Human Cancer Genetics ProgramSpanish National Cancer Research Centre—CNIOMadridSpain
  5. 5.Department of Surgery and Translational MedicineUniversity of FlorenceFlorenceItaly
  6. 6.Department of Experimental and Clinical MedicineUniversity of FlorenceFlorenceItaly

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