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Open Access Research article

The use of whole genome amplification to study chromosomal changes in prostate cancer: insights into genome-wide signature of preneoplasia associated with cancer progression

Simon Hughes1, Maisa Yoshimoto1, Ben Beheshti2, Richard S Houlston3, Jeremy A Squire146* and Andrew Evans56

Author Affiliations

1 Applied Molecular Oncology, Ontario Cancer Institute, Princess Margaret Hospital, Toronto, Ontario M5G 2M9, Canada

2 Faculty of Medicine, University of Toronto, Toronto, Ontario M5G 2M9, Canada

3 Section of Cancer Genetics, Institute of Cancer Research, Sutton SM2 5NG, UK

4 Department of Medical Biophysics, Faculty of Medicine, University of Toronto, Toronto, Ontario M5G 2M9, Canada

5 Department of Pathology, Princess Margaret Hospital, Toronto, Ontario M5G 2M9, Canada

6 Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5G 1L5, Canada

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BMC Genomics 2006, 7:65  doi:10.1186/1471-2164-7-65

Published: 30 March 2006

Abstract

Background

Prostate cancer (CaP) is a disease with multifactorial etiology that includes both genetic and environmental components. The knowledge of the genetic basis of CaP has increased over the past years, mainly in the pathways that underlie tumourigenesis, progression and drug resistance. The vast majority of cases of CaP are adenocarcinomas that likely develop through a pre-malignant lesion and high-grade prostatic intraepithelial neoplasia (HPIN). Histologically, CaP is a heterogeneous disease consisting of multiple, discrete foci of invasive carcinoma and HPIN that are commonly interspersed with benign glands and stroma. This admixture with benign tissue can complicate genomic analyses in CaP. Specifically, when DNA is bulk-extracted the genetic information obtained represents an average for all of the cells within the sample.

Results

To minimize this problem, we obtained DNA from individual foci of HPIN and CaP by laser capture microdissection (LCM). The small quantities of DNA thus obtained were then amplified by means of multiple-displacement amplification (MDA), for use in genomic DNA array comparative genomic hybridisation (gaCGH). Recurrent chromosome copy number abnormalities (CNAs) were observed in both HPIN and CaP. In HPIN, chromosomal imbalances involving chromosome 8 where common, whilst in CaP additional chromosomal changes involving chromosomes 6, 10, 13 and 16 where also frequently observed.

Conclusion

An overall increase in chromosomal changes was seen in CaP compared to HPIN, suggesting a universal breakdown in chromosomal stability. The accumulation of CNAs, which occurs during this process is non-random and may indicate chromosomal regions important in tumourigenesis. It is therefore likely that the alterations in copy number are part of a programmed cycle of events that promote tumour development, progression and survival. The combination of LCM, MDA and gaCGH is ideally suited for the identification of CNAs from small cell clusters and may assist in the discovery of potential genomic markers for early diagnosis, or identify the location of tumour suppressor genes (TSG) or oncogenes previously unreported in HPIN and CaP.