CGH microarrays and cancer
Introduction
DNA copy number changes are common in cancer and lead to altered expression and function of genes residing within the affected region of the genome. Traditionally, such segments in the tumor genome are thought to harbor either oncogenes or tumor suppressor genes depending on whether they are present in increased or decreased copy number, respectively. Identification of regions with copy number aberrations and especially the genes involved thus offers a basis for better understanding of cancer development and more importantly is likely to provide improved tools for clinical management of cancer, such as new diagnostics and therapeutic targets.
Comparative genomic hybridization (CGH) technique was developed in the early 1990s for genome-wide characterization of copy number changes, especially in cancer [1]. In this technique, total genomic DNA is isolated from tumor and normal control cells, labeled with different fluorochromes and hybridized to normal metaphase chromosomes. Differences in the tumor to normal fluorescence ratio along the metaphase chromosomes are then quantitated and reflect changes in the DNA sequence copy number in the tumor genome. Subsequently array-based CGH (aCGH), where arrays of genomic sequences replaced the metaphase chromosomes as hybridization targets, was established [2, 3, 4] and solved many of the technical difficulties and problems caused by working with cytogenetic chromosome preparations. The main advantage of aCGH is, however, the ability to perform copy number analyses with much higher resolution than was ever possible using chromosomal CGH [5, 6, 7].
Different kinds of aCGH platforms are currently available ranging from arrayed bacterial artificial chromosome (BAC) clones to cDNA clones and various oligonucleotide-based formats [5, 6, 7]. The technical and methodological issues of aCGH as well as the general applications of this technology both in cancer research and in human genetics have been recently discussed in several excellent reviews [5, 6, 7]. This article will concentrate on recent discoveries obtained in cancer research through the aCGH approach and will especially focus on studies published within a two-year period from 2005 to 2007. The use of aCGH for genome-wide screening of copy number changes as well as for targeted analyses of specific regions of interest will be discussed. Studies with more focused applications, such as tumor classification or identification of specific copy number changes associated with clinicopathological tumor characteristics, tumor progression, patient outcome, and therapy response, will also be covered (Figure 1).
Section snippets
Global analysis of copy number aberrations and identification of putative target genes
A vast number of tumor samples representing both common tumor types, such as breast [8, 9, 10, 11] and colorectal cancers [12, 13], as well as more rare tumor entities, including gastrointestinal stromal tumors [14, 15, 16], insulinomas [17], and ependymomas [18], have been analyzed in genome-wide aCGH studies. These studies have sought to provide a comprehensive high-resolution view of copy number changes in various tumor types and have provided a wealth of new information on the patterns of
Tumor classification by aCGH
Previous genome-wide copy number analyses have indicated that different tumor types typically possess more or less specific sets of genetic changes although some individual aberrations, such as amplification of the ERBB2 locus at 17q12, can indeed be observed across multiple tumor types. To specifically explore the utility of copy number patterns for tumor classification, Jong et al. performed a meta-analysis combining aCGH data from 373 primary tumors obtained using three different array
Clinical significance of copy number changes in cancer
Association of specific genetic changes or patterns of changes to known tumor characteristics, tumor progression, or patient outcome has been one area of interest in aCGH studies. As might be expected, comparison of tumor samples representing different stages of tumor development, such as premalignant or in situ lesions, invasive cancers, and metastatic disease, has demonstrated that the overall number of copy number changes increases during tumor progression [10, 17, 38, 39, 40, 41, 42]. For
Conclusions
During the past two years, a large number of studies utilizing the aCGH technology in cancer have been published. These studies highlight the overall patterns of copy number aberrations in various tumor types and identify in high-resolution-specific genetic alterations associated with certain tumor entities, disease progression, therapy response, or patient outcome. Thereby aCGH data provide an excellent starting point for the identification of genes involved in these aberrations. However, it
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
The work presented in this paper was supported partly by the Finnish Cancer Organizations and the Medical Research Fund of Tampere University Hospital.
References (51)
- et al.
Recurrent genomic alterations with impact on survival in colorectal cancer identified by genome-wide array comparative genomic hybridization
Gastroenterology
(2006) - et al.
Identification of homozygous deletions of tumor suppressor gene FAT in oral cancer using CGH-array
Oncogene
(2007) - et al.
Assessment of differentiation and progression of hepatic tumors using array-based comparative genomic hybridization
Clin Gastroenterol Hepatol
(2006) - et al.
Combined cDNA array comparative genomic hybridization and serial analysis of gene expression analysis of breast tumor progression
Cancer Res
(2006) - et al.
Increasing genomic instability during premalignant neoplastic progression revealed through high resolution array-CGH
Gene Chromosome Canc
(2007) - et al.
Array comparative genomic hybridization reveals genomic copy number changes associated with outcome in diffuse large B-cell lymphomas
Blood
(2006) - et al.
Whole genome oligonucleotide-based array comparative genomic hybridization analysis identified fibroblast growth factor 1 as a prognostic marker for advanced-stage serous ovarian adenocarcinomas
J Clin Oncol
(2007) - et al.
Comparative genomic hybridization for molecular cytogenetic analysis of solid tumors
Science
(1992) - et al.
Matrix-based comparative genomic hybridization: biochips to screen for genomic imbalances
Gene Chromosome Canc
(1997) - et al.
High resolution analysis of DNA copy number variation using comparative genomic hybridization to microarrays
Nat Genet
(1998)