Editorial

Comparative Genomic Hybridization:FISH and Chips in our Future?

Comparative genomic hybridization (CGH) is one ofthe newest items in the cytogeneticist’s toolbox. Unlikestandard fluorescence in situ hybridization (FISH) us-ing region-specific probes, or DNA studies using geneticmarkers, CGH requires no prejudgment as to whatgenomic regions are likely to be involved, and does notrequire metaphase chromosome preparations from thetissue to be studied. In the six years since the techniquewas first described by Kallioniemi et al. (’92), it hasproved to be a valuable research method for genome-wide scanning for regions of genomic amplification ordeletion, in tissues where standard cytogenetics isdifficult or impossible. So far the chief application hasbeen in tumor genetics research, where it has been usedto define sets of genomic changes associated withparticular tumors or stages of tumor progression, andto identify previously unknown regions that are likelysites of tumor-related genes.

While CGH does not require more than a standardthree-color fluorescent filter set, it is quite a difficulttechnique to master, subject to problems of reproducibil-ity and dependent upon a dedicated software for appro-priate analysis. CGH has therefore not been widelyadopted for clinical use. Although recently severalreports have described applications to common prob-lems such as the identification of supernumerary chro-mosome markers or unbalanced rearrangements (Grif-fin et al., ’98; Levy et al., ’98), it is likely that one of themulticolor FISH painting techniques will turn out to bethe method of choice for identification of most segmen-tal aneuploidies, when chromosomal preparations areavailable.

However, there are many areas of nontumor cytoge-netics where CGH could provide information whenchromosome preparations cannot be made or are unreli-able. Archived material in paraffin blocks could be usedto scan for aneuploidy in cases of spontaneous abortionor neonatal death. CGH could also be used directly onDNA from fresh fetal material, to avoid the commonproblems of culture failure or growth of maternaltissue. In this issue, Lestou et al. (’99) describe the firstapplication of CGH to the problem of detection ofmosaic aneuploidy in placental tissue. Given the clini-cal relevance and relatively high frequency of undetec-ted placental chromosomal mosaicism that has been sowell-documented by Kalousek and others (Kalousek

and Vekemans, ’96; Robinson et al., ’97), screening ofplacentas in this way might be valuable in cases ofintrauterine growth retardation or to investigate prena-tally detected mosaicism.

Using CGH, Lestou et al. (’99) were able to detecttrisomy mosaicism in 39 of 40 tissues known to haveeither mosaic trisomy 7 or 16 by FISH. However, thisrequired interpreting any shift at all away from theexpected ratio of 1.0 as true mosaicism. It is likely thatusing this criterion in an ‘‘unknown’’ situation may leadto false-positive results, given the considerable variabil-ity inherent in the technique. This variability is demon-strated by the reported lack of relationship between thedegree of deviation from the ratio of 1.0 and thepercentage of aneuploidy as determined by FISH. Thisstudy provides a very impressive demonstration of thesensitivity of the technique to detect a known aneu-ploidy, but does not address the specificity of the test,nor its sensitivity when the chromosome involved is notpreviously known. These are important questions to beanswered before CGH can be widely applied to clinicaldiagnosis. A complete test of the procedure wouldrequire a study done blind to the particular aneuploidyinvolved, and using placentas both with and withoutknown mosaic aneuploidy.

Although originally devised to be applied to meta-phase chromosomes as a template, CGH promises tohave many more widespread applications for futuregenetic research and diagnosis. The development ofDNA ‘‘chips’’ for the comparison of two samples dependsupon the same principles of competitive hybridizationof differentially labeled probes, and the use of micro-scopically determined fluorescence ratios for their analy-sis. This technology has great potential for the precisedetection of segmental aneuploidy through the use ofarrayed genomic clones, as well as for the comparison oftissue and time-dependent gene expression througharrayed cDNA clones. Potential for automated micro-scopic scanning is an inherent property of this tech-nique, and with microarrays, an entire genome scancan be performed on only a few slides (Forozan et al.,

*Correspondence to: Dorothy Warburton, Ph.D., Genetics DiagnosticLaboratory, Babies Hospital, 3959 Broadway, BHS406, New York, NY10032–1537. E-mail: cuh@cuccfa.ccc.columbia.edu

Received 23 November 1998; Accepted 14 December 1998

TERATOLOGY 59:321–322 (1999)

r 1999 WILEY-LISS, INC.

’97). It is thus likely that the concept of CGH will haveprofound implications for future genetic testing.

DOROTHY WARBURTON*Department of Genetics and DevelopmentColumbia UniversityNew York, New York

LITERATURE CITEDForozan F, Karhu R, Kononen J, Kallioniemi A, Kallioniemi OP. 1997.

Genome screening by comparative genomic hybridization. TrendsGenet 13:405–409.

Griffin DK, Sanoudou D, Adamski E, McFiggert C, O’Brien P, Wien-berg JK. 1998. Chromosome specific comparative genomic hybridiza-tion for determining the origin of intrachromosomal duplications. J MedGenet 35:37–41.

Kallioniemi A, Kallioniemi OP, Sudar D, Rutovitz D, Gray JW,Waldman F, Pinkel D. 1992. Comparative genomic hybridization formolecular cytogenetic analysis of solid tumors. Science 258:818–821.

Kalousek DK, Vekemans M. 1996. Confined placental mosaicism. JMed Genet 33:529–533.

Lestou VS, Lomax BL, Barrett IJ, Kalousek DK. 1999. Screening ofhuman placentas for chromosomal mosaicism using comparativegenomic hybridization. Teratology 59:325–330.

Levy B, Dunn TM, Kaffe S, Kardon N, Hirschhorn K. 1998. Clinicalapplications of comparative genomic hybridization. Genet Med1:4–12.

Robinson WP, Barrett JJK, Bernard L, Telenius A, Bernasconi F,Wilson RD, Best RG, Howard-Peebles PN, Langlois S, Kalousek DK.1997. Meiotic origin of trisomy in confined placental mosaicism iscorrelated with presence of fetal uniparental disomy, high levels oftrisomy in trophoblast, and increased risk of fetal intrauterinegrowth restriction. Am J Hum Genet 60:917–927.

322 D. WARBURTON