Genomics Studies - Biomedical Informatics in Translational Research - page 80

chromosomal loss leads to loss of genes and, subsequently, alterations in gene
expression. Therefore, the two studies (aCGH and microarray analysis of gene
expression) provide complementary data: aCGH reports the chromosomal regions
that have been amplified or deleted, biomedical informatics identifies the genes
located in the affected regions, microarrays identify the genes whose expression is
affected, and biomedical informatics relates the genes to their metabolic function.
This information is then correlated with patient outcome. In addition, many meta-
bolic pathways in cells are interconnected, so deleting one gene is likely to lead to
changes in multiple pathways.
A recent report [61] presented both aCGH and microarray gene expression data
from the same tissue and then examined it to see if it correlated with patient out-
come. This analysis showed that those tumors associated with a more malignant
clinical determination had more chromosomal aberrations. Secondly, certain chro-
mosomal loci (from aCGH data) were consistently amplified or deleted in more
malignant cases of adenocarcinoma. Thirdly, certain differentially expressed genes
(from microarrays) were also found to be associated with poorer patent prognosis.
Finally, comparison of the aCGH and microarray data showed that the differen-
tially expressed genes were often found in the chromosomal regions identified as
being amplified or deleted. Of these regions a small number were found to be associ-
ated with patient prognosis. This raises the hope that not only can this set of tools be
used for identifying a particular treatment regimen that will be optimal for patient
survival, but it may also allow the development of a personalized drug treatment
based on underexpressed or overexpressed genes.

5.5 Summary

This chapter focused on obtaining data from the analysis of gene structure and
expression in human specimens. The methodologies described here include DNA
sequencing, DNA copy analysis using array comparative genomic hybridization,
genotyping using SNPs, gene expression analysis using microarrays, gene expression
analysis using PCR, and chips for alternative splicing analysis.
For each methodology, the fundamentals of the technology were described, fol-
lowed by examples of how the method is used and an outline of the experimental
procedure. Other issues such as QA/SOP considerations, biomedical informatics
requirements, and future directions of the technologies were also discussed wherever
appropriate. Two case studies were presented to illustrate how the genomic technol-
ogies can be applied to translations research.

References

[1] Saiki, R. K., et al., “Primer-Directed Enzymatic Amplification of DNA with a Thermostable

DNA-Polymerase.” Science, Vol. 239, 1988, pp. 487-491.

[2] Sanger, F., S. Nicklen, and A. R. Coulson, “DNA Sequencing with Chain-Terminating

Inhibitors,” Proc. Natl. Acad. Sci. USA, Vol. 74, 1977, pp. 5463-5467.

[3] Maxam, A. M., and W. Gilbert, “New Method for Sequencing DNA,” Proc. Natl. Acad.Sci.

USA, Vol. 74, 1977, pp. 560-564.