[MOL] Vagaries of Cancer revealed by genes on a chip....A must read! [00102] Medicine On Line


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[MOL] Vagaries of Cancer revealed by genes on a chip....A must read!



Vagaries of Cancer Revealed by Genes On a Chip
>
>     STANFORD, Calif.--(BW HealthWire)--March 1, 2000--By looking at which
>genes are switched on and off in a variety of cancers, Stanford researchers
>are learning what thousands of our genes do and why their behavior changes in
>malignant cells. Using the so-called DNA chip, the researchers can study tens
>of thousands of genes at the same time and see how they vary in different
>tissues and how they respond to different drugs.
>
>     Scientists in the laboratories of Patrick Brown, MD, PhD, a Howard
>Hughes investigator and associate professor in biochemistry and David
>Botstein, PhD, professor of genetics, have mastered the technique of applying
>thousands of genes to a small piece of glass and deciphering the patterns
>that appear when they expose the genes to genetic material from human cells.
>Fluorescent tags make the genes glow red when they are highly active and
>green when they are idle. A computer program then sorts all the genes into
>color patterns that can be interpreted by the researchers.
>
>     Doug Ross, MD, PhD, a postdoctoral fellow in Brown's laboratory,
>examined 8,000 human genes in 60 different cancers including leukemia;
>cancers of the central nervous system; renal cell and non-small-cell lung
>carcinoma; melanoma; and ovarian, breast, colon and prostate cancer. Cells
>from these cancers have been cultivated in the laboratory and comprise a cell
>panel constructed by the National Cancer Institute to test new anti-cancer
>drugs.
>
>     Ross, Brown and Botstein with their collaborators in the laboratory of
>John Weinstein, MD, PhD, at the NCI, describe the results of their studies in
>two papers published in the March 1 issue of Nature Genetics.
>
>     Scientists already know what some of the genes on the chip do; however,
>approximately half of them merely have a name or a code number and their
>function is unknown. When Ross and his colleagues analyzed groups of genes
>that are switched on or off in a similar way, they found that the groups
>often contained a mixture of known genes and unknown genes. According to
>Ross, the researchers assume that genes that are regulated in the same way
>have similar jobs, which enables them to tentatively assign functions to the
>unknown genes.
>
>     "The expression patterns can give you some information about the roles
>unknown genes might play," said Ross. "Those with the same pattern are very
>likely involved in the same function."
>
>     The researchers saw many complex patterns of gene expression among the
>cells but it was clear to them that the predominant pattern corresponded to
>the tissue from which the cancer originally derived. For example, a large
>group of genes highly expressed in melanoma cancers contained many genes with
>known roles in melanocyte biology, and leukemia cells were distinguished by a
>small set of genes specific to white blood cells. So the dominant feature of
>the gene expression pattern of each cancer cell related to the type of tissue
>in which the cancer formed and was not overshadowed by any changes in the
>gene's activity as a result of cultivating the cells in the lab.
>
>     Ross's collaborator, Uwe Scherf, PhD, a postdoctoral fellow at the NCI,
>then looked at how the genes' expression patterns related to the cancer
>cells' sensitivity to different drugs. Researchers at the NCI have compiled a
>database that records the sensitivities of the 60 cancer cells to each of
>70,000 chemical compounds. Scherf analyzed how the gene expression patterns
>correlated to the cancer cells' sensitivities to a subset of these compounds
>that included all the chemotherapy drugs commonly used today in anti-cancer
>treatments.
>
>     "Since the variation in the way the drug works is determined by the gene
>expression patterns, we should be able to learn something about the role of
>different genes in determining the sensitivity of the cell to different
>compounds," said Ross.
>
>     An example of the type of information the researchers are trawling for
>is provided by a drug called L-asparaginase and a gene called asparagine
>synthetase (AS). Certain malignant cells lack this gene and are therefore
>more sensitive to the drug. Physicians already know that acute lymphoblastic
>leukemia cells are killed by L-asparaginase. When the researchers looked for
>the AS gene they found it was expressed at a very low level in the acute
>lymphoblastic leukemia cells and expressed at a high level in cells from a
>different kind of leukemia -- one that had been shown to be relatively
>resistant to the drug. The researchers can now take what they know about the
>AS gene expression pattern and L-asparaginase sensitivity and apply it to
>other cancer cells, hoping to find a matching pattern that will identify
>other cancers susceptible to this drug.
>
>     "We can characterize gene expression in different cell lines and we can
>characterize drug sensitivity in different cell lines, and correlate the two.
>We hope that will teach us something about the mechanisms of drug
>sensitivity," said Ross.
>
>     The researchers acknowledge that there are so many possible
>relationships that it will take some time to sort out all the correlations
>between drug activity and gene expression.
>
>     Members of the Brown and Botstein labs are continuously expanding their
>DNA chip, which is known scientifically as a DNA array. The arrays they are
>currently working with have more than 20,000 genes and the researchers are
>producing more than 400 arrays each month to meet the demands of the lab
>members and their Stanford collaborators. Soon they hope to be squeezing
>40,000 genes onto each chip.
>
>     Other Stanford authors who contributed to the studies include Michael
>Eisen, PhD, now at the University of California, Berkeley, who contributed to
>the study when he was a research fellow in Botstein's lab; Charles Perou,
>PhD, and Christian Rees, PhD, postdoctoral fellows in Botstein's lab; Paul
>Spellman, PhD, and Alexander Pergamenschikov, a graduate student and research
>assistant in Botstein's lab; Vishwanath Iyer, PhD, a postdoctoral fellow in
>Brown's lab; Stefanie Jeffrey, MD, assistant professor of surgery; and Matt
>Van de Rijn, MD, PhD, assistant professor of pathology.
>
>     The research at Stanford was supported by the National Cancer Institute
>and the Howard Hughes Medical Institute. Ross is a Walter and Idun Berry
>Fellow, Eisen is an Alfred E. Sloan Foundation Fellow and Perou is a
>SmithKline Beecham Pharmaceuticals Fellow.
Warmly, lillian
 
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