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"Probing the genomic basis for cancer" MSK

Research planning perspectives: eg. probing the genomic basis for cancer.(1)

One of the strengths that has put Memorial Sloan-Kettering at the forefront of the search for genomic changes in cancer is its extensive tumor bank. These specimens are stored anonymously to protect patient confidentiality but are linked to clinical information about the patients, such as whether they responded to certain treatments, where the cancer metastasized (if it did), and whether the patients were ultimately cured.
Another resource that gives MSK a distinct advantage in the field is its Genomics Core Laboratory and its DNA Sequencing Core Laboratory. Both facilities are led by Agn├Ęs Viale. The latter recently received a huge boost in sequencing capabilities through the purchase of an instrument called a 454 -- a "next generation" DNA sequencer.The genomics lab analyzes tumor cells using various microarrays (also called "chips"), which can monitor thousands of genes at the same time to look for changes in the number of copies of a gene or determine whether a gene is expressed, for example. Data from these microarrays might explain differences between tumor cells and normal cells or distinguish different subtypes of the same cancer.
Using next-generation sequencing, investigators are able to sequence each individual DNA molecule separately, rather than combining the sequences of all fragments, as older sequencing machines do. Dr. Viale explains: What this means is that if only 1 percent of cells in a tumor have an additional mutation that confers resistance to a drug treatment, we can find it. That small number of cells is what likely would be responsible for disease recurrence, and up until now we had no way to detect that rare additional mutation. This technology is beautiful, absolutely cutting edge.'

In 2005, 15 years after the start of the Human Genome Project and 2 years after the full human genome sequence was completed, NIH's National Cancer Institute and its National Human Genome Research Institute launched the pilot phase of The Cancer Genome Atlas. Known as TCGA -- the initials also represent the four chemical building blocks in DNA (thymine, cytosine, guanine, and adenine) -- the project seeks to accelerate the understanding of the molecular basis of cancer through the application of a variety of genome analysis technologies.
Cancer Genome Characterization Centers (CGCCs) were established at 7 institutions around the country to study different types of genetic changes in the same tumor samples, and MSK was funded to house one of these CGCCs, under the leadership of molecular pathologist Marc Ladanyi.(2)

Other characterization centers are looking at additional aspects of genetic changes in tumors, including patterns of gene expression, changes in microRNAs (which regulate gene expression), and alterations called DNA methylation (a modification that does not change the gene sequence but alters expression of neighboring genes). There are also 3 Genome Sequencing Centers that use high-throughput methods similar to those used for the Human Genome Project, and a bioinformatics center to analyze all of the data that is being generated.

The CGCC at MSK is one of 4 centers that are studying changes in the number of copies of genes -- whether particular bits of the genome are gained (have extra copies) or have been deleted (have lost copies) in a given tumor sample. Dr. Ladanyi explains:When you do this in hundreds of samples of the same cancer, you see that there are characteristic genetic changes that occur over and over again, in tumors from different patients. The other centers looking at copy numbers are using different approaches and in some cases different technologies. The idea is that each technology has its own advantages and disadvantages, and by using several methods to measure the same thing, you can get the most accurate picture of this class of genetic abnormalities.

Some members of the research community have criticized TCGA's approach, questioning whether it is the most efficient way to find genetic changes related to cancer and expressing concern about the cost of the project in relation to the amount of data it is likely to generate. One alternative that's been suggested is a so-called functional genomics approach, which looks for normal cellular pathways that play a role in cancer by using molecules called short hairpin RNAs (which are engineered to target and suppress specific genes) and studying the response of cancer cells.

(1)http://www.mskcc.org/mskcc/html/84549.cfm
(2)http://www.mskcc.org/mskcc/html/84548.cfm


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This page contains a single entry from the blog posted on October 19, 2008 9:20 AM.

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