Increases Effectiveness of Genetic Tests for Cancer Risk
The Johns Hopkins scientists whose research led to the first blood tests for colon cancer predisposition have now developed a technology that dramatically improves the accuracy of such tests. They can now detect -- nearly 100 percent of the time -- genetic mutations associated with certain hereditary diseases. A report of their work is in the February 17, 2000, issue of Nature.
"Of those who seek genetic testing, up to 50 percent will walk away with no clear answer, not because a gene mutation wasn't there, but because the technology was not sophisticated enough to detect it," says Bert Vogelstein, M.D., Clayton Professor of Oncology at Johns Hopkins and Investigator, Howard Hughes Medical Institute. "Now, we can tell people who seek testing, with much greater certainty, whether or not they have inherited specific genetic predispositions to colon cancer."
The team from the Johns Hopkins Oncology Center and the Howard Hughes Medical Institute overcame a major obstacle to testing for genetic mutations in inherited diseases by unmasking mutated genes. The new technology, called Conversion, takes advantage of what has long been a weakness in genetic testing.
Every person carries two copies of a gene, scientifically known as alleles (one inherited from the father, one from the mother). Normal genes can "mask" or hide defective ones. Conventional genetic tests analyze both copies of potentially mutated genes at the same time. Conversion separates the two copies of the gene, allowing them to be individually analyzed.
"With current tests, if a portion of a gene was deleted, that deletion mutation could be masked or hidden by the normal copy of the gene. By separating and looking at each copy individually, we can now detect these and other kinds of genetic alterations that were previously missed," explains Kenneth W. Kinzler, Ph.D., professor of oncology and co-director of the study.
Researchers uncovered masked mutant genes by fusing human cells with specially designed mouse cells to create mouse-human cell lines. Each cell line contained a copy of the gene they wanted to study. Then, they looked for gene mutations by using conventional DNA sequencing methods.
"Conversion does not replace conventional technologies for genetic testing," notes Vogelstein. "But, by providing separated alleles, Conversion markedly enhances these technologies, making it possible for them to detect mutations that would otherwise be masked."
In the Nature report, the scientists said they used blood samples from 22 patients with a hereditary form of colorectal cancer, known as hereditary non-polyposis colorectal cancer (HNPCC). Conventional genetic testing was unable to verify mutations in 10 of the 22 patients. Conversion allowed the researchers to identify mutations in all 22 patients.
"This technology does not change who is eligible to receive a genetic test (i.e. people at high risk for a known mutation), but it will make the tests much more useful for those who decide to take them," says Hai Yan, Ph.D., research fellow at the Oncology Center and first author of the study.
Although Conversion has only been tested so far on colon cancer mutations, the technique should apply to other hereditary cancers, including breast and kidney cancer, as well as a wide variety of neurological and cardiovascular disease genes.
The new gene separation technology described in the Nature report is expected to be available this summer through Johns Hopkins in conjunction with genetic counseling and risk assessment for individuals with two types of inherited predisposition for colorectal cancer, which are hereditary non-polyposis colorectal cancer (HNPCC) and familial adenomatous polyposis (FAP).
If you have a family history of colorectal cancer, call 410-955-4041 for information.
In addition to Vogelstein, Kinzler, and Yan, other research participants included Nickolas Papadopoulos, Ph.D., from Columbia University; Giancarlo Marra, M.D., Ph.D., Claudia Perrera, Ph.D., and Josef Jiricny, Ph.D., from the Institute of Medical Radiobiology, Zurich, Switzerland; C. Richard Boland, M.D., from the University of California, San Diego; Henry T. Lynch, M.D., from Creighton University School of Medicine; Robert B. Chadwick, Ph.D., and Albert de la Chapelle, M.D., Ph.D., from Ohio State University; Karin Berg, M.D., James R. Eshleman, M.D., Weishi Yuan, B.S., from The Johns Hopkins University; Sanford Markowitz, M.D., from Case Western Reserve University; and Steven J. Laken, Ph.D., and Christoph Lengauer, Ph.D., from The Johns Hopkins University.
Under a licensing agreement between The Johns Hopkins University and GMP Companies, Inc. (Ft. Lauderdale, FL), the Conversion technology is exclusively licensed to GMP for worldwide commercial applications. Bert Vogelstein, M.D., Kenneth W. Kinzler, Ph.D., Hai Yan, Ph.D., and Nicholas Papadopoulos, Ph.D., are entitled to a share of the royalty received by the University from sales of the licensed technology. The Conversion technology will be made freely available to academia for research purposes. Vogelstein and Kinzler are consultants to GMP Companies, Inc. The University and the researchers own GMP Companies, Inc. stock, which is subject to certain restrictions under University policy. The terms of this arrangement are being managed by the University in accordance with its conflict of interest policies.
Related web sites:
Johns Hopkins Oncology Center: www.hopkins.cancercenter.jhmi.edu
Johns Hopkins Molecular Genetics Laboratory (includes more information about hereditary colon cancer and the Conversion Method): www.coloncancer.org/conversion.htm and www.coloncancer.org/hccr.htm (available Wednesday, February 16, 2 p.m.)
National Society of Genetic Counselors: www.nsgc.org
Genetics Basics from Howard Hughes Medical Institute: www.hhmi.org/genetictrail
The Genetics Alliance: Participation in Genetic Research Studies: www.geneticalliance.org/infoconsent.html
Journal
Nature