Johns Hopkins Gazette | March 23, 2009
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The newspaper of The Johns Hopkins University March 23, 2009 | Vol. 38 No. 27
'Personalized' Genome Sequencing Reveals Coding Error

By Vanessa Wasta
Johns Hopkins Medicine

Scientists at the Sol Goldman Pancreatic Cancer Research Center at the Johns Hopkins Kimmel Cancer Center have used "personalized genome" sequencing on an individual with a hereditary form of pancreatic cancer to locate a mutation in a gene called PALB2 that is responsible for initiating the disease. The discovery marks their first use of a genome-scanning system to uncover suspect mutations in normal inherited genes.

The findings, they say, underscore the value of so-called "personalized genome" sequencing, which decodes a person's genes and compares the changes to those found in healthy people.

"Gene sequencing has always had the potential to help us learn if a person is susceptible to certain diseases," said Alison Klein, director of the National Familial Pancreas Cancer Tumor Registry at Johns Hopkins. "By finding the genetic error responsible for this patient's pancreatic cancer, our team has provided an excellent example of the power of this approach."

The coding error in PALB2 (which stands for "partner and co-localizer of BRCA2") causes a shortened version of the protein encoded by this gene, rendering it incapable of working with another cancer-related gene, BRCA2, to repair broken DNA. Mutations in BRCA2 are also known to cause hereditary forms of cancer.

Klein and her team caution that their finding has not yet resulted in a clinical test for the hereditary pancreas cancer gene, but laboratories at Johns Hopkins and possibly elsewhere will be developing one, which she says can be used to increase cancer surveillance for early signs of disease in those at risk.

Reporting their findings in the March 5 edition of Science Express, the Johns Hopkins researchers say that they sequenced genes taken from a person with pancreatic cancer whose sister also had the disease, suggesting an inherited predisposition.

Sian Jones, research associate at the Johns Hopkins Kimmel Cancer Center, said, "Generally, we need data from very large families to identify the inherited gene, and that was not available in this case." Instead, the investigators used high-powered computer software to scan all known protein- coding genes in the patient — approximately 20,000 of them — to find more than 15,000 variations.

Most of the variations were normal ones coding for such things as eye or hair color, but the search was designed to track down particular mutations that caused certain proteins to be shortened, a process that commonly occurs in cancer, said James Eshleman, associate professor of pathology and oncology.

The search yielded one gene variant, PALB2, resulting from a substitution of a single DNA letter coding for cytosine with a different one that codes for thymidine.

The research team then scanned for the PALB2 gene in 96 other individuals with pancreatic cancer who each had at least one relative with pancreatic cancer. Three of them had coding errors in the PALB2 gene that shortened the protein in a similar way. Klein estimates that 3 percent of people with hereditary pancreatic cancer have mutations in PALB2, making it the second-most-common gene mutation in these patients after BRCA2.

The investigators said they believe that their approach could be used to identify inherited alterations that predispose people to other types of cancer, as well as to other genetic-based diseases. "The more information we have about normal variants, the easier it will be to find disease- causing ones," said Michael Goggins, professor of pathology, medicine and oncology at Johns Hopkins.

In the future, scanning genomes for hereditary disease-causing genes could become "reasonably routine," according to Bert Vogelstein, an investigator at the Howard Hughes Medical Institute and co-director of the Ludwig Center at Johns Hopkins.

The investigators say that the cost to determine the sequence of all genes in an individual was approximately $150,000 for this effort and that this cost would likely decrease considerably in the future.

Funding for the project was provided by the Lustgarten Foundation for Pancreatic Cancer Research, Sol Goldman Pancreatic Cancer Research Center, Virginia and D.K. Ludwig Fund for Cancer Research, National Institutes of Health and Michael Rolfe Pancreatic Cancer Foundation.

In addition to Klein, Eshleman, Goggins and Vogelstein, investigators who conducted the research are Ralph Hruban, Mihoko Kamiyama, Michael Borges, Xiaosong Zhang, D. Williams Parsons, Jimmy Cheng-Ho Lin, Emily Palmisano, Keiran Brune, Elizabeth Jaffee, Christine Iacobuzio-Donahue, Anirban Maitra, Giovanni Parmigiani, Scott Kern, Victor Velculescu and Kenneth Kinzler, all of Johns Hopkins.


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