'Personalized' genome sequencing reveals coding error in gene for inherited pancreatic cancer

March 5, 2009

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," says Alison Klein, Ph.D., 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 they sequenced genes taken from a person with pancreatic cancer whose sister also had the disease, suggesting an inherited predisposition. "Generally, we need data from very large families to identify the inherited gene, and that was not available in this case," says Siân Jones, Ph.D., research associate at the Johns Hopkins Kimmel Cancer Center. 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, says James Eshleman, M.D., Ph.D., 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. She estimates that three 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 believe that their approach could be used to identify inherited alterations that predispose people to other types of cancer as well as other genetic-based diseases. "The more information we have about normal variants, the easier it will be to find disease-causing ones," says Michael Goggins, M.D., 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, M.D., 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 for this project was approximately $150,000, but that this cost will likely decrease considerably in the future.

More information: Science Magazine: www.sciencemag.org

Source: Johns Hopkins Medical Institutions

Explore further: 'Labyrinth' chip could help monitor aggressive cancer stem cells

Related Stories

'Labyrinth' chip could help monitor aggressive cancer stem cells

September 21, 2017
Inspired by the Labyrinth of Greek mythology, a new chip etched with fluid channels sends blood samples through a hydrodynamic maze to separate out rare circulating cancer cells into a relatively clean stream for analysis. ...

Scientists find bacteria in pancreatic tumors that metabolize a common drug

September 15, 2017
To the reasons that chemotherapy sometimes does not work, we can now add one more: bacteria. In a study published today in Science, researchers describe findings that certain bacteria can be found inside human pancreatic ...

DNA and protein 'liquid biopsy' for early pancreatic cancer better than either alone

September 4, 2017
Johns Hopkins scientists say they have developed a blood test that spots tumor-specific DNA and protein biomarkers for early-stage pancreatic cancer. The combined "liquid biopsy" identified the markers in the blood of 221 ...

Pancreatic cancer development

September 1, 2017
Pancreatic ductal carcinoma (PDAC) is one of the most lethal types of cancer, with new therapeutic options needed.

Trial to test new drug in patients with advanced cancer

August 23, 2017
A clinical trial to test a new cancer drug in patients with advanced solid tumours, launches in four centres across the UK, through Cancer Research UK's Centre for Drug Development.

Researchers develop new strategy to target KRAS mutant cancer

September 14, 2017
Although KRAS is one of the major oncogenes associated with aggressive cancers, drugs designed to block KRAS function have not been able to halt cancer progression in a clinical setting. Until now, KRAS has remained infamously ...

Recommended for you

Newly revealed autism-related genes include genes involved in cancer

September 25, 2017
The identification of genes related to autism spectrum disorder (ASD) could help to better understand the disorder and develop new treatments. While scientists have found many genetic differences in different people with ...

Scientists first to use genetic engineering technique to investigate Tourette's

September 25, 2017
Scientists at Rutgers University-New Brunswick are the first to use a genetic engineering technique to create brain cells from the blood cells of individuals in a three-generation family with Tourette syndrome to help determine ...

Study reveals an ancient Achilles heel in the human genome

September 21, 2017
In a major study published today, researchers at deCODE genetics use whole-genome data from 14,000 people from across the population of Iceland, including 1500 sets of parents and children, to provide the most detailed portrait ...

Forgotten strands of DNA initiate the development of immune cells

September 21, 2017
Intricate human physiological features such as the immune system require exquisite formation and timing to develop properly. Genetic elements must be activated at just the right moment, across vast distances of genomic space.

Genome editing reveals role of gene important for human embryo development

September 20, 2017
Researchers have used genome editing technology to reveal the role of a key gene in human embryos in the first few days of development. This is the first time that genome editing has been used to study gene function in human ...

A piece of the puzzle: Eight autism-related mutations in one gene

September 19, 2017
Scientists have identified a hotspot for autism-related mutations in a single gene.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.