One Person's Genes Offer Clues to Pancreatic Cancer
One way to discover susceptibility genes for an inherited disease is to analyze DNA from large families with many affected members. But this strategy unfortunately does not work with inherited forms of pancreatic cancer because the disease is so deadly that there are very few large families with adequate numbers of samples.
Genome sequencing may offer a solution. Researchers at the Johns Hopkins Kimmel Cancer Center have shown for the first time that sequencing the genes in both the normal and the cancer cells of a single patient can reveal genes that are altered in both types of cells. Some of these changes, when they occur in the same gene in both the normal and the cancer cells, can help identify susceptibility genes.
The team tested this strategy in a man with an inherited form of pancreatic cancer and discovered a gene that in some families appears to cause familial pancreatic cancer.
Among some 20,600 sequenced genes, three had inactivating mutations in both copies of the gene. The researchers focused on a gene called PALB2, because the mutations resulted in a truncated protein and because the gene has been linked to cancer previously. Further analysis showed that PALB2 was mutated in 3 more patients with familial pancreatic cancer out of 96 patients tested.
A New Strategy
Reporting their findings online in Science on March 5, the researchers said PALB2 mutations may be important in about 3 percent of familial pancreatic cancers. They stressed that the work may have implications beyond this disease.
“This strategy offers a new way to find hereditary susceptibility genes, and it applies to other cancers as well as to other hereditary diseases,” said senior author Dr. Alison Klein, who directs the National Familial Pancreas Tumor Registry at Johns Hopkins.
The process involves sifting through thousands of normal genetic variations and apparently harmless DNA changes to discover, in this case, a prime suspect. PALB2 has been implicated in Fanconi anemia and breast cancer, and the gene also interacts with the breast cancer susceptibility gene BRCA2, which normally helps repair damaged DNA. The loss of this gene in cancer is certainly plausible, the researchers said.
“This gene is part of a very important pathway in cancer, and it immediately made sense to us as a candidate,” said coauthor Dr. Michael Goggins, professor of pathology, medicine, and oncology at Johns Hopkins. As further circumstantial evidence, mutations in the gene’s partner, BRCA2, occur in some familial pancreatic cancers, he noted.
The results support the view that when both copies of a gene are lost or damaged, cancer may result, especially if the gene normally repairs DNA, thereby suppressing tumors. According to this theory, a person may inherit a mutated copy of a DNA-repair gene and then acquire mutations in the second copy later in life.
Given this scenario, the “brute force” sequencing approach used in this study is potentially a “very fast and productive method for finding these genes,” said coauthor Dr. James Eshleman, associate professor of pathology and oncology at Johns Hopkins. Pending funding, his group plans to sequence eight more patients with familial pancreatic cancer, further extending work that began with a genome analysis of pancreatic tumors reported last year.
“The scientific logic behind the study is sound and based on paradigms that have stood the test of time,” commented Dr. Steven Gallinger, an investigator at the University of Toronto. “This is definitely a breakthrough. And like all breakthroughs it needs to be validated, but then we can move on and find other genes.”
The hope is that understanding the genetics of a small number of familial cases will lead to insights into more common forms of the disease, as has happened with colorectal and other cancers, added Dr. Gallinger, who was not involved in the research.
Preventing Pancreatic Cancer
Familial pancreatic cancer is likely to involve many genes, and “this study points a way around the problems associated with traditional genetic analysis in pancreatic cancer,” said Dr. Teresa Brentnall of the University of Washington School of Medicine, who was not an author of the study.
Dr. Brentnall is cautiously optimistic that in the future PALB2 could be part of a panel used to evaluate patients with familial pancreatic cancer. There are no effective ways to detect early signs of pancreatic cancer, which is the fourth most deadly cancer, though it is not among the 10 most common.
A test for predisposing mutations could help identify people at high risk of the disease who could be monitored for precancerous changes. “If we can identify high-risk families, then we can enroll them in screening programs and potentially prevent them from ever getting pancreatic cancer,” said Dr. Goggins.
A clinical test for PALB2 mutations is not yet available but appears likely. It would need to be a sequencing-based test in order to capture a broad spectrum of mutations. Larger studies will also be needed to further assess the frequency of these mutations and to determine how often people with these mutations progress to cancer.
As is often the case, the findings raise interesting questions that can now be explored. One is whether there are identifiable subtypes of familial pancreatic cancer with distinct clinical features (e.g., BRCA2 mutations versus PALB2 mutations), noted Dr. Gloria Petersen of the Mayo Clinic, who leads a consortium of research institutions that studies and supports patients with familial pancreatic cancer.
“This study is very exciting because it demonstrates for the first time that sequencing the protein-coding genes of a single patient can lead to the discovery of novel susceptibility genes,” said Dr. Petersen. “We hope that this approach will soon be within reach of researchers who are doing the genomic analyses of pancreatic cancers, and our groups can start to mine the data,” she added.
The cost to determine the sequence of all genes in an individual for this project was approximately $150,000. The costs of sequencing have declined significantly in recent years and are expected to continue dropping in the future.
—Edward R. Winstead