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Conquest - Connecting the Threads, Calculating the Probabilities

Making the Connection 2001-2008

Connecting the Threads, Calculating the Probabilities

Date: April 20, 2010

CRF Making Headlines in 2007

Investigators have developed a risk “calculator” for one of the most lethal forms of
cancer. A novel computer software tool described in the April 10, 2007, Journal of
Clinical Oncology, will help identify people at risk of developing pancreatic cancer due
to an inherited genetic predisposition. Physicians and genetic counselors can use the tool to decide who would benefit from early screening. The calculator, called PancPRO, computes the chance that a person carries a pancreas cancer gene and his or her lifetime risk of developing the disease. It is based on similar tools used in breast and colon cancer risk assessment.

An estimated 10 percent of pancreas cancers are caused by inherited gene alterations. “Even if there is a 100 percent chance that an individual carries a pancreas cancer gene, the person’s lifetime risk for developing the disease is only 32 percent by age 85,” says CRF investigator ALISON KLEIN, PH.D. Pancreas cancer is often diagnosed
after it has spread, leading to very low survival rates and making early risk assessment
key to improving outcomes. Though researchers don’t yet know specific genes that cause the disease, Klein says their understanding of how genes behave coupled with information about a family, such as age, family size and causes of death, mean that her model can provide a good estimate of an individual’s risk. Klein and team tested the software
with data collected from about 6,000 people from 961 families when the registry
was established more than a decade ago. They compared PancPRO predictions
with actual occurrence of pancreas cancer in these families over an 11-year period. PancPRO predicted that 31 of the registry participants would develop cancer, just slightly higher than the 26 who actually did.


Kimmel Cancer Center investigators have identified the genetic culprits that trigger a cancer-related fatal lung disease. Idiopathic pulmonary fibrosis (IPF) affects approximately 50,000 Americans each year, and like cancer, it is often fatal within three years. The findings were reported in the The New England Journal of Medicine, March 29, 2007. About 20 percent of cases are thought to be caused by genetic alterations that
predispose carriers to the disease. Until this discovery, however, they were unknown. The Hopkins team screened DNA obtained from blood samples from 73 people with inherited IPF. In six of the participants, they discovered mutations of two genes that produce an
enzyme know as telomerase. Like the plastic caps on the end of shoelaces, telomerase helps protect the ends of chromosomes, known as telomeres.

Mutations in telomerase-producing genes can cause chromosome ends to fray and wear down more quickly, triggering cell death and have been associated with cancer development. The investigators first uncovered the connection between telomerase and IPF while studying the genetic traits of a family with a rare, premature-aging disorder
caused by short telomeres. Many of the family members were suffering from pulmonary
fibrosis. “We thought there might be a link between telomerase mutations and IPF,” said CRF investigator MARY ARMANIOS, M.D. In their study, the researchers found
that mutation carriers’ telomeres were one-third the length of family members with no mutations. “If we follow the genetic threads of families that inherit IPF,” says Armanios, “it may lead us to a better understanding of the genetic properties causing more common forms of the disease.” ?


In cancer, it may be wise to make mountains out of molehills. In their latest research reported in the October 11, 2007, Science Express, the team that just over one year ago began mapping the colon and breast cancer genome, completed the job and found the gene landscape to contain a variety of different, less frequently occurring mutations
that vary from patient to patient. This explains why seemingly similar cancers often respond very differently to standard therapies. On the molecular level, they are genetically different. While there are a few mountains, like APC and p53 gene mutations, that still remain the most  commonly mutated genes in colon cancer, there are far more “hills” less frequently occurring mutations but just as culpable as the mountains in the incredibly complex  process that leads to colon and breast cancer development and progression.
Everest-like genes such as APC and p53 have stood out among other mutations because they were so commonly mutated. These genes, and others like them, have been the focus of cancer research for years because they were the only genes known to contribute to
cancer, said the researchers, which included CRF investigators VICTOR VELCULESCU, M.D. , P H . D. , and BEN PARK, M.D. “Now that we can
see the whole picture, it is clear that lower peaks or ‘gene hills,’ though mutated less frequently, are the predominant feature,” says Velculescu.

In a systematic search of 18,191 genes, about 5,000 more than the first screen and
representing 90 percent of the proteincoding genes in the human genome, the
investigators found that an average of 77 genes are mutated in an individual colon
cancer and 81 in breast cancer. About 15 mutations likely contribute to a cancer’s
key characteristics, and most of the mutated genes may be different for each patient.
The research team is now looking for pathways that these varied genes have in common. “The hard part used to be finding these mutant genes,” says Velculescu. “Now the challenge will be to link them to specific pathways and understand their function.” They say scientists should expect to see a similar genetic landscapefew mountains surrounded by many hills in other cancers. ?

On any given day, our bodies are assaulted by a number of environmental pollutants —cigarette smoke, diesel exhaust, carbon monoxide and more. But the same processes our body uses to protect itself from these outside assaults have been corrupted by lung cancer cells to help them evade anticancer drugs. CRF investigator SHYAM BISWAL, PH.D. , is the leading expert on a gene called NRF2 that protects our cells from these pollutants. He found that NRF2 directs proteins to absorb pollutants and chemicals and then pump them out, clearing cells of toxins. Another gene, KEAP1, he says, lets cells know when the toxins are removed, shutting down NRF2 and stopping the cell-cleansing process.
In lung cancer, however, Biswal discovered that cancer cells manipulate these genes to view lung cancer-attacking drugs as toxins and pump them out before they can get to cancer cells. In essence, the lung cancer cells shut down KEAP1, which leaves the NRF2-directed cell cleansing mechanism continually activated, sweeping anticancer drugs away with other cell toxins before they can do their job against cancer cells.

In Biswal’s study, six of 12 lung cancer cell lines and 10 of 54 tissue samples from non-small cell lung cancer patients had mutations in the KEAP1 gene, rendering it inactive and unable to keep NRF2 activity in check. In addition, half of the tissue samples were missing one copy of the KEAP1 gene (cells usually have two copies of each gene). No
missing genes or mutations were observed in normal lung tissues from the same patients.

Biswal believes that blocking NRF2 expression in lung cancer patients receiving chemotherapy could improve the effectiveness of the drug therapy. He plans to confirm the findings with a larger set of samples and then screen for drugs that block the gene.

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