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Lung cancer detection by methylation-preserving PCR

Institution: University of Southern California
Investigator(s): Ite Offringa, Ph.D.
Award Cycle: 2011 (Cycle 20) Grant #: 20XT-0021 Award: $324,325
Subject Area: Cancer
Award Type: Exploratory/Developmental Award

Initial Award Abstract
Lung cancer is the cancer that kills the most men and women in the United States, despite the fact that it is less common than prostate and breast cancer. One important reason why lung cancer is so deadly is because it is often detected too late, when it has already spread from its original site to other parts of the body. Early detection is the key to saving the lives of cancer patients, but unlike breast and prostate cancer, early detection procedures for lung cancer are still under development. Current imaging procedures can very sensitively detect abnormalities in the lung, but most such lesions are not cancer. The development of a blood-based test for lung cancer would be extremely beneficial. It could be used to complement imaging, and if powerful enough, could perhaps one day be used on its own to test people at risk for lung cancer. If lung cancer is detected early, when it is still very small, it can be removed by surgery. Such patients would be cured, and hundreds of thousands of lives could be saved. Thus, the development of a blood-based marker for early lung cancer detection should be a top priority.

A very promising marker that could be used to detect lung cancer is DNA methylation. DNA methylation is a modification of DNA (the genetic material) that is changed in cancer cells compared to normal cells. In cancer patients, DNA tends to leak from the cancer cells into the blood. If the special methylated DNA can be detected in the blood, cancer patients could be identified, hopefully before their cancer has spread to other parts of the body. To detect DNA in a patient’s blood we use a test called the polymerase chain reaction (???). This is the same approach that the police use to forensically detect a suspect’s DNA at a crime scene. However, a special chemical step is needed to detect the methylated DNA, and this step causes a lot of the DNA to be degraded. This in turn makes it more difficult to detect the methylated DNA molecules, particularly in patients with early stage cancer, since their tumors are still small and don’t shed as much DNA into the blood. The Laird-Offringa lab has been working for many years on the development of DNA methylation markers for lung cancer. We have identified a number of very promising candidates, but we need to develop more sensitive methods to detect these molecules. Here we propose to develop a new method that will allow us to avoid the chemical step that causes the DNA to degrade. We hypothesize that with this method, more cancer DNA will be detectable in the blood. This will make it easier to identify those few cancer-derived methylated molecules that are floating around in a patient’s blood stream. In other words, this method would allow us to detect cancer earlier in more patients. We will test the method using blood plasma samples from lung cancer patients and from individuals without cancer, which we have collected from the University of Southern California University Hospital and the Los Angeles County Hospital. If we are successful, it will be an incredibly important development that will greatly improve our abilities to detect lung cancer, and to cure early stage lung cancer patients through surgery.