Mar. 28, 2000 Researchers at Johns Hopkins have developed a novel approach for detecting cancer based on new targets for genetic mutations found outside a cell's nucleus.
The research team, led by David Sidransky, M.D., professor of otolaryngology and oncology, uses mitochondrial DNA to identify genetic mutations in bladder, head and neck and lung cancers. Their work is reported in the March 17, 2000, issue of Science. Mitochondria are specialized parts of cells largely responsible for generating energy. Multiple copies exist in all cells, and they contain the only DNA located outside of the cell nucleus. The Hopkins team first identified mitochondrial mutations linked to bladder, head and neck and lung cancers. Then, they studied paired urine, saliva, and lavage samples from twenty patients with these cancers in search of similar mitochondrial mutations that could be used in diagnostic tests.
The team detected mutations in all of bladder and lung cancer patients and most (six out of nine) of the head and neck cancer patients. The mitochondrial mutations observed in the bodily fluids were identical to those obtained in the primary tumors. "Until now, finding cancer-specific mutations in bodily fluids was like looking for a needle in a haystack," says Sidransky. "Finding mitochondrial mutations is much easier. With additional research, we expect to be able to identify mitochondrial mutations through a simple blood test," he says.
Until now, most cancer-related genetic mutations have been identified in nuclear DNA only. A cell nucleus contains only two copies of DNA, one inherited from each parent. In contrast, many copies of mitochondrial DNA are contained within each cell, and these increased numbers make them easier to identify than nuclear mutations, explains Makiko S. Fliss, M.D., one of Sidransky's co-investigators and first author of the paper. When the researchers compared mitochondrial mutations to p53 mutations found in nuclear DNA in the tumor and bodily fluid samples they studied, they observed a 20-200 fold increase in the number of mutations among mitochondria. "It's not that the nuclear mutations are not important, it's that the sheer numbers of mutated mitochondrial DNA are easier to identify," says Scott Eleff, M.D., M.S., associate professor of anesthesiology and collaborator in this study.
Sidransky envisions use of mitochondrial DNA for cancer screening, one day, working much like mammography does in screening for breast cancer. "For example," he says, "someone at higher risk of developing lung cancer because of a history of smoking could provide a sputum sample. That sample would be analyzed to obtain a base line description of the individual's mitochondrial genome. In subsequent visits, new sputum samples would be collected and compared to the base line for changes. If new mutations are observed, we would be in a better position to intervene while the cancer is in an early and curable stage."
Further trials of this new cancer detection method in a variety of human cancers may begin as early as next year.
Lung, head and neck, and bladder cancers strike more than 265,000 people in the U.S. and take the lives of an additional 180,000 people. Lung cancer is the most common type of cancer, but because symptoms often do not appear until the disease is advanced, early detection has been difficult.
In addition to Sidransky, Fliss, and Eleff, additional participants in this research include Henning Usadel; Otavia L. Caballero; Li Wu; Martin R. Buta, B.A.; and Jin Jen, M.D., Ph.D.
This research was funded by the National Institutes of Health and the National Cancer Institute's newly formed Early Detection Research Network.
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