At first blush, it sounds like molecular biological Freudianism: It's all mother's fault.

In this particular permutation of the theory, it's her subpar DNA that's to blame for her offspring's cancer. Or, to be exact, the offspring's mitochondrial DNA, which is inherited exclusively from the mother because it resides in the cytoplasm.

Mitochondrial DNA mutations are known to play a role in some cancers, but because of the distribution of cells with vs. without mutations, they were assumed to be acquired rather than inherited. New research from scientists at Emory University, the Winship Cancer Institute and the Veteran's Affairs Medical Center, all in Atlanta, as well as the University of California at Irvine, might begin to change that conception.

John Petros, associate professor of urology and pathology at Emory University School of Medicine and the Winship Cancer Institute, and his colleagues found that certain inherited mutations in mitochondrial DNA, specifically in the cytochrome oxidase gene, are present in high rates in prostate cancer patients, and increase tumor growth in mice. They report their findings in the Jan. 18, 2005, issue of the Proceedings of the National Academy of Sciences.

They began by sequencing mitochondrial DNA from a group of prostate cancer patients. Based on previous research, the scientists were expecting to find acquired mutations, but, much to their surprise, they found inherited, as well as acquired, mutations.

"The finding that [some of these mutations] are inherited is really quite unprecedented," Petros told BioWorld Today. But sequencing of lymphocytes from blood samples showed that "every single cell in the patient's body has them," which is not possible for an acquired mutation.

Mutation Hot Spot' Yields Cancer Clues

Petros said the scientists decided to focus in more detail on the cytochrome oxidase gene because "it became apparent very early, probably within the first six to 10 cases, that this was a hot spot" of mutation.

They sequenced the cytochrome oxidase gene of 260 prostate cancer tissue samples or blood cells from patients with prostate cancer, 54 tissue samples from patients who had no prostate cancer as determined by biopsies, and roughly 1,000 control samples from the general population.

The scientists found mutations in the cytochrome oxidase I gene in 12 percent of cancer patients, 2 percent of no-cancer controls and about 8 percent of the general population.

Asked why the rate of mutations was actually lower in the no-cancer controls than in the general population, Petros said that "having a mutation [in the cytochrome oxidase gene] may be instrumental in moving you into the bucket of prostate cancer patient." In other words, most men with cytochrome oxidase mutations may have gone on to actually develop prostate cancer by age 50 (the minimum age of individuals in the cancer group and the no-cancer controls), though that has not been tested with a prospective study.

The scientists next tested whether the mitochondrial DNA mutations affected prostate tumor growth. That was done through the creation of so-called cybrids - hybrids of the cytoplasm of one cell and the nucleus of another. In mice, cybrids, consisting of prostate cancer cell nucleus with mutant mitochondrial DNA in its cytoplasm, grew into tumors that were about seven times as big as tumors of cybrids that had cytoplasm containing no mutant mitochondrial DNA. Those tumors showed decreased oxidative phosphorylation and increased production of radical oxygen species, which are known to damage cells; those findings might reveal the mechanism of the mutations' deleterious effects.

The most obvious practical applications of the findings are diagnostic. "This paper would support the concept that you could screen patients at any point in their lives, and if they are found to have the mutation, assume that they are at high risk" for developing prostate cancer, Petros said. Such high-risk could be monitored more frequently. He said that several VC-funded companies, which he declined to name, are interested in pursuing the commercial implications of the findings.

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