John A. Petros, MD, associate professor of urology and pathology at Emory University School of Medicine and the Winship Cancer Institute, and Douglas C. Wallace, PhD, director of the Center for Molecular and Mitochondrial Medicine and Genetics at the University of California, Irvine, sequenced segments of mtDNA from prostate cancer patients and found a variety of mutations, including various mutations in the mtDNA cytochrome oxidase subunit (COI) gene.
They then sequenced the COI gene in 260 prostate cancer tissue samples or blood cells from patients with confirmed cancer who had undergone radical prostatectomies between 1995 and 2002, and 54 tissue samples from patients who had prostate biopsies but were found to be cancer free. Twelve percent of all the prostate cancer samples had mutations in the COI gene, while less than 2 percent of the samples from patients found to be cancer free harbored mutations in this gene. In a control sample of 1,019 individuals from the general population, 7.8 percent had mutations in the COI gene. The researchers found both germ-line (inherited) and somatic (acquired) mutations in the prostate cancer samples.
Because COI mutations are known to be more common in individuals of African descent, the scientists also analyzed a group of patients and controls of European ancestry. In this group they found the COI mutations in 11 percent of the prostate cancer specimens, in 0 percent of the no-cancer group and in 6.5 percent in a general population sample of 898 Europeans.
To determine whether mtDNA mutations are causally related to prostate cancer, the researchers introduced into a prostate cancer cell line mtDNAs harboring a known disease-causing mtDNA mutation and, as a control, the same mtDNA but without the disease mutation. They then injected these modified prostate cancer cells into mice to assess their tumor-forming ability. The prostate cancer cells with the mutant mtDNAs generated tumors that were on average seven times larger than the prostate cancer cells with normal mitochondria. Hence, the deleterious mtDNA mutation greatly enhanced prostate cancer growth.
Since mitochondria make oxygen radicals as a by-product of making energy, and oxygen radicals can stimulate cell growth, the researchers then tested the tumors for oxygen radical production. The tumors with the mutant mtDNAs generated significantly more oxygen radicals than those with normal ntDNAs, suggesting that this may be an important contributory factor in the mitochondrial enhancement of prostate cancer tumor growth. Because the study found that COI mutations were common in the general population (7.8 percent), but very infrequent (<2 percent) in men without prostate cancer, the investigators noted that men harboring these mutations are at increased risk for developing prostate cancer.
"We believe this study provides convincing evidence that mitochondrial mutations play an important role in prostate cancer," said Dr. Petros. "This is the first evidence that individuals who inherit a mutation of the mitochondrial DNA are at an increased risk of developing prostate cancer later in life. Interestingly, mitochondrial DNA is inherited from your mother, so this may explain those familial cases that are not passed from father to son, but rather through the unaffected mother to her sons."
The research was funded by the Emory Urology Trust for Urologic Research, the U.S. Department of Defense, the National Institutes of Health and an Ellison Medical Foundation Senior Investigator Grant.
Journal
Proceedings of the National Academy of Sciences