Gene Mutation Differences Help Explain Racial Disparities in Uterine Cancer Survival
SAN DIEGO, CA -- The kind of acquired genetic mutations found in tumors, rather than cultural attitudes, treatment choices or access to health care, appears to explain why black women with uterine cancer have much poorer survival than their white counterparts, according to a new study.
Researchers from Duke University Medical Center have found that spontaneous mutations of one tumor suppressor gene are more common in whites than blacks with advanced uterine cancer. Combined with a previous Duke finding that another gene is mutated more frequently in blacks than whites, the discovery helps account for most of the survival disparity in this disease, said principal investigator Dr. Andrew Berchuck, who prepared the findings for presentation at the annual meeting of the Society of Gynecologic Oncologists.
Mortality of blacks with uterine, or endometrial, cancer is almost double that of their white counterparts, according to the American Cancer Society, making it the largest racial gap in the survival of any kind of cancer. The cancer society estimated 37,400 new cases of uterine cancer in the U.S. last year, and 6,400 deaths from the disease.
"While early stage uterine cancer is fairly benign, for African-American women the disease is deadlier at both early and advanced stages than it is for white women," said Berchuck, professor of gynecologic oncology at the Duke Comprehensive Cancer Center. "By finding and understanding the reasons for the survival disparity in this disease, we hope to erase it."
But even though racial differences have been found in the mutation rates of the two genes, the scientists say it will be some time before they can translate the information into a new path of prevention, diagnosis or treatment to improve the survival of blacks with the disease.
"We're still at the beginning," Berchuck said. "We have the first few pieces of the puzzle, but we don't have the corners or the edge pieces. In short, we've found some reasons, but we don't yet understand them."
In their study, mutations in a gene called PTEN, known to correlate with a better prognosis and easier-to-treat disease, were four times more common in tumors of white women with advanced uterine cancer. An earlier study found that mutations in a gene called p53 - already linked with a worse outcome and more aggressive disease - were about three times more common in black patients.
The findings don't have immediate implications for clinical practice, but they underscore the need for all women, especially black women, to seek immediate health care for any unexplained vaginal bleeding, Berchuck said.
The genetic mutations in PTEN and p53 responsible for the prognostic differences are not inherited, but rather occur spontaneously, as do most genetic changes associated with cancer. Much more laboratory work is needed to identify what causes these mutations, how they affect the course of the disease and why a given race is more prone to develop mutations in one as opposed to the other gene, said the scientists.
In their most recent study, the Duke scientists examined 140 tumor samples, and blood samples when available, collected between 1975 and 1997, for two specific cancer-related changes. In addition to searching for PTEN mutations, they also looked for a characteristic called microsatellite instability that is related to better survival in uterine cancer, even though it seems to indicate a loss of the cancer cells' ability to fix mistakes in its DNA.
Microsatellites are short, repetitive regions of DNA usually lying outside of genes, and which frequently are copied incorrectly when DNA is replicated in dividing cells. The replicating machinery essentially loses track of how many of the segments have been copied, for example, including eight or 12 repeats instead of a correct 10. Normally a cell's natural DNA repair mechanism detects these errors and fixes them, but many cancer cells collect these mistakes over time.
In their study, microsatellite instability was found in 15 percent of the tumors tested, with no difference between blacks and whites, Berchuck said. The characteristic also was associated with less aggressive disease and better survival, as in other studies.
The researchers found that PTEN mutations were much more common in white women: 17 out of 78 white patients had PTEN mutations, while only 3 of 62 black patients had these favorable mutations.
In the study, average survival of black patients was 1.02 years while that of white patients was 2.52 years, a difference consistent with other studies. The patients all had advanced uterine cancer, which confers a much worse prognosis than earlier stage disease. Berchuck said approximately 20 percent to 30 percent of new uterine cancer cases are advanced.
The researchers first began to seek genetic factors when known contributors to the survival disparity between blacks and whites could not completely account for the difference. For example, estrogen replacement therapy, which increases uterine cancer risk, is more frequently prescribed to white women due to their greater risk of debilitating effects from osteoporosis after menopause. However, the type of uterine cancer associated with estrogen use is less aggressive than others, boosting survival rates in whites by increasing the incidence of easier-to-treat cases. Now estrogens usually are supplemented with another hormone, progesterone, so replacement therapy does not increase uterine cancer risk.