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Possible Genetic Basis for Racial Disparities in Endometrial Ca


 

Differences in gene expression may be at least partially responsible for the differences in endometrial cancer survival rates and tumor aggression seen between black and white women, results of two studies suggest.

Many previous studies have ascribed racial disparities in endometrial cancer outcome to less aggressive treatment. The two new studies, which were presented at the annual meeting of the Society of Gynecologic Oncologists, identified a racial disparity in endometrial cancer even in a health care setting where patients receive similar care and suggested a genetic role for differences in outcome, according to Lt. Col. C.G. Larry Maxwell, MC, USA, the studies' lead investigator.

In the first study, the investigators compared tumor aggression and survival rates between 168 blacks and 997 whites with stage III, IV, or recurrent endometrial cancer. The data were drawn from four randomized controlled treatment trials performed by the Gynecologic Oncology Group of Roswell Park Cancer Institute, Buffalo, N.Y.

All patients received chemotherapy with doxorubicin alone or in combination with paclitaxel and/or cisplatin.

Blacks were more likely to have advanced stage disease and poorly differentiated and nonendometrioid tumors—all of which are associated with increased mortality. After adjusting for clinical and treatment factors using multivariate regression, blacks had a 25% increased relative risk of death, compared with whites. The overall survival rate was 10.6 months for blacks and 12.2 months for whites.

“This study clearly shows a survival disadvantage for blacks, even when they are treated as aggressively as whites,” Dr. Maxwell, director of the Gynecologic Disease Center at Walter Reed Army Medical Center, Washington, said in an interview.

“This is extremely important because many prior investigators primarily have attributed the poor survival in African Americans to unequal treatment,” he added.

The second study examined gene expression in 45 fresh frozen endometrial tumors. No differences in expression were found between the races in the first analysis, which included early-stage tumors. But when the researchers analyzed only the 28 advanced tumors (stage II, III, or IV; 10 black, 14 white), clustering emerged. There were 325 genetic transcripts that were differently expressed between the groups, and 66 were differentially expressed by at least twofold.

Among these genes were phosphoserine phosphatase (PSPH), which was most unregulated; Ras-related associated with diabetes (RRAD); and two genes associated with insulin-like growth factor, insulin-like growth factor 1 receptor (IGF1R) and a variant, IMP-2.

The IGF1R is a very important finding, as IGF can support the growth of cancer cells, especially endometrial cancer cells. There also may be a link between some of these differentially expressed genes and obesity, diabetes, and hormonal milieu, he said.

PSPH is an enzyme that catalyzes the last step in the biosynthesis of serine from carbohydrates, he noted. “One paper has linked it to gastric carcinoma metastasis.”

The studies' conclusions do not mean that blacks and whites are genetically different, Dr. Maxwell stressed—only that the genes are differently expressed. “The genes may be structurally similar, but there may be environmental influences between the two races that result in epigenetic modulation of gene upregulation or downregulation,” he said. “Genes have promoters that can be affected by environmental exposures, such as diet or hormones.”

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