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4.09.2013

UM Researchers Help Pinpoint Genetic Variants that Increase Risk for ER-Negative Breast Cancer

Two Miller School researchers are part of an international consortium that identified four genetic “spelling mistakes” that can increase the risk of one of the most aggressive forms of breast cancer all too common in South Florida. The findings are reported in one of five studies produced by the Collaborative Oncological Gene-environment Study (COGS), a European Union-based consortium of more than 160 research groups, and published in a special issue on genetic risk factors for common cancers in the journal Nature Genetics.

Jennifer J. Hu, Ph.D., Associate Director for Cancer Prevention and Control at Sylvester Comprehensive Cancer Center and professor of epidemiology and public health, and Jorge L. Rodriguez Gil, B.S., research assistant at Sylvester, collaborated on the study that identified four risk loci specific to Estrogen receptor-negative (ER-negative) breast tumors. Disproportionally occurring in younger women and women of African ancestry, ER-negative tumors represent 20 to 30 percent of all breast cancers and are associated with worse short-term prognoses than ER-positive tumors.

Hu said the genetic variants identified in the study, “Genome-wide association studies identify four ER-negative specific breast cancer risk loci,” could have significant impact on the South Florida community, which has a higher percentage of underserved Hispanic, Black or African American women who suffer ER-negative breast cancer.

“Working closely with our many Sylvester collaborators, we are currently conducting two clinical research projects funded by the National Cancer Institute and the Florida Biomedical Research Program to evaluate the impact of genomic factors on breast cancer disparities in diagnosis, treatment response, and survival,” Hu said. “The genetic variants identified in this study will be further evaluated in our local study population to address their contribution to racial/ethnic difference in ER-negative breast cancer, as well as their functional implications in targeted treatment development to improve long-term survival.”

Collectively, the five COGS studies published in the April issue of Nature Genetics pinpointed more than 80 single nucleotide polymorphisms — essentially genetic typos — that increase the risk of breast, prostate and ovarian cancer, providing a clearer picture of the total number of genetic alterations that can be linked to these cancers.

For the breast cancer study, hundreds of researchers worldwide evaluated associations between ER-negative disease and 67 loci for overall breast cancer risk, 41 of which COGS researchers had newly identified. Based on their meta-analysis of 10,707 ER-negative cases and 76,649 controls, they found seven loci of risk of ER-negative disease, four of which had not previously been identified.

“In summary,” the study concluded, “our analyses provide further evidence for distinct etiological pathways for invasive ER-positive and ER-negative breast cancers. Fine mapping and functional studies of the susceptibility loci for ER-negative disease should provide important insights into the biological mechanisms of ER-negative breast cancer, potentially leading to the identification of new targets for therapy and prevention.”

In the largest genotyping project in the world, COGS researchers are targeting the identification of SNPs, which naturally occur in humans, that could influence the risk of common cancers. For the five studies, they performed genetic analyses on 100,000 patients with breast, ovarian or prostate cancer and 100,000 healthy individuals from the general population. They specifically looked for alterations –the spelling mistakes – in the composition of the nitrogen bases A, G, C and T on 200,000 selected sections of the DNA strand. When cancer patients had significantly different compositions compared to healthy control subjects, the differences were considered to be relevant to risk of disease.

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