Study Identifies New Gene Mutations Linked to Colorectal Cancer in African-Americans

Medical Xpress, January 12, 2015

Case Comprehensive Cancer Center researchers have identified new gene mutations unique to colon cancers in African Americans–the population with the highest incidence and death rates of any group for this disease.

This discovery–namely, that colorectal cancers appear different on a molecular level in African Americans–offers new hope for these patients. With this groundbreaking knowledge, scientists now will seek to develop treatments that target the distinct nature of the disease in African Americans–and, they hope, begin to reduce the devastation disproportionately wrought on this population.

The findings, published in the Jan. 12 edition of PNAS (Proceedings of the National Academy of Sciences), only became possible because of technological advances in gene sequencing and computational analysis. The study that revealed this invaluable information ultimately involved review of 1.5 billion bits of data.

“This milestone study builds on our previous genetic research on colorectal cancer,” said Sanford Markowitz, MD, PhD, corresponding author on the study, and principal investigator of the $11.3 million federal gastrointestinal cancers research program (GI SPORE) that includes this project. {snip}

Announced in 2011, this GI SPORE program is one of just five in the country. Markowitz, Ingalls Professor of Cancer Genetics at Case Western Reserve School of Medicine and a medical oncologist at University Hospitals Case Medical Center, included studies of the disease’s behavior in minority patients as part of his team’s original grant application. The disparity between colorectal cancer rates in African Americans and other groups has long existed; the most recent federal statistics, for example, put age-adjusted incidence at 46.8 cases for every 100,000 African Americans, and 38.1 cases for every 100,000 Caucasian Americans. Yet scientists have struggled to determine what factors–biological, economic, environmental, or others–account for this disparity.

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One of the lead researchers on the project was senior author Joseph E. Willis, MD, associate professor of pathology, Case Western Reserve School of Medicine, director of tissue management, Case Comprehensive Cancer Center, and Vice Chair of Pathology for Clinical Affairs at UH Case Medical Center.

“We wondered if colon cancer is the same disease molecularly in African Americans individuals as it is in Caucasian individuals. Or could colon cancer be the same disease behaving differently in one population compared to another,” he said. “This study gave us our answer. Colon cancer in African American patients is a different disease molecularly.”

The scientists made their discovery by using DNA sequencing to compare 103 colorectal cancer samples from African American patients with 129 colorectal cancer samples from Caucasian patients, all of whom had received care at UH Case Medical Center in Cleveland. The scientists examined 50 million bits of data from 20,000 genes in every cancer.

From these extensive data, investigators first uncovered 20 new gene mutations in the colorectal cancers of African Americans that never before had been seen in patients with this disease. Investigators then confirmed that 15 of these gene mutations preferentially affected the African American patients. Just over 40 percent of cancers in African Americans carried mutations in one or more these genes. In addition, the scientists found these mutations were 3.3-fold more common in African American cancers than in colorectal cancer tissues from Caucasians.

The investigators particularly zeroed in on mutations in 2 of these 15 genes, EPHA6 and FLCN, detected exclusively in African American patients. EPHA6 belongs to a family of proteins linked to causing cancer; this study marks the first time this gene has been implicated in colorectal cancer. In addition, individuals born with FLCN mutations are known to be susceptible to certain cancers. EPHA6 gene mutations were detected in 5.8 percent of colorectal cancers of African American patients, and FLCN gene were in 2.91 percent.

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This discovery–namely, that colorectal cancers appear different on a molecular level in African Americans–offers new hope for these patients. With this groundbreaking knowledge, scientists now will seek to develop treatments that target the distinct nature of the disease in African Americans–and, they hope, begin to reduce the devastation disproportionately wrought on this population.

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