Investigators Find Potential Genetic Clues to Disparities in Colon Cancer

Kishore Guda, DVM, PhD

Researchers from the Case Comprehensive Cancer Center have discovered new gene mutations that are unique to colon cancer in African American patients, who have the highest incidence and death rate from the disease.

The research, published in the Proceedings of the National Academy of Sciences, found 20 new gene mutations in the colorectal cancers of African Americans that have never before been seen in this disease.

For the study, the scientists used 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.

Of the 20 new mutations found, investigators confirmed that 15 of these gene mutations preferentially affected the African American patients. Just over 40% of cancers in African Americans carried mutations in one or more of 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 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% of colorectal cancers of African American patients, and FLCN in 2.91%.

“This is the first study to perform a comprehensive gene mutation characterization and comparison of these colorectal cancer tumors in two ethnicities—African American and Caucasian,” said lead author Kishore Guda, DVM, PhD, assistant professor, General Medical Sciences (Oncology), Case Comprehensive Cancer Center. “Our next step will be to collaborate with other centers in investigating African American populations in different regions of the United States to determine whether they also share the unique gene signature found in the Cleveland African American community.”

In addition, the investigators want to delve into exactly how these mutations act and what they do, including whether these gene mutations make colon cancer act more aggressively. Most importantly, they hope the findings ultimately lead to more precise molecular diagnostic tests and treatments for African American patients.

“We are eager to explore and pinpoint colorectal cancer—causing gene mutations,as the first step to improving outcomes, and hopefully some day to saving lives, among African American patients affected by this illness,” corresponding study author Sanford Markowitz, MD, PhD, said in a statement. He is also principal investigator of the $11.3 million federal gastrointestinal cancers research program (GI SPORE) that includes this project.

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.

However, scientists have struggled to determine what factors—biologic, economic, environmental, or others—account for this disparity.

Markowitz said he and his team have long believed that genetics were at the core of the disparity.

“Identifying gene mutations has been the basis of all the new drugs that have been developed to treat cancer in the last decade,” Markowitz said. “Many of the new cancer drugs on the market today were developed to target specific genes in which mutations were discovered to cause specific cancers.”

“This milestone study builds on our previous genetic research on colorectal cancer,” Markowitz continued. “It illustrates the extraordinary impact that dedicated, collaborative teams can make when they combine scientific experience and ingenuity with significant investment.”