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Case Western Team Uncovers Genes Mutated in Colorectal Tumors Affecting African-Americans

NEW YORK (GenomeWeb) – Through a combination of whole-exome and targeted sequencing, researchers led by a team at Case Western Reserve University have uncovered more than a dozen genes that are preferentially mutated in colorectal tumors affecting African-American patients.

As it reported in the Proceedings of the National Academy of Sciences yesterday, the team examined somatic mutations in colorectal cancer samples obtained from 103 African-American patients. By comparing the mutations they found in that cohort to those found in a Caucasian patient cohort, the research group homed in on variants that appeared to be specific to African-Americans. Further, mutations in two genes — ephrin type A receptor 6 (EPHA6)
 and folliculin (FLCN)
— seem to be driver genes in African Americans.

"We identified new genes that are significantly mutated in colon cancer and that are highly preferentially targeted for mutations in colon cancers arising in African-Americans as compared with Caucasians," the team led by Case Western's Sanford Markowitz and Joseph Willis wrote in PNAS. "These findings suggest differences in routes of colon carcinogenesis between the different ethnic groups and also may have implications for the ethnicity associated differences in tumor incidence and outcome."

According to the US National Cancer Institute, there were some 136,800 new cases of colorectal cancer and 50,310 deaths due to colorectal cancer in the US in 2014. Although African-Americans have higher colon cancer incidence and mortality than other ethnic groups, Markowitz, Willis, and their colleagues noted that African-Americans have been underrepresented in many previous sequencing studies of colorectal cancer, leaving gaps in what's known about the mutational landscape of the disease and how it arises in African-Americans.

Markowitz, Willis, and their colleagues performed whole-exome DNA sequencing using the Illumina HiSeq platform on a discovery cohort of 31 advanced-stage colorectal cancer samples and controls. From this, they found nearly 2,700 mutations that appeared to affect protein-coding genes. Additionally, the researchers found some 385 genes that harbored mutations in more than one sample — 78 of which hadn't been reported previously as being associated with colorectal cancer.

Using an Agilent SureSelect custom-capture library, the researchers resequenced that set of 78 genes in the paired tumor and normal discovery samples. After resequencing, 52 genes still had mutations in more than one of those discovery samples.

Those 52 genes were then resequenced in a separate cohort of 77 early stage colorectal cancer samples, and based on this, the researchers homed in on a group of 20 genes that were reproducibly mutated and that hadn't been before linked to colorectal cancer.

Because this set of genes hadn't been seen before in colorectal cancer, Markowotz, Willis, and their colleagues wondered whether these genes were mutated more often in African-Americans with colorectal cancer as compared to Caucasians.

To test this idea, they resequenceed those 20 genes in 129 late-stage colorectal cancer samples from Caucasian patients. These 20 genes, the researchers reported, had a two-fold increase in the number of mutations per tumor in African Americans as compared to Caucasians. The top 15 genes, they noted, drove this effect with a 3.3-fold increase in mutations among colorectal cancers affecting African-Americans.

For example, mutations in EPHA6 were found in 5.8 percent of African American colorectal cancers, but in none of the Caucasian colorectal cancers. Mutations in FLCN and HTR1F were similarly only found in African-American cases of colorectal cancer.

EPHA6 and FLCN, Markowitz, Willis, and their colleagues said, belong to known oncogenenic pathways, and they confirmed the mutations they saw in these two genes using Sanger sequencing,

One mutation of the six mutations in EPHA6 they detected changed a splice site while four missense mutations were also predicted to affect protein function. This pattern, the researchers said, is consistent with EPHA6 acting as a colorectal cancer tumor suppressor.

The researchers noted that in Caucasians, EPHA3 and EPHB6 have been reported to be significantly mutated.

"Intriguingly, to our knowledge the present study is the first to implicate EPHA6 in CRCs, with the finding of EPHA6 somatic mutations in [about] 6 [percent] of the AA CRC cases suggesting a provocative ethnicity-associated difference in selection of a different EPH family member for mutational targeting," they said.

The three FLCN mutations, they added, included two frameshift mutations and one nonsense mutation. Previously, FLCN mutations have been associated with Birt-Hogg-Dubé syndrome, which is marked by medullary thyroid carcinomas, perifollicular fibromas, and renal cancer.

This, Markowitz, Willis, and their colleagues said, suggests that EPHA6 and FLCN are candidate driver genes that are preferentially mutated in colorectal cancers affecting African-Americans.

"These previously unsuspected differences in the mutational landscapes of CRCs arising among individuals of different ethnicities have potential to impact on broader disparities in cancer behaviors," the researchers said.