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Esophageal Cancer Susceptibility Risk Variants Found in South African Population

NEW YORK – An international team has tracked down genetic variants linked to enhanced risk for esophageal squamous cell carcinoma (ESCC) in individuals from sub-Saharan Africa, including ESCC-associated variants at loci that overlap with those described in a high-risk population in China.

As they reported in the American Journal of Human Genetics on Tuesday, the researchers performed a genome-wide association study involving 1,686 South African individuals with ESCC and more than 3,200 unaffected individuals from the same populations to search for ties to ESCC risk. Based on profiles for almost 14.5 million directly genotyped or imputed SNPs, they highlighted variants with significant ties to ESCC at loci on chromosomes 9 and 2.

"Our GWAS of ESCC conducted in a population of African ancestry indicates a substantial genetic contribution to ESCC risk in Africa," senior and corresponding author Christopher Mathew, a human geneticist affiliated with the University of the Witwatersrand's Sydney Brenner Institute for Molecular Bioscience and King's College London, and his colleagues wrote.

The results build on prior studies pointing to socioeconomic and lifestyle contributors to ESCC, which has been linked to factors such as cooking fire smoke, tobacco smoking, alcohol use, or dental problems.

Although ESCC is relatively common and carries poor prognoses in sub-Saharan Africa, the team explained, prior research on genetic risk factors for the esophageal cancer has largely focused on high-risk groups in other countries, including populations in China and other parts of East Asia.

"Previous studies have provided strong evidence for genetic risk factors for ESCC, but most large-scale genetic studies were conducted in Asian populations, with smaller candidate gene studies conducted in African populations," the authors wrote, noting that the "unique geographical distribution of high-risk regions for ESCC across north-central China to the Caspian Sea and eastern to southern Africa suggests possible shared disease etiology among populations located far apart."

The strongest association involved risk variants upstream of the chromosome 9 gene FAM120A, which has been linked to oxidative stress response and the detoxification of molecules that might otherwise damage DNA, the researchers reported. They noted that the risk variants included quantitative trait loci influencing the expression of FAM120A opposite strand sequence FAM120AOS in esophageal tissues such as esophageal mucosa.

While FAM120A was one of three loci with genome-wide significant ties to ESCC susceptibility in a subsequent cross-ancestry meta-analysis that included almost 3,700 ESCC-affected individuals of African or Chinese ancestry and more than 5,900 unaffected, ancestry-matched controls, chromosome 2 risk variants involving variants in and around the myosin 1b-coding gene MYO1B appeared to be African-specific.

The other two loci with genome-wide significant ESCC associations across the two ancestry groups fell at a chromosome 22 site encompassing the tumor suppressor-coding gene CHEK2 and a chromosome 10 locus involving the PLCE1 gene.

"[T]his study provides evidence of a substantial genetic contribution to ESCC risk in an African population and has identified novel and shared risk loci for this important African cancer," the authors explained, noting that the work "provides an example of the power of trans-ethnic meta-analysis to identify common and distinct risk loci in populations of diverse ancestry."