NEW YORK (GenomeWeb) – A Chinese research team has uncovered new germline contributors to esophageal squamous cell carcinoma (ESCC) risk, including a low-frequency change to the CYP26B1 cytochrome P450 drug metabolism gene that appears to affect blood serum levels of a tumor suppressor called all-trans retinoic acid (atRA).
Using exome sequences for more than 3,700 individuals with ESCC and nearly 3,900 individuals without, the researchers looked for SNPs or low-frequency variants associated with risk of the disease, which is especially common in parts of China. From these data, they narrowed in on half a dozen risk sites that could be replicated in another 7,002 cases and 8,757 controls, including three common SNPs and three low-frequency variants. Their results appeared online today in Nature Genetics.
"We have identified six new ESCC susceptible variants located in exonic regions, including low-frequency variants that have not been identified in the previous GWAS with common variants," senior author Dongxin Lin, an etiology and carcinogenesis researcher with the Chinese Academy of Medical Sciences and Peking Union Medical College, and his colleagues wrote, noting that the work "highlights the important roles of low-frequency genetic variants in the development of this malignancy."
For their study, Lin and colleagues used Illumina HumanExome Beadchip arrays to profile low-frequency protein-coding variants in 3,721 ESCC cases and 3,889 controls from Beijing. After tossing out samples with insufficient or low-quality data, they were left comparing exome patterns for 3,714 of the ESCC cases and 3,880 controls — an analysis that led to 30 suspicious variants.
The team attempted to verify the potential ESCC risk variants with OpenArray- or TaqMan-based genotyping on individuals from two replication cohorts: 3,120 ESCC cases and 3,919 controls from Wuhan province and another 3,882 individuals with ESCC and 4,838 without from the Chinese province of Hebei.
In the process, the researchers uncovered six new risk variants at four sites in or around the CCHCR1, TCN2, TNXB, LTA, CYP26B1, and FASN genes. Three of the associations — at the TCN2, CYP26B1, and FASN gene loci — were based on low-frequency variants that appeared to have higher-than-usual effect sizes.
An ESCC-associated variant at CYP26B1, called rs138478634, had particularly close ties to ESCC risk in individuals with a history of smoking and/or drinking, although the team noted that rs138478634 was not linked to smoking or drinking status in control individuals. Through a series of follow-up cell line and patient serum expression profiling experiments, the group saw lower-than-usual levels of the atRA tumor suppressor in cells or individuals pumping out the rs138478634 variant-containing version of CYP26B1.
The authors concluded that results of the new study "extend previous findings and advance our understanding of the genetic etiology of ESCC, which might be useful for risk assessment, early detection, and targeted treatment of ESCC."