NEW YORK – An international team led by investigators at Sun Yat-sen University Cancer Center narrowed in on two new susceptibility genes for nasopharyngeal carcinoma using a combination of genome-wide association analyses, regulatory and functional profiling, and cell line experiments — results they reported in the American Journal of Human Genetics on Thursday.
"The new findings of this study expand the genetic architecture of [nasopharyngeal carcinoma] and help to uncover the underlying genetic etiology of NPC development," senior and corresponding author Wei-Hua Jia, an oncology researcher at Sun Yat-sen, said in an email, noting that the functional SNPs identified "show potential to be used as predictive biomarkers and to be integrated into the current [nasopharyngeal carcinoma] polygenic risk model for disease risk prediction."
In an effort to unearth new genetic contributors to nasopharyngeal carcinoma, along with their biological consequences, the researchers analyzed available genome-wide association study data for 4,506 individuals with nasopharyngeal carcinoma and 5,384 unaffected individuals. After new validation testing on nearly 7,500 more individuals with or without nasopharyngeal carcinoma, they were left with two previously unappreciated genetic risk loci on chromosomes 9 and 17.
The team subsequently analyzed the new nasopharyngeal carcinoma-associated loci — alongside chromosome 5 and chromosome 9 risk loci reported in the past — using histone marker-based chromatin immunoprecipitation sequencing, promoter capture Hi-C, ATAC-seq-based chromatin accessibility profiling, and other experiments in nasopharyngeal carcinoma cell lines.
"Although many cancer susceptibility loci have been identified in large-scale GWASs, it is challenging to explain the biological mechanisms of the observed associations by using genetic data alone," Jia noted. "Multidimensional bioinformatic profiles are beneficial for prioritizing functional SNPs from a group of association signals with strong linkage disequilibrium, and for identifying the target genes that may be linearly far away but regulated by the functional SNPs."
Together with follow-up reporter assays and CRISPR interference experiments, the regulatory and functional analyses highlighted biological roles for two key susceptibility genes: PHF2 and CDKN2B-AS1.
In particular, the chromosome 9 histone demethylase-coding gene PHF2 appeared to have a tumor suppressor role, while nasopharyngeal carcinoma-associated SNPs showed enhancer activity affecting the expression of CDKN2B-AS1 — another chromosome 9 gene that prompts enhanced nasopharyngeal carcinoma proliferation when it is expressed at higher-than-usual levels.
"We nominated PHF2 as a susceptibility gene regulated by functional SNPs in 9q22.33 and provided supportive evidence that CDKN2B-AS1 was a susceptibility gene regulated by functional SNPs in 9p21.3, which can largely expand the current understanding of the [nasopharyngeal carcinoma] genetic etiology," the authors wrote.