Source: Sun Yat-sen University Cancer Center
Edited by: Jin Feng

Researchers from Sun Yat-sen University Cancer Center have identified two genes (TERT/CLPTM1L and CIITA) associated with nasopharyngeal carcinoma (NPC) susceptibility. These findings have been reported in the journal of Human Molecular Genetics.

NPC is a human squamous-cell carcinoma that derives from epithelial cells in the nasopharynx. It has, for the most part, a specific ethnic and geographic distribution, with a strikingly high incidence rate in Guangdong Province and neighboring regions Guangxi and Hong Kong. Radiotherapy is often curative for early stage NPC patients, while those at advanced stages have poorer outcomes. Therefore, high-risk population screening as well as early diagnosis is paramount if we are to reduce NPC mortality rates.

To identify the risk factors that contribute to NPC susceptibility, Professor Yi-Xin Zeng initiated a long-term genetic program in 1996, establishing related cohorts, a biobank and genetic databases. Their current study was based on these important resources, and served as an extended investigation of their previous genome-wide association study (GWAS) reported in Nature Genetics, in 2010.

By boosting statistical power with a larger sample size and validating more genetic variations (single nucleotide polymorphisms, SNPs) on the ranking list based on the GWAS P-values, the researchers identified a novel susceptibility loci associated with NPC. The joint analysis of 7,046 cases and 8,570 controls resulted in two associations surpassing genome-wide significance (P<5 ×10^-8), including TERT-CLPTM1L at chromosome 5p15 (rs401681) and CIITA at chromosome 16p13 (rs6498114).

SNP rs401681 has been linked with multiple cancer susceptibilities. Moreover, bioinformatics analyses showed that both SNPs are located in the regulatory regions, and correlated with the expression of nearby genes (rs401681 for CLPTM1L and TERT, and rs6498114 for CIITA). CLPTM1L and TERT have been implicated in cancers, and CIITA is considered the “master control factor” for the expression of NPC-associated MHC class II genes. These suggest that both SNPs might lead to NPC.

These findings expand the understanding of the genetic contribution to NPC risk and provide novel biological insights into NPC pathogenesis. The results also suggest that low-frequency and rare variations should be given more attention in the hunt for genetic contribution to NPC risk.

With further identification of more NPC susceptibility genes, a more comprehensive NPC risk prediction model is expected to be developed in combination with the other risk factors. This approach might provide a convenient and effective strategy to identify individuals with a high risk of developing NPC, thereby reducing the scale of NPC endemic in the population.

The article is available online:
Title: An extended genome-wide association study identifies novel susceptibility loci for nasopharyngeal carcinoma