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International Team IDs New Throat Cancer Risk Genes in Southern Chinese Population

By a GenomeWeb staff reporter

NEW YORK (GenomeWeb News) – A team of researchers led by investigators in China and Singapore reported in the early, online edition of Nature Genetics yesterday that they have identified three new genes associated with a type of throat cancer called nasopharyngeal carcinoma in individuals of southern Chinese descent.

Through their genome-wide association study and subsequent validation experiment, the researchers evaluated roughly 5,000 individuals of southern Chinese descent with nasopharyngeal carcinoma and about as many healthy controls. Along with variants in the human leukocyte antigen (HLA) genes — immune-related genes that have been linked to nasopharyngeal carcinoma in past studies — the team also identified cancer-associated variants in three non-HLA genes previously tied to leukemia risk.

"The identification of susceptibility genes involved in the risk of [nasopharyngeal carcinoma] will help to develop a model for risk prediction and then screen for high-risk populations, which in turn will be helpful for early diagnosis of [nasopharyngeal carcinoma]," co-senior author Yi-Xin Zeng, president of the Sun Yat-sen University Cancer Center in Guangzhou, China, who is also affiliated with southern China's State Key Laboratory of Oncology, said in a statement.

Nasopharyngeal carcinoma is a form of throat cancer that forms in the lining of the upper throat behind the nose — a region known as the nasopharynx. It has been nicknamed the "Cantonese cancer" by some, given its unusually high rates in southern China, where nasopharyngeal carcinoma rates are roughly 25 times higher than rates in most other parts of the world.

Environmental factors, including Epstein-Barr virus, salty and pickled foods, and smoking, have all been implicated in nasopharyngeal cancer risk. But the disease appears to have a genetic component as well. Past studies have turned up risk variants in the HLA locus, the researchers noted. Non-HLA risk genes have also been identified in GWAS of Taiwanese and Malaysian Chinese populations.

For the current study, Zeng and his co-workers initially tested nearly 621,000 SNPs in 1,615 Han Chinese individuals with nasopharyngeal cancer and more than 2,000 healthy controls — including 1,025 Han Chinese individuals and 1,008 Singapore Chinese individuals — using Illumina Human610-Quad and Human1M-Duo BeadChip arrays.

After doing their quality control steps, the team was left with data on 1,583 nasopharyngeal carcinoma cases and 1,894 controls at 464,328 autosomal SNPs.

Consistent with previous studies linking nasopharyngeal cancer to HLA genes, the researchers found associations with major histocompatibility complex regions on several chromosomes. On the other hand, they did not see associations with other alleles identified through GWAS, including those found in the Taiwanese and Malaysian populations.

For the validation phase of the study, the team tested the top 49 SNPs in another group of southern Chinese individuals from the Guangdong and Guangxi provinces, this time looking at 3,507 cases and 3,063 controls. In the process, they verified six of the SNPs — three in HLA genes and three in or around the non-HLA genes TNFRSF19, MDSI-EVI1, and CDKN2A/2B. One more SNP remained associated with nasopharyngeal carcinoma following the validation testing, but did not reach statistical significance.

The same seven SNPs were also associated with the disease in additional validation samples and in 279 family trios from Guangdong, which the researchers assessed using transmission disequilibrium testing.

Together, the researchers explained, the new findings point to roles for not only HLA genes but also TGF-beta and JNK signaling pathways in nasopharyngeal carcinoma.

And because all three of the newly identified genes have been tied to leukemia risk in past studies, they speculated that the two cancers might share at least some pathogenic features — a theory that they say would help explain why leukemia and related cancers appear to be more common in individuals with nasopharyngeal carcinoma throat cancer.

"Further studies are needed to investigate the interactions between genetic susceptibility loci and well-established non-genetic risk factors," the researchers concluded, "particularly [Epstein-Barr virus] infection, and their contributions to the endemics of [nasopharyngeal carcinoma] in southern China."