乌鸦传媒

ATLANTA -- A germline single nucleotide polymorphism (SNP) in JAK3 may serve as a potential biomarker of laryngeal cancer in African Americans, according to a new study.

Genetic profiling of head and neck squamous cell carcinoma (HNSCC) tumor samples revealed that the germline variant in JAK3 was present in one-fourth of the samples from African Americans, said Jean-Nicolas Gallant, PhD, of Vanderbilt University in Nashville.

And further research revealed that the JAK3 SNP (rs3212723) conferred a 25% increased HNSCC risk.

If confirmed in a larger cohort, "ultimately, we'd like to find genes or sets of genes that patients who are at risk [of HNSCC] can be screened for," Gallant told 乌鸦传媒 at the 2018 meeting of the American Academy of Otolaryngology-Head and Neck Society Foundation here.

African American patients with HNSCC have significantly worse outcomes than white patients. And the lower survival probability among African Americans is independent of socioeconomic factors, comorbidities, clinical characteristics, and treatment modality. "Given this, we hypothesized that perhaps biology underlies part of this health disparity," he said.

Gallant's group profiled 32 tumors from African Americans with HNSCC using a commercially available cancer hot-spot panel. As expected, variants in known cancer genes TP53 and PIK3CA were found in 50% and 25%, respectively.

"What stood out to us was the mutation in JAK3, which we found in four African American males. This mutation turned out to be a germline mutation known as rs3212723," he said. "It's a germline mutation found exclusively in people of African descent. Anyone of African descent has about an 8% chance of having this SNP. "

JAK3 is an intracellular protein tyrosine kinase that is involved in T-cell signaling. The mutation has been found as a somatic mutation in a variety of megakaryoblastic leukemias.

To add data to these preliminary findings, an additional 76 head and neck tumors were sequenced, 50% from African American patients and 50% from white patients. The JAK3 germline variant was found in six patients in this series, all of whom were African Americans with laryngeal cancer.

To add power to the findings, the investigators conducted a retrospective cohort study of rs3212723 using Vanderbilt's biorepository of DNA extracted from discarded blood (BioVU). Thirty one patients were found to have the JAK3 SNP (30 African Americans). While none of the patients had head and neck cancer, Gallant attributed this to the fact that most were born after the year 2000.

The search was expanded to include heterozygotes, which uncovered 645 more patients with the SNP, 92% of whom were African American. These were matched to 1,933 controls. The SNP was found to confer a 25% increased risk of head and neck cancer, but the small number of cases precluded achieving significance (95% CI 0.94-3.41).With the exception of the presence of the JAK3 SNP, the populations did not differ in their gender, age, race, or rates of smoking and alcohol use.

To confirm the association between rs3212723, African Americans, and HNSCC, Gallant plans to interrogate the Southern Community Cohort Study, which is powered to assess the incidence of cancer in 50,000 persons in the Southeast U.S. The cohort contains clinical data and DNA from 300 patients with HNSCC, most of whom are African American.

If grant funding is obtained, these samples will undergo next-generation sequencing. By comparison, The Cancer Genome Atlas has about 50 samples from African Americans with HNSCC, he said. "The Southern Community Cohort Study is by far the largest sequencing study of any African American head/neck cancer cohort," Gallant said. "We think the association is real but it's just that the numbers are so small it's hard to definitively say."

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