Specific Gene Alterations Explain Survival Disparities in HNSCC

Partner | Cancer Centers | <b>Johns Hopkins Cancer Center</b>

Alterations in specific genes involved in the formation of tissues and organs during embryonic development could be responsible for survival disparities seen between African-American and non-Latino white men with head and neck cancer.

Rafael Guerrero-Preston, DrPH, MPH

Alterations in specific genes involved in the formation of tissues and organs during embryonic development could be responsible for survival disparities seen between African-American and non-Latino white men with head and neck cancer, according to a study presented at a special conference on health disparities held by the American Association for Cancer Research.

The study found disparities in specific alterations between African-American and non-Latino white patients, specifically in the PAX gene family that selectively impacts canonical NOTCH and the p53 pathway. These variations may help explain why the average death rate among African-American patients with head and neck cancer is approximately 18% higher than non-Latino white patients with the same malignancy.

“During the last 30 years, the overall five-year relative survival rates for head and neck squamous cell carcinoma have increased, but despite that, the gap in overall survival rates between non-Latino white patients and African-American patients has remained unchanged,” said Rafael Guerrero-Preston, DrPH, MPH, assistant professor of otolaryngology—head and neck surgery and oncology at Johns Hopkins University in Baltimore, Maryland. “This disparity may be due to differences in genetic and epigenetic alterations among African-American patients.”

In the analysis, researchers performed an integrated molecular analysis using methylation sequencing, exome sequencing, mRNA expression and qPCR platforms in 107 samples from patients with head and neck squamous cell carcinoma (HNSCC). Findings from the study were validated against 279 samples from The Cancer Genome Atlas project. Altogether, the researchers identified 316 genes harboring cancer specific promoter methylation and identified 10 tumor suppressor genes with concurrent promoter methylation and somatic mutations.

Across all patients with HNSCC examined in the study, higher promoter methylation in PAX5 combined with mutations in p53 translated into worse overall survival when compared to patients with only p53 mutations. Upon closer analysis of the survival data, a connection was found between racial survival disparities and PAX5 promoter methylation.

“Our results highlight the differential genomic and epigenomic alterations in PAX, NOTCH, and TP53 pathways between African-American and non-Latino white HNSCC patients, which underlie the complex biology of morphologically similar tumors and explain HNSCC survival disparities,” Guerrero-Preston said in a release.

In detail, the study found that African-American patients with HNSCC had a higher frequency of mutations and methylation events compared to non-Latino white patients. Alterations in TP53 occurred in 50% versus 39%, FBXW7 mutations in 13% versus 7%, and NOTCH1 mutations in 25% compared to 16%, for African-Americans and non-Latino whites, respectively. Overall, no difference was observed for PAX1 and PAX5 between races.

However, when examining samples from patients with HNSCC outside of the oropharynx, the findings differed substantially. Respectively, for African-American and non-Latino white patients, promoter methylation was 100% versus 70% in ZIC4, 60% versus 50% for PLCB1, and 80% versus 73% for PAX5. Additionally, p53 mutations were detected in 60% compared to 48% and NOTCH1 mutations were 0% compared to 18%.

For tumors within the oropharynx, 86% of non-Latino white patients were found to have promoter methylation of PAX5 compared to 67% in African-American patients. Additionally, within the oropharynx, combined alterations in p53 and PAX5 were found in 33% of non-Latino white patients compared to 14% of African-American patients. Combined alterations in NOTCH1 and PAX1 were prevalent in 33% of African-American patients compared to 10% in non-Latino white patients.

“If further validated in larger cohorts, these discoveries could be used to develop genomic and epigenomic panels that will enable more treatment options, a reduction in treatment cost, and improvement in survival rates for patients with HNSCC,” Guerrero-Preston suggested.

Guerrero-Preston R, Hadar T, Michailidi C, Marchionni L, Koch W, Sidransky D. Integrated genomic and epigenomic deep sequencing analyses reveal head and neck cancer survival disparities associated to alterations in the PAX, NOTCH1 and TP53 pathways. Presented at: 6th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved held December 6-9, 2013, Atlanta, GA. Abstract PR06