ATLANTA -- Certain genetic alterations to the PAX gene family may be responsible for survival disparities seen between African-American and non-Latino white men with head and neck cancer, according to results presented here at the Sixth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved, held Dec. 6-9.
"During the last 30 years, the overall five-year relative survival rates for head and neck squamous cell carcinoma (HNSCC) 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, Dr.P.H., assistant professor at Johns Hopkins University in Baltimore, Md. "This disparity may be due to differences in genetic and epigenetic alterations among African-American patients."
To test this theory, Guerrero-Preston and colleagues performed a two-stage epigenomic study. In the stage-one discovery phase, the researchers used next-generation sequencing and array-based technologies to evaluate 107 HNSCC samples. In the stage-two validation phase, they validated the findings of the discovery phase and evaluated their effect on survival rates in 279 patient samples from The Cancer Genome Atlas project.
"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. "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."
The researchers found that African-American HNSCC patients had higher frequencies of p53, FBXW7, and NOTCH1 mutations and no differences in PAX1 or PAX5 methylation across all tumor sites combined. However, when they looked at data based on each tumor site, some differences were discovered.
African-American patients with HNSCC had higher ZIC4, PLCB1, and PAX5 promoter methylation and p53 mutations compared with non-Latino white patients. African-American patients also had no NOTCH1 mutations in nonoropharynx HNSCC. However, in the oropharynx, African-American patients had a higher frequency of combined NOTCH1 mutations and PAX1 methylation.
In contrast, non-Latino white patients with HNSCC had a higher frequency of PAX5 promoter methylation and combined p53 mutation or PAX5 methylation in the oropharynx compared with African-American patients.
All patients with greater PAX5 methylation and p53 mutations had worse overall survival, the researchers found.
This study was funded by the National Cancer Institute, the National Institute of Dental and Craniofacial Research grants, Head and Neck Cancer SPORE, and the Johns Hopkins University Commonwealth Fund. Guerrero-Preston declared no conflicts of interest.
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Abstract Number: PR06
Presenter: Rafael Guerrero-Preston, Dr.P.H.
Title: Integrated genomic and epigenomic deep sequencing analyses reveal head and neck cancer survival disparities associated to alterations in the PAX, NOTCH1 and TP53 pathways
Authors: Rafael Guerrero-Preston, Tal Hadar, Christina Michailidi, Luigi Marchionni, Wayne Koch, David Sidransky. Johns Hopkins University, Baltimore, MD.
Black and Puerto Rican men have a higher head and neck cancer (HNSCC) burden than Non-Latino White (NLW) men in the United States, but the biological basis for these health disparities are poorly understood. The disparity in overall HNSCC survival rates between NLW and Black patients in the United States has remained at 18% for more than 30 years. This survival disparity in HNSCC may be due, among other factors, to a different profile of genetic and epigenetic alterations among Black patients. However, there is a lack of molecular or genomic studies that examine health disparities in HNSCC.
We performed an integrated molecular analysis using methylation sequencing, exome sequencing, mRNA expression and qPCR platforms in 107 head and neck squamous cell carcinoma (HNSCC) samples. Our findings were validated in 279 samples from The Cancer Genome Atlas (TCGA) project.
We uncovered 316 genes harboring cancer specific promoter methylation and identified 10 tumor suppressor genes with concurrent promoter methylation and somatic mutations. We found clustering of genetic and epigenetic events that distinguished smokers from non-smokers, HPV positive from HPV negative tumors, and Blacks from NLW HNSCC patients.
We observed disparities in the frequency of mutated and methylated events in the PAX, NOTCH1 and TP53 pathways. Black HNSCC patients have higher frequencies of TP53 (B-50% vs 39%), FBXW7 (B-13% vs 7%), and NOTCH1 (B-25% vs 16%) mutations and no differences in PAX1 (B-63% vs 65%) or PAX5 (B-86% vs 88%) greater promoter methylation across all tumor sites combined. Interestingly, these patterns differed when we stratified on tumor site. Blacks have higher ZIC4 (B-100% vs 70%), PLCB1 (B-60% vs 50%), and PAX5 (B-80% vs 73%) greater promoter methylation and p53 (B-60% vs 48%) mutations than NLW, and no NOTCH1 (B-0% vs 18%) mutations, outside the oropharynx. Conversely, NLW have a higher frequency of PAX5 (B-67% vs 86%) greater promoter methylation in the oropharynx when compared with Blacks. In the oropharynx NLW also had a higher frequency of combined p53mut or PAX5met (B-14% vs 33%), while Blacks had a higher frequency of combined NOTCH1mut or PAX1met (B-33% vs 10%). We found that for all HNSCC patients combined, PAX5 greater promoter methylation and p53 mutations had worse overall survival than patients with p53 mutations. Survival analyses revealed that overall HNSCC survival disparities were associated to age and PAX5 greater promoter methylation.
Co-localization analyses uncovered genomic and epigenomic alterations in the PAX gene family, which selectively impact canonical NOTCH and TP53 pathways to determine cell fate, cell survival, and genome maintenance. Our results highlight the differential genomic and epigenomic alterations between PAX, NOTCH, and p53 pathways in Black and NLW HNSCC patients, which underlie the complex biology of morphologically similar tumors and explain HNSCC survival disparities.