Abstract PR6: Integrated genomic and epigenomic deep sequencing analyses reveal head and neck cancer survival disparities associated to alterations in the PAX, NOTCH1 and TP53 pathways (2014)

Abstract 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. This abstract is also presented as Poster A87. Citation Format: Rafael Guerrero-Preston, Tal Hadar, Christina Michailidi, Luigi Marchionni, Wayne Koch, David Sidransky. Integrated genomic and epigenomic deep sequencing analyses reveal head and neck cancer survival disparities associated to alterations in the PAX, NOTCH1 and TP53 pathways. [abstract]. In: Proceedings of the Sixth AACR Conference: The Science of Cancer Health Disparities; Dec 6–9, 2013; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2014;23(11 Suppl):Abstract nr PR6. doi:10.1158/1538-7755.DISP13-PR6