JAK3 Variant, Immune Signatures, DNA Methylation, and Social Determinants Linked to Survival Racial Disparities in Head and Neck Cancer Patients

Abstract

To inform novel personalized medicine approaches for race and socioeconomic disparities in head and neck cancer, we examined germline and somatic mutations, immune signatures, and epigenetic alterations linked to neighborhood determinants of health in Black and non-Latino White (NLW) patients with head and neck cancer. Cox proportional hazards revealed that Black patients with squamous cell carcinoma of head and neck (HNSCC) with PAX5 (P = 0.06) and PAX1 (P = 0.017) promoter methylation had worse survival than NLW patients, after controlling for education, zipcode, and tumor-node-metastasis stage (n = 118). We also found that promoter methylation of PAX1 and PAX5 (n = 78), was correlated with neighborhood characteristics at the zip-code level (P < 0.05). Analyses also showed differences in the frequency of TP53 mutations (n = 32) and tumor-infiltrating lymphocyte (TIL) counts (n = 24), and the presence of a specific C → A germline mutation in JAK3, chr19:17954215 (protein P132T), in Black patients with HNSCC (n = 73; P < 0.05), when compared with NLW (n = 37) patients. TIL counts are associated (P = 0.035) with long-term (>5 years), when compared with short-term survival (<2 years). We show bio-social determinants of health associated with survival in Black patients with HNSCC, which together with racial differences shown in germline mutations, somatic mutations, and TIL counts, suggests that contextual factors may significantly inform precision oncology services for diverse populations.

Figure 1.

Venn diagrams that show the intersection of genes that in 49 AA and NLW HNSCC patients compared to 51 UPPP controls.

Figure 2.

Choropleth maps geographically depicted the spatial distribution of selected variables at the zipcode level for all the HNSCC patients in our cohort who reside in Baltimore: (2A) PAX5 promoter methylation map (in quartiles); and (2B) home vacancy rates map (zip code level). Darker colors represent a higher quartile in the PAX5 promoter methylation map, or a higher percentage of home vacancies per zip code in the home vacancy map. Choropleth thematic maps were labeled with zip-code level information for two zipcodes that represent opposite ends of the socio-economic spectrum in Baltimore: Roland Park (21210) and Madison/East End (21205). The residents of Roland Park have a median annual income of $90,492 (the highest in Baltimore City), while the residents of Madison/ East End have a median annual income of $30,389.

Figure 3

A) Pooled logistic regression analysis showed a marginally significant association between the percentage of residents with High School Diploma at the zip-code level (HD) with PAX5 (p=0.09) and PAX1 (p=0.05) promoter methylation. 3B) Multivariable Cox proportional hazards regression analysis shows that AA patients with PAX5 (p=0.06) and PAX1 (p=0.017) promoter methylation had worse survival than NLW, after controlling for HD, zipcode and TNM stage.

Figure 4.

Results from a Kaplan Meier analysis of 279 HNSCC patients from TCGA. (A). Patients with promoter methylation of PAX5 have worse outcomes than patients without PAX5 methylation (p=0.026). (B) Patients with combined somatic TP53 mutations and PAX5 promoter methylation have poorer outcomes when compared to patients with TP53 mutations, who do not have PAX5 methylation (p<0.012).

Figure 5.

Tumor Infiltrating lymphocytes (TILs) as immuno-oncology determinants in HNSCC, quantified with the QuanTILfy assay, a droplet digital PCR assay. Larger numbers of TILs are associated with survival (5A), larynx cancer (5B) and Black race (5C).

Figure 6

A. Molecular markers, combined with external and internal environment variables, can be used as biosocial markers of head and neck cancer outcome disparities, head and neck cancer markers and precision medicine markers for head and neck cancer patients. Figure 6B shows that PAX5 methylation levels inversely correlate (r=−0.83) with TIL counts in HNSCC patients. Figure 6C shows that JAK3 expression in Black HNSCC patients differs by anatomic location. Figure 6D shows that Notch1 mutations and PAX1 methylation levels also differ by anatomic location and race in HNSCC patients.