BACKGROUND : African American (AA) thyroid cancer patients have worse prognoses than European Americans (EA) which has been attributed to both healthcare disparities and possible genetic differences. We investigated the impact of both germline and somatic variants on clinical outcome in a cohort of AA non-medullary thyroid cancer (NMTC) patients who had received therapeutic intervention from cancer centers.

METHODS : Whole exome sequencing was performed on DNA from available blood/normal tissues (N=37) and paired tumor samples (N=32) collected from 37 and 29 AA NMTC patients, respectively. Variants with CADD score of ≥20 and VarSome Clinical classification of likely pathogenic or pathogenic were classified as presumed pathogenic germline or somatic variants (PPGV/PPSVs). PPGV/PPSVs in cancer-related genes and PPGVs in cardiovascular risk genes were further investigated, and PPGV/PPSVs associated with African (AFR) ancestry were identified.

RESULTS : Among 17 PPGVs identified in 16 cancer predisposition or known cancer-related genes, only WRN was previously known to associate with NMTC predisposition. Among PPSVs, BRAFV600E was most prevalent and detected in 12 of the 29 (41%) tumors. Examining PPGV/PPSVs among 3 patients who died from NMTC, one patient who died from papillary thyroid carcinoma/anaplastic thyroid carcinoma (PTC/ATC) led us to speculate that the PPGV ERCC4R799W may have increased the risk of PPSV TP53R273H acquisition. Among PPGVs identified in 18 cardiovascular risk genes, PPGVs in SC5NA, GYG1, CBS, CFTR, and SI are known to have causal and pathogenic implications in cardiovascular disease.

CONCLUSION : In this cohort, most AA-NMTC patients exhibit favorable outcomes after therapeutic intervention given at cancer centers, suggesting that healthcare disparity is the major contributor for worse prognoses among AA-NMTC patients. Nevertheless, the clinical impact of PPGVs that might facilitate acquisition of TP53 tumor mutations, and/or PPGVs that predispose individuals to adverse cardiovascular events which could be exacerbated by therapy-induced cardiotoxicity, need to be further explored. Integrated analysis of PPGV/PPSV profiles among NMTC patients with different stages of disease may help to identify NMTC patients who require close monitoring or proactive intervention.