Risk Haplotypes Uniquely Associated with Radioiodine Refractory Thyroid Cancer Patients of High African Ancestry. Thyroid : official journal of the American Thyroid Association Hurst, Z., Liyanarachchi, S., He, H., Brock, P., Sipos, J. A., Nabhan, F., Kebebew, E., Green, P., Cote, G. J., Sherman, S. I., Walker, C. J., Chang, Y. S., Xue, S., Hollingsworth, B., Li, W., Genutis, L., Menq, E., de la Chapelle, A., Jhiang, S. M. 2019


BACKGROUND: Thyroid cancer patients with radioiodine refractory (RAI-R) disease, resulting from insufficient RAI delivery and/or RAI resistance, have increased mortality and limited treatment options. To date, studies have largely focused on tumor mutations associated with different stages of disease, which could provide prognostic value for RAI-R disease. We hypothesize that germline variants contributing to intrinsic differences in iodine metabolism, tumor microenvironment and/or immune surveillance are associated with RAI-R disease.METHODS: Whole-genome genotyping data analysis was performed on 1,145 Caucasian (CAU) patients, 244 of whom were RAI-R, and 55 African American (AA) patients, 9 of whom were RAI-R. Germline variant association studies were conducted using candidate genes involved in iodine metabolism or DNA-damage repair, as well as genome-wide association analysis. Initial data indicated several notable variants in a small number of patients (N=7), who were later determined to be AA patients of >80% African ancestry (N=37). This prompted us to focus on germline SNPs uniquely associated with RAI-R AA patients. Sanger sequencing was performed to validate risk alleles and identify the incidence of common somatic mutations BRAFV600E, NRASQ61R, and HRASQ61R, in AA patients whose primary tumor samples were available (N=28/55).RESULTS: We identified TG, BRCA1 and NSMCE2 haplotypes uniquely associated with RAI-R AA patients of >80% African ancestry. All patients with the TG haplotype (N=4) had a biochemical incomplete response to RAI therapy. Patients with the NSMCE2 haplotype (N=4) were diagnosed at a young age (13, 17, 17, and 26 years old) with distant metastatic disease at initial diagnosis. The BRCA1 haplotype co-occurred in 3/4 patients with the NSMCE2 haplotype. The incidence of BRAFV600E appears lower in papillary thyroid carcinoma (PTC) from AA patients of >80% African ancestry (N=3/14, 21%) than in AA patients of <80% African ancestry (N=6/9, 67%), albeit only approaching statistical significance (p=0.077). The tumors available from three RAI-R AA patients were negative for BRAFV600E, NRASQ61R, HRASQ61R.CONCLUSIONS: The identification of candidate RAI-R risk haplotypes may allow early stratification of clinical manifestations of RAI-R disease followed by early intervention and personalized treatment strategies. Functional annotation of candidate RAI-R risk haplotypes may provide insight into the mechanisms underlying RAI-R disease.

View details for PubMedID 30654714