Risk Haplotypes Uniquely Associated with Radioiodine-Refractory Thyroid Cancer Patients of High African Ancestry

Thyroid. 2019 Apr;29(4):530-539. doi: 10.1089/thy.2018.0687. Epub 2019 Feb 13.

Abstract

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. It was hypothesized 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 1145 Caucasian (CAU) patients, 244 of whom were RAI-R, and 55 African American (AA) patients, nine 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 led to the study focusing on germline single nucleotide polymorphisms uniquely associated with RAI-R AA patients. Sanger sequencing was performed to validate risk alleles and identify the incidence of the common somatic mutations BRAFV600E, NRASQ61R, and HRASQ61R in AA patients whose primary tumor samples were available (28/55).

Results: TG, BRCA1, and NSMCE2 haplotypes were identified as being 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 three out of four patients with the NSMCE2 haplotype. The incidence of BRAFV600E appears lower in papillary thyroid carcinomas from AA patients of >80% African ancestry (3/14; 21%) than in AA patients of <80% African ancestry (6/9; 67%), albeit only just approaching statistical significance (p = 0.077). The tumors available from three RAI-R AA patients were negative for BRAFV600E, NRASQ61R, and 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 insights into the mechanisms underlying RAI-R disease.

Keywords: African American; germline variants; radioiodine refractory; thyroid cancer.

Publication types

  • Comparative Study
  • Multicenter Study
  • Research Support, N.I.H., Extramural

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • BRCA1 Protein / genetics
  • Biomarkers, Tumor / genetics*
  • Black or African American / genetics*
  • Female
  • Genetic Predisposition to Disease
  • Germ-Line Mutation*
  • Haplotypes
  • Humans
  • Incidence
  • Iodine Radioisotopes / therapeutic use*
  • Ligases / genetics
  • Male
  • Middle Aged
  • Phenotype
  • Polymorphism, Single Nucleotide*
  • Proto-Oncogene Proteins B-raf / genetics
  • Radiation Tolerance / genetics*
  • Radiopharmaceuticals / therapeutic use*
  • Risk Assessment
  • Risk Factors
  • Thyroglobulin / genetics
  • Thyroid Neoplasms / ethnology
  • Thyroid Neoplasms / genetics*
  • Thyroid Neoplasms / pathology
  • Thyroid Neoplasms / radiotherapy*
  • United States / epidemiology
  • White People / genetics*
  • Young Adult

Substances

  • BRCA1 Protein
  • BRCA1 protein, human
  • Biomarkers, Tumor
  • Iodine Radioisotopes
  • Radiopharmaceuticals
  • TG protein, human
  • Thyroglobulin
  • BRAF protein, human
  • Proto-Oncogene Proteins B-raf
  • Ligases
  • NSMCE2 protein, human