Immune cell infiltrate-associated dysregulation of DNA repair machinery may predispose to papillary thyroid carcinogenesis

Surgery. 2020 Jan;167(1):66-72. doi: 10.1016/j.surg.2019.02.024. Epub 2019 Aug 19.

Abstract

Background: An altered immune microenvironment may contribute to papillary thyroid cancer development, as immune infiltrates are identified postoperatively in many papillary thyroid cancer cases with or without diagnosed thyroiditis. Oxygen radicals, endogenous or inflammation-induced, can generate DNA damage, which causes mutations when repaired incorrectly. We hypothesized that infiltrating immune cells might promote aberrant DNA repair, predisposing thyrocytes to papillary thyroid cancer.

Methods: Quantitative reverse-transcriptase polymerase chain reaction assays measured gene expression in fresh-frozen samples (n = 55). RNA-seq data was obtained for papillary thyroid cancer and normal thyroid samples from the Cancer Genome Atlas (n = 564), and Hashimoto's-affected and normal thyroids from the Genotype-Tissue Expression project (n = 279). Immune cell marker expression levels were compared to histological estimates and to selected DNA repair genes. Immunohistochemistry localized gene expression to specific cell types.

Results: DNA polymerase theta expression by quantitative reverse-transcriptase Polymerase chain reaction was higher in papillary thyroid cancer and papillary thyroid cancer-adjacent samples than in benign normal thyroid (P < .001). Immune markers including CD4 correlated with DNA polymerase theta expression (r = 0.50) but not other DNA repair genes examined. Benign tissue with Hashimoto's exhibited increased DNA polymerase theta (P < .0001) and CD3E (P < .0001) expression. DNA polymerase theta localized to thyrocytes, not lymphocytes.

Conclusion: We identified a strong correlation between immune cell infiltrate and dysregulated thyrocyte DNA repair genes, likely reflecting a pathway to papillary thyroid cancer development.

MeSH terms

  • Adult
  • CD4-Positive T-Lymphocytes / immunology
  • CD4-Positive T-Lymphocytes / metabolism
  • Carcinogenesis / genetics*
  • Carcinogenesis / immunology
  • DNA Repair / immunology*
  • DNA-Directed DNA Polymerase / immunology
  • DNA-Directed DNA Polymerase / metabolism
  • Female
  • Humans
  • Lymphocytes, Tumor-Infiltrating / immunology*
  • Male
  • RNA-Seq
  • Reactive Oxygen Species / immunology
  • Thyroid Cancer, Papillary / genetics
  • Thyroid Cancer, Papillary / immunology*
  • Thyroid Cancer, Papillary / surgery
  • Thyroid Epithelial Cells / immunology
  • Thyroid Epithelial Cells / metabolism
  • Thyroid Epithelial Cells / pathology
  • Thyroid Gland / cytology
  • Thyroid Gland / immunology
  • Thyroid Gland / pathology
  • Thyroid Gland / surgery
  • Thyroid Neoplasms / genetics
  • Thyroid Neoplasms / immunology*
  • Thyroid Neoplasms / surgery
  • Thyroidectomy
  • Tumor Microenvironment / immunology

Substances

  • Reactive Oxygen Species
  • DNA polymerase theta
  • DNA-Directed DNA Polymerase