Fig. 4: Germline genetic susceptibility to ThC and BNG.

We hypothesize that two biological processes with distinct genetic architecture cause thyroid nodules: (1) hyperplasia, a polyclonal follicular cell proliferation with no malignant potential; and (2) neoplasia, a clonal growth driven by somatic genetic alterations. Neoplastic nodules can be benign or malignant, and the mismatch between biological mechanisms (hyperplasia and neoplasia) and GWAS phenotype definitions (benign and malignant thyroid nodules) has led to apparent genetic pleiotropy. The pathway and genes associated with BNG but not ThC in the GWAS meta-analysis (for example, the insulin-like growth factor 1 (IGF1) and fibroblast growth factor (FGF) signaling pathways) predispose to benign nodules. Pathways and genes associated with both BNG and ThC (for example, telomere maintenance) predispose to neoplastic thyroid nodules, either benign or malignant. In the absence of other genetic risk factors, patients develop benign adenomas or low-risk ThCs. Alternatively, genetic alterations in cell cycle and DNA damage response genes (associated predominantly with ThC but not BNG in the GWAS meta-analysis) predispose to high-risk ThC.