Deconvolving mutation and selection reveals stage-specific drivers of thyroid cancer

ObjectiveMutational profiles of primary and metastatic thyroid cancer (THCA) have been examined by comparison of somatic mutation prevalences in the two stages, using P values to identify significant differences. However, prevalences and P values for mutations do not directly quantify the cancer effects of somatic variants. MethodsWe calculated cancer effect sizes accounting for substantial gene- and site-specific mutation rates, to quantify somatic selection across stages. This approach provides a direct measure of cancer-driving impact of new mutations and reveals the genes that drive tumorigenesis and progression, and whether mutations have greater effects in primary or metastatic THCA. ResultsTrinucleotide mutation profiles were similar between primary and metastatic THCA. Most canonical driver genes (BRAF, NRAS, TP53, ATM, EIF1AX, KMT2C, NF1, RBM10, ARID1A, PIK3CA, and NKX2-1) exhibited stronger selection during initial tumorigenesis (from organogenesis to primary THCA) than during progression (from primary to metastatic THCA). Notably, TERT mutations have been shown to be at higher prevalence in metastatic tumors, yet their strongest selection occurred earlier, during tumor initiation. In contrast, RET mutations exhibited the opposite trajectory, experiencing weaker selection during tumorigenesis but stronger selection during metastatic progression. ConclusionCancer effect size analysis revealed dynamic shifts in selective pressures across THCA evolution, distinguishing genes that drive initiation from those that promote metastatic progression. This evolutionary framework provides a quantitative basis for understanding THCA pathogenesis and provides guidance for stage-specific precision-medicine therapeutic strategies.