Thyroglobulin in Metastatic Thyroid Cancer: Culprit or Red Herring?

To the Editor: Siraj et al. have presented an interesting paper on a highly relevant topic—understanding the biological relevance of diagnostic or prognostic markers for papillary thyroid cancer (PTC).1 The study included a large PTC series (>800) from Saudi Arabia, a geographic region known to be highly enriched with thyroid cancer. In addition to identifying genes in the RAS/MAPK signaling pathway (BRAF [MIM: 164757], KRAS [MIM: 190070], NRAS [MIM: 164790], and HRAS [MIM 190020]), which are well established as oncogenic drivers in PTC, the authors found other genes that were somatically mutated in their cohort. Of these genes, the authors focused on thyroglobulin (TG [MIM: 188450]), shown to be somatically mutated in ～3% of thyroid tumors. Statistical analysis of clinicopathological parameters revealed that TG somatic mutations were associated with poorer clinical outcome. Finally, the authors noted a higher enrichment of TG somatic mutations in metastatic PTC tissues and suggested clonal expansion from the primary tumors. Although these findings are compelling and translationally relevant, some fundamental aspects remain to be addressed