Genetic drivers of etiologic heterogeneity in thyroid cancer
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Thyroid cancer is the most common endocrine malignancy, yet its biological underpinnings remain incompletely understood. We conducted a multi-ancestry genome-wide association study meta-analysis of thyroid cancer (16,167 cases and 2,430,374 controls), identifying 51 independent loci, including 21 novel signals. We analyzed the associations of thyroid cancer risk alleles with 151 other thyroid-cancer-related traits. These pleiotropic relationships reveal mechanistic clusters linked to thyroid function, oncogenic pathways, and mixed physiological function. Two thyroid-specific clusters associated with thyroid stimulating hormone, influencing thyroid growth and function and were enriched in thyroid tissues. Oncogenic clusters included DNA repair ( ATM , CHEK2 , TP53 ) and telomere maintenance ( TERT ) genes, implicating shared cancer mechanisms. Cluster-specific polygenic scores were associated with thyroid disease, cancer, and metabolic traits across ancestry groups, suggesting distinct genetic subtypes of thyroid cancer risk. These results demonstrate the utility of pleiotropy-based approaches in uncovering thyroid cancer mechanisms and advancing genetically informed risk stratification.
