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<p>Thyroid cancer is the most common endocrine malignancy, yet its biological underpinnings remain incompletely understood. Here we show that common risk alleles for thyroid cancer point to distinct biological pathways underlying disease susceptibility. We perform a multi-ancestry genome-wide association meta-analysis of thyroid cancer (16,167 cases and 2,430,374 controls), identifying 51 independent loci, including 21 not previously reported. By integrating these loci with genetic associations for 151 thyroid-cancer-related traits, we identify pleiotropic mechanistic clusters linked to thyroid function, oncogenic pathways, and mixed physiological function. Two thyroid-specific clusters, associated with thyroid stimulating hormone or thyroid growth and function, are enriched in thyroid tissues. Oncogenic clusters include DNA repair (<i>ATM</i>, <i>CHEK2</i>, <i>TP53</i>) and telomere maintenance (<i>TERT</i>) genes, implicating shared cancer mechanisms. Cluster-specific polygenic scores are associated with thyroid disease, cancer, and metabolic traits across ancestry groups, suggesting distinct genetic subtypes of thyroid cancer risk and supporting pleiotropy-based approaches to genetic risk stratification.</p>

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Genetic drivers of etiologic heterogeneity in thyroid cancer

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月10日

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  • Yon Ho Jee,
  • Nikita Pozdeyev,
  • Christopher R. Gignoux,
  • Samantha White,
  • Bryan R. Haugen,
  • Anurag Verma,
  • Raitis Peculis,
  • Vita Rovite,
  • Ashley J. Mulford,
  • Alan R. Sanders,
  • Cari M. Kitahara,
  • Mary Pat Reeve,
  • Peter Kraft,
  • Alicia R. Martin

摘要

Thyroid cancer is the most common endocrine malignancy, yet its biological underpinnings remain incompletely understood. Here we show that common risk alleles for thyroid cancer point to distinct biological pathways underlying disease susceptibility. We perform a multi-ancestry genome-wide association meta-analysis of thyroid cancer (16,167 cases and 2,430,374 controls), identifying 51 independent loci, including 21 not previously reported. By integrating these loci with genetic associations for 151 thyroid-cancer-related traits, we identify pleiotropic mechanistic clusters linked to thyroid function, oncogenic pathways, and mixed physiological function. Two thyroid-specific clusters, associated with thyroid stimulating hormone or thyroid growth and function, are enriched in thyroid tissues. Oncogenic clusters include DNA repair (ATM, CHEK2, TP53) and telomere maintenance (TERT) genes, implicating shared cancer mechanisms. Cluster-specific polygenic scores are associated with thyroid disease, cancer, and metabolic traits across ancestry groups, suggesting distinct genetic subtypes of thyroid cancer risk and supporting pleiotropy-based approaches to genetic risk stratification.