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Impact of Co-Mutations and Genetic Variations on Malignancy Risk in RAS-Positive Indeterminate Thyroid Nodules: an

Lawrence Q Wong1, Zubair W Baloch2

  • 1Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, 6 Founders Pavilion, 3400 Spruce Street, Philadelphia, PA, 19104, USA.

Endocrine Pathology
|March 5, 2026
PubMed

Insights

RAS mutations in thyroid nodules are common but their prognostic role is unclear. Co-occurring genetic alterations with RAS mutations significantly increase malignancy risk, unlike isolated RAS mutations, highlighting the need for comprehensive molecular profiling.

Area of Science:

  • Endocrinology
  • Oncology
  • Molecular Biology

Background:

  • RAS proto-oncogenes (NRAS, HRAS, KRAS) mutations are frequently detected in thyroid nodules.
  • The prognostic significance of RAS mutations, especially in conjunction with other genetic alterations, remains incompletely understood.
  • Accurate risk stratification of thyroid nodules is crucial for appropriate patient management.

Purpose of the Study:

  • To investigate the clinical and pathological implications of isolated RAS mutations versus RAS mutations with co-occurring genetic alterations in thyroid nodules.
  • To determine the association between specific molecular profiles and the risk of malignancy.
  • To evaluate the impact of co-occurring mutations on tumor aggressiveness.

Main Methods:

  • Retrospective analysis of 354 thyroid nodules from 346 patients diagnosed between 2018 and 2023.
  • Comprehensive molecular profiling to identify RAS mutations and co-occurring genetic alterations (e.g., EIF1AX, TERT).
  • Correlation of molecular findings with clinical data, pathological diagnoses, and surgical follow-up outcomes.

Main Results:

  • Isolated RAS mutations were found in 41.0% of nodules, while 54.8% had RAS with additional alterations; NRAS was the most frequent RAS subtype.
  • Malignancy rate was 52.3% overall, with NRAS mutations in 64.6% of malignant cases.
  • Nodules with RAS mutations plus concomitant alterations showed a significantly higher malignancy risk (54.3% with one additional alteration, nearly 100% with three) compared to isolated RAS mutations (p=0.0026).
  • Isolated RAS mutations were more frequently associated with benign or indolent neoplasms, whereas co-occurring mutations indicated more aggressive phenotypes.

Conclusions:

  • Co-occurring genetic alterations with RAS mutations substantially increase thyroid nodule malignancy risk and are linked to aggressive tumor phenotypes.
  • Isolated RAS mutations are more often found in indolent neoplasms.
  • Comprehensive molecular profiling is essential for precise risk stratification and guiding the management of indeterminate thyroid nodules.
Keywords:
NRAS/HRAS/KRASRAS mutationFollicular-patterned lesionsIEFVPTCIndeterminate cytologyNIFTPNext-generation sequencingThyroid nodule

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