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Purpose <p>Earlier guidelines for multiple endocrine neoplasia type 2 (MEN 2) imply that certain <i>RET</i> germline mutations cause more “<i>aggressive</i>” MEN 2 phenotypes, specifically more <i>“aggressive</i>” medullary thyroid cancer (MTC). This research aimed to evaluate tumor onset versus tumor invasion and metastasis in MEN 2.</p> Methods <p>Tumor onset (tumorigenesis) versus tumor invasion and metastasis (aggressiveness) were explored using Kaplan-Meier analyses and log-rank test stratified by <i>RET</i> category, index status, tumor entity (MTC, pheochromocytoma, primary hyperparathyroidism), and MTC progression (node metastases, extranodal growth, distant metastases).</p> Results <p>Included were 708 patients (222 index and 486 non-index patients) with germline mutations falling into the highest (55 carriers), high (249 carriers), intermediate (182 carriers) and low (222 carriers) <i>RET</i> category. Onset and penetrance of MTC, pheochromocytoma and primary hyperparathyroidism differed significantly between <i>RET</i> categories, with little difference between index and non-index patients. Only 1 (0.5%) of 210 pheochromocytomas and 0 of 34 parathyroid tumors were malignant. Node metastases were associated with 8.1–18.8&#xa0;mm larger MTCs, taking significantly more time to develop. In index and non-index patients with node positive MTC, no appreciable lead time preceding the development of extranodal growth or distant metastases was noted in any <i>RET</i> category, implicating other causative factors than time or strength of the RET mutation.</p> Conclusion <p><i>RET</i> germline mutations drive tumorigenesis but not tumor aggressiveness. This finding, warranting further research into the drivers of tumor invasion and metastasis, reenforces the need for early tumor detection and prompt surgical intervention to reduce morbidity and mortality in MEN 2.</p>

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RET germline mutations drive tumorigenesis but not tumor aggressiveness in MEN 2

  • 期刊论文

  • 发表日期：

    2026年2月16日

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  • Andreas Machens,
  • Henning Dralle,
  • Kerstin Lorenz

摘要

Purpose

Earlier guidelines for multiple endocrine neoplasia type 2 (MEN 2) imply that certain RET germline mutations cause more “aggressive” MEN 2 phenotypes, specifically more “aggressive” medullary thyroid cancer (MTC). This research aimed to evaluate tumor onset versus tumor invasion and metastasis in MEN 2.

Methods

Tumor onset (tumorigenesis) versus tumor invasion and metastasis (aggressiveness) were explored using Kaplan-Meier analyses and log-rank test stratified by RET category, index status, tumor entity (MTC, pheochromocytoma, primary hyperparathyroidism), and MTC progression (node metastases, extranodal growth, distant metastases).

Results

Included were 708 patients (222 index and 486 non-index patients) with germline mutations falling into the highest (55 carriers), high (249 carriers), intermediate (182 carriers) and low (222 carriers) RET category. Onset and penetrance of MTC, pheochromocytoma and primary hyperparathyroidism differed significantly between RET categories, with little difference between index and non-index patients. Only 1 (0.5%) of 210 pheochromocytomas and 0 of 34 parathyroid tumors were malignant. Node metastases were associated with 8.1–18.8 mm larger MTCs, taking significantly more time to develop. In index and non-index patients with node positive MTC, no appreciable lead time preceding the development of extranodal growth or distant metastases was noted in any RET category, implicating other causative factors than time or strength of the RET mutation.

Conclusion

RET germline mutations drive tumorigenesis but not tumor aggressiveness. This finding, warranting further research into the drivers of tumor invasion and metastasis, reenforces the need for early tumor detection and prompt surgical intervention to reduce morbidity and mortality in MEN 2.