The influence of age-independent somatic driver alterations on clinical outcomes in paediatric and young adult thyroid cancer

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Background: Paediatric and young adult differentiated thyroid carcinoma (DTC) often presents at an advanced stage but carries an excellent prognosis. While age-related genomic differences from adult DTC are recognized, it remains unclear whether outcomes are driven by age or tumour biology. Methods: We analysed a multi-institutional cohort of 363 patients aged 0-25 years who underwent molecular testing and surgical management. Age was categorized using cut-offs at ≤8, 9-14, 15-18, and 19-25 years. The primary endpoint was disease status at last follow-up, categorized according to American Thyroid Association (ATA) response criteria. Multivariable ordered logistic regression was used to test the independent prognostic effect of somatic driver mutations while adjusting for age, sex, and follow-up duration. Results: Distinct age-related patterns of oncogenic drivers were observed: RET and NTRK1/3 fusions were predominant in younger patients, BRAF V600E was most frequent in adolescents, and RAS mutations were enriched in young adults. After adjustment, driver mutations independently predicted long-term outcomes. NTRK1/3 fusions (aOR = 5.29, 95% CI: 1.77-15.79), BRAF V600E (aOR = 3.45, 95% CI: 1.37-8.70), and RET fusions (aOR = 3.34, 95% CI: 1.13-9.90) were associated with significantly higher odds of a non-excellent outcome. Conversely, RAS mutations showed a favourable trend, and all DICER1-mutant cases achieved excellent outcomes. While prognosis steadily improved with age, mutation status remained the dominant factor determining outcomes. Conclusion: Somatic drivers offer prognostic insights independent of age in paediatric and young adult DTC, establishing a molecular framework for precision risk stratification that complements traditional clinical staging and age-based assessments.

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