Investigation of genetic sex-specific molecular profile in well-differentiated thyroid cancer: Is there a difference between females and males?

Background: Although more common in females, thyroid cancer is deemed to be more aggressive in males. The reasons for sex disparities in thyroid cancer are not well understood. We hypothesised that differences in molecular mutations between females and males contribute to this phenomenon.

Methods: Retrospective multicentre multinational study of thyroid nodules that underwent preoperative molecular profiling between 2015 and 2022. The clinical characteristics and mutational profiles of tumours in female and male patients were compared. Collected data included demographics, cytology results, surgical pathology, and molecular alterations.

Results: A total of 738 patients were included of which 571 (77.4%) were females. The extrathyroidal extension was more common in malignancies in males (chi-squared, p = 0.028). The rate of point mutations and gene fusions were similar in both sex groups (p > 0.05 for all mutations). Patients with nodules with BRAF mutations were significantly younger than BRAF wild-type nodule patients (t-test, p = 0.0001). Conversely, patients with TERT promoter mutations were significantly older than patients with wild-type TERT (t-test, p < 0.0001). For patients harbouring both BRAF and TERT mutations, the difference in age at presentation was significantly different in females (t-test, p = 0.009) but not in males (t-test, p = 0.433). Among females, patients with BRAF and TERT mutations were significantly older than their wild-type or single-mutation counterpart (t-test, p = 0.003).

Conclusion: The absolute rate of molecular mutations was similar in females and males. We found that extrathyroidal extension was more common in males. Moreover, BRAF and TERT mutations occur at a younger age in males than in females. These two findings are factors that may explain the tendency of more aggressive disease in males.