RET p.Cys634-driven progression of hereditary vs. sporadic medullary thyroid cancer

Conceptually, pitting hereditary mutations, pervading all cells of the body since conception, against the same sporadic mutations, acquired by tumor cells only later in life, could give valuable insights into tumorigenesis and tumor progression. This research sought to explore RET p.Cys634-driven tumorigenesis and progression which, preceding the time of clinical detection, cannot be measured directly.

Comparative study of 14 previously untreated index patients with hereditary medullary thyroid cancer (MTC) and 15 previously untreated patients with sporadic MTC who presented with a diagnosis of MTC, for which they underwent initial neck surgery at a tertiary referral center.

After Bonferroni correction for multiple testing, only few variables continued to differ significantly between RET p.Cys634-driven hereditary and sporadic MTC: age at thyroidectomy (medians of 33.5 vs. 54 years; P <0.001), and multifocal growth (79 vs. 7%, and medians of 2 foci vs. 1 focus; both P <0.001).

The present investigation suggests that tumor progression in MTC before clinical detection is a function of the time passed since tumor onset, whereas tumor onset is defined by the transformatory strength of the RET mutation. This notion, debunking the myth of immanent tumor ‘aggressiveness’ or “risk” imparted by RET mutations in favor of the concept of genetically encoded tumor onset, emphasizes the need for early diagnosis and intervention, ideally while tumors are still confined to the thyroid.