This cohort study refers to patients who were diagnosed with familial medullary thyroid carcinoma (MTC) and underwent RET genetic testing in Cyprus between years 2002 and 2017.
When grouped by mutational risk (highest; high; moderate-high; low-moderate; polymorphism), the age-related progression of MTC was significant for all four categories of RET mutations, which differed significantly across and within the three histopathological groups.
Expression analysis found an increase of RET transcript in p.Cys630=;p.Cys634Arg patient compared with that found in 7 MTCs harboring p.Cys634 mutations.
Together these findings identify germline ESR2 mutation as a novel cause of familial MTC/CCH and provide important insights into a novel mechanism causing increased RET expression in tumourigenesis.
Polyphen-2 Hum Div/Var may provide additional clinical data to help distinguish benign from MEN2/familial medullary thyroid carcinoma-causing RET variants as well as less aggressive phenotypes (ATA A) from more aggressive ones (ATA B-C).
The effective management of patients with MEN2A, MEN2A, and FMTC depends on an understanding of the variable behavior of disease expression in patients with a specific RET mutation.
Twenty years ago, the groundbreaking discovery that rearranged during transfection (RET) mutations underlie multiple endocrine neoplasia 2 (MEN2) and familial medullary thyroid cancer (FMTC) ushered in the era of personalized medicine.
MTC samples with the C634 RET mutation exhibited a higher expression of VEGFR3 and KIT than the M918T RET-mutated and non-mutated RET tumor samples (P=0.005 and P=0.007 respectively) and a lower expression of VEGFR1 (P=0.04).