Abstract
PurposeHaving previously demonstrated that tissue miR-375 expression in medullary thyroid carcinoma (MTC) tissues is linked to prognosis, the aim of this study was to assess the diagnostic and prognostic value of circulating miR-375 levels in MTC patients.MethodsA series of 68 patients with MTC was retrospectively retrieved and assessed in terms of their clinicopathological characteristics. MiR-375 levels were measured in all patients’ presurgical blood samples. Both serum and tissue levels were tested prior to surgery in a subgroup of 57 patients. Serum miR-375 levels were also measured in serum from 49 patients with non-C-cell thyroid nodular diseases (non-CTN), 14 patients with pheochromocytoma, and 19 healthy controls.ResultsCirculating miR-375 levels were 101 times higher in the serum of patients with MTC than in all other patients and controls, with no overlap (P < 0.01). No correlation emerged between serum and tissue miR-375 levels. Serum miR-375 levels were higher in MTC patients with N0 than in those with N1 disease (P = 0.01), and also in patients who were biochemically cured than in those who were not (P = 0.02). In the whole series of patients and controls, calcitonin (CT) and serum miR-375 levels were correlated at diagnosis (R2 = 0.40, P < 0.01), but in a U-shaped manner: a positive correlation was found with low CT levels, then the correlation turns negative as CT rises (in MTC patients). A negative correlation was indeed found in MTC patients between serum miR-375 and CT (R2 = −0.10, P = 0.01). On ROC curve analysis, a cut-off of 2.1 for serum miR-375 proved capable of distinguishing between MTC patients and the other patients and controls with a 92.6% sensitivity and a 97.6% specificity (AUC: 0.978, P < 0.01).ConclusionsSerum miR-375 levels can serve as a marker in the diagnosis of MTC, with a remarkable specificity. Serum miR-375 also proved a novel marker of prognosis in this disease. Further in vitro experiments to corroborate our results are currently underway.
Highlights
Medullary thyroid cancer (MTC) is a neuroendocrine neoplasm arising from thyroid parafollicular C-cells.Sporadic MTC carries somatic REarranged during Transfection (RET) mutations in approximately 50% of cases, with a subset of sporadic and RET-negative MTC carrying a mutation in RAS genes [1]
Median tissue miR-375 levels were higher in males (0.044, interquartile ranges (IQR): 0.03–0.14 in males and 0.02, IQR: 0.008–0.06 in females, P = 0.04), in cases with positive lymph nodes (0.07, IQR: 0.03–0.17 in N1 patients; 0.02, IQR: 0.007–0.05 in N0 patients, P = 0.02), in patients with higher tumor stages at diagnosis (0.02, IQR: 0.007–0.05 for stages I+II; 0.08, IQR: 0.03–0.17 for stages III+IV; P = 0.02), and in patients not biochemically cured by the end of the follow-up (0.02, IQR: 0.008–0.03 in those who were biochemically cured; 0.06, IQR: 0.01–0.12 in those who were not; P = 0.03)
Median circulating miR-375 levels were higher in the serum of MTC patients (15.15, IQR: 5.82–36.51) than in the other patients and controls (P < 0.01), with no overlap in the IQR for these two groups’ miR-375 levels
Summary
Sporadic MTC (sMTC) carries somatic REarranged during Transfection (RET) mutations in approximately 50% of cases, with a subset of sporadic and RET-negative MTC carrying a mutation in RAS genes [1]. It is well known that somatic RET mutations point to a poor prognosis in sMTC, and somatic RAS mutations to a better prognosis [2]. It is useful to assess patients’ mutational status for prognostic purposes, and crucial to the choice of new target treatments such as the nowapproved tyrosine kinase cabozantinib [3, 4] or the highly selective RET inhibitor pralsetinib currently being trialed for use against MTC [5]. The discovery of new molecular changes remains pivotal to improving the prognostic stratification of patients with MTC, and to the search for novel targets for therapy
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