Distinctive role of DICER1 mutations in distant metastatic thyroid cancer

Objective: This study investigated the clinical significance of DICER1 mutations in patients with distant metastatic follicular cell-derived thyroid cancer (FDTC).

Methods: This study included 310 Chinese patients with distant metastatic FDTC. We analyzed the interactions between DICER1 mutations and other gene alterations and compared the clinicopathological characteristics of patients with pathogenic (P) or likely pathogenic (LP) DICER1 mutations (n=9), other gene alterations (n=253), and no gene alterations (n=37). To compare FDTCs with different drivers, isolated BRAFV600E, RAS mutations, and RET fusions were compared with isolated DICER1 mutations.

Results: The prevalence of DICER1 mutations was 6.5% (20/310) in the patient cohort. Among patients with DICER1 mutations, 45% (9/20) harbored P or LP DICER1 variants and 55% (11/20) harbored DICER1 variants of uncertain significance (VUS). The coexistence of DICER1 mutations and other gene alterations was detected in 65% (13/20) of patients. Compared with VUS, P or LP DICER1 variants were almost mutually exclusive with early driver alterations (such as BRAFV600E) (11.1% vs. 81.8%, P=0.002) and more coexisted with late-hit events, particularly TP53 mutations (44.4% vs. 27.3%, P=0.642). Clinically, compared with the no alteration and other alteration groups, the DICER1 mutation group exhibited larger primary tumors, higher poorly differentiated thyroid cancer proportion, more extrathyroidal extension, more extrapulmonary metastases, and higher radioactive iodine-refractory proportion (all P<0.05). Cases with isolated DICER1 mutations differed from those with isolated BRAFV600E and RET fusions in terms of tumor size, poorly differentiated thyroid cancer proportion, and metastatic sites, but were similar to cases with isolated RAS mutations in the high proportion of follicular thyroid cancer, N0, and extrapulmonary metastases.

Conclusions: Mutation of DICER1 gene is a non-negligible molecular event and it may represent an aggressive subset of FDTCs. DICER1 has RAS-like clinical characteristics and DICER1-mutant tumors exhibit more aggressive clinical behaviors compared with those with BRAFV600E and RET fusions.