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 di...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 in65%(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.展开更多
Objective: Patients with radioactive iodine-refractory differentiated thyroid cancer(RAIR-DTC) are often diagnosed with delay and constrained to limited treatment options. The correlation between RAI refractoriness an...Objective: Patients with radioactive iodine-refractory differentiated thyroid cancer(RAIR-DTC) are often diagnosed with delay and constrained to limited treatment options. The correlation between RAI refractoriness and the underlying genetic characteristics has not been extensively studied.Methods: Adult patients with distant metastatic DTC were enrolled and assigned to undergo next-generation sequencing of a customized 26-gene panel(Thyro Lead). Patients were classified into RAIR-DTC or non-RAIR groups to determine the differences in clinicopathological and molecular characteristics. Molecular risk stratification(MRS) was constructed based on the association between molecular alterations identified and RAI refractoriness, and the results were classified as high, intermediate or low MRS.Results: A total of 220 patients with distant metastases were included, 63.2% of whom were identified as RAIRDTC. Genetic alterations were identified in 90% of all the patients, with BRAF(59.7% vs. 17.3%), TERT promoter(43.9% vs. 7.4%), and TP53 mutations(11.5% vs. 3.7%) being more prevalent in the RAIR-DTC group than in the non-RAIR group, except for RET fusions(15.8% vs. 39.5%), which had the opposite pattern. BRAF and TERT promoter are independent predictors of RAIR-DTC, accounting for 67.6% of patients with RAIR-DTC. MRS was strongly associated with RAI refractoriness(P<0.001), with an odds ratio(OR) of high to low MRS of 7.52 [95%confidence interval(95% CI), 3.96-14.28;P<0.001] and an OR of intermediate to low MRS of 3.20(95% CI,1.01-10.14;P=0.041).Conclusions: Molecular alterations were associated with RAI refractoriness, with BRAF and TERT promoter mutations being the predominant contributors, followed by TP53 and DICER1 mutations. MRS might serve as a valuable tool for both prognosticating clinical outcomes and directing precision-based therapeutic interventions.展开更多
基金supported by the National High Level Hospital Clinical Research Funding(No.2022-PUMCHB-072)。
文摘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 in65%(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.
基金supported by the Project on InterGovernmental International Scientific and Technological Innovation Cooperation in National Key Projects of Research and Development Plan (No. 2019YFE0106400)the National Natural Science Foundation of China (No. 81771875)。
文摘Objective: Patients with radioactive iodine-refractory differentiated thyroid cancer(RAIR-DTC) are often diagnosed with delay and constrained to limited treatment options. The correlation between RAI refractoriness and the underlying genetic characteristics has not been extensively studied.Methods: Adult patients with distant metastatic DTC were enrolled and assigned to undergo next-generation sequencing of a customized 26-gene panel(Thyro Lead). Patients were classified into RAIR-DTC or non-RAIR groups to determine the differences in clinicopathological and molecular characteristics. Molecular risk stratification(MRS) was constructed based on the association between molecular alterations identified and RAI refractoriness, and the results were classified as high, intermediate or low MRS.Results: A total of 220 patients with distant metastases were included, 63.2% of whom were identified as RAIRDTC. Genetic alterations were identified in 90% of all the patients, with BRAF(59.7% vs. 17.3%), TERT promoter(43.9% vs. 7.4%), and TP53 mutations(11.5% vs. 3.7%) being more prevalent in the RAIR-DTC group than in the non-RAIR group, except for RET fusions(15.8% vs. 39.5%), which had the opposite pattern. BRAF and TERT promoter are independent predictors of RAIR-DTC, accounting for 67.6% of patients with RAIR-DTC. MRS was strongly associated with RAI refractoriness(P<0.001), with an odds ratio(OR) of high to low MRS of 7.52 [95%confidence interval(95% CI), 3.96-14.28;P<0.001] and an OR of intermediate to low MRS of 3.20(95% CI,1.01-10.14;P=0.041).Conclusions: Molecular alterations were associated with RAI refractoriness, with BRAF and TERT promoter mutations being the predominant contributors, followed by TP53 and DICER1 mutations. MRS might serve as a valuable tool for both prognosticating clinical outcomes and directing precision-based therapeutic interventions.
