STK11 c.1062 C > G germline variant in medullary thyroid carcinoma: implications for familial predisposition and genetic counseling.
Medullary thyroid carcinoma (MTC) is characterized by frequent RET mutations, while non-RET alterations remain less well studied. Previous reports have identified a recurrent STK11 c.1062 C > G (p.Phe354Leu) variant in MTC, but its clinicopathologic and functional significance remains uncertain.
A total of 129 MTCs (128 families) were analyzed by Sanger sequencing to screen for the STK11 c.1062 C > G variant. Germline status was assessed in cases with available normal tissue. Targeted next-generation sequencing was performed in 30 tumors (29 families). Functional effects of the STK11 c.1062 C > G variant were evaluated using an overexpression model in TT cells, with assessment of AMPKα phosphorylation. Progression-free survival was analyzed using Kaplan-Meier methods.
The STK11 c.1062 C > G variant was identified in 12 of 129 MTCs (9.3%) and in 11 of 128 families (8.6%). It was significantly enriched in hereditary cases compared with sporadic tumors: 27.8% (5/18) vs. 7.7% (1/12) for individual MTC cases, and 23.5% (4/17) vs. 7.7% (1/12) for families. In evaluable cases, the variant was confirmed to be germline. Tumors harboring STK11 c.1062 C > G showed a mutational spectrum predominantly involving RET, whereas variant-negative tumors exhibited more heterogeneous alterations, including genes related to DNA repair and chromatin remodeling. No significant difference in progression-free survival was observed between groups (P = 0.54). In vitro, the STK11 c.1062 C > G variant was associated with reduced AMPKα phosphorylation compared with wild-type STK11.
Given the population frequency and ClinVar benign/likely benign classification of this variant, our data do not support STK11 c.1062 C > G as a primary driver of MTC; rather, it may represent a recurrent germline variant that could act as a low-penetrance modifier in a subset of patients, warranting cautious interpretation and further validation.
A total of 129 MTCs (128 families) were analyzed by Sanger sequencing to screen for the STK11 c.1062 C > G variant. Germline status was assessed in cases with available normal tissue. Targeted next-generation sequencing was performed in 30 tumors (29 families). Functional effects of the STK11 c.1062 C > G variant were evaluated using an overexpression model in TT cells, with assessment of AMPKα phosphorylation. Progression-free survival was analyzed using Kaplan-Meier methods.
The STK11 c.1062 C > G variant was identified in 12 of 129 MTCs (9.3%) and in 11 of 128 families (8.6%). It was significantly enriched in hereditary cases compared with sporadic tumors: 27.8% (5/18) vs. 7.7% (1/12) for individual MTC cases, and 23.5% (4/17) vs. 7.7% (1/12) for families. In evaluable cases, the variant was confirmed to be germline. Tumors harboring STK11 c.1062 C > G showed a mutational spectrum predominantly involving RET, whereas variant-negative tumors exhibited more heterogeneous alterations, including genes related to DNA repair and chromatin remodeling. No significant difference in progression-free survival was observed between groups (P = 0.54). In vitro, the STK11 c.1062 C > G variant was associated with reduced AMPKα phosphorylation compared with wild-type STK11.
Given the population frequency and ClinVar benign/likely benign classification of this variant, our data do not support STK11 c.1062 C > G as a primary driver of MTC; rather, it may represent a recurrent germline variant that could act as a low-penetrance modifier in a subset of patients, warranting cautious interpretation and further validation.
Authors
Kong Kong, Bao Bao, Wang Wang, Zhao Zhao, Gu Gu, Pan Pan, Zhang Zhang, Zhang Zhang, Xing Xing, Wang Wang
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