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Purpose <p>Medullary thyroid carcinoma (MTC) is characterized by frequent <i>RET</i> mutations, while non-<i>RET</i> alterations remain less well studied. Previous reports have identified a recurrent <i>STK11</i> c.1062&#xa0;C &gt; G (p.Phe354Leu) variant in MTC, but its clinicopathologic and functional significance remains uncertain.</p> Methods <p>A total of 129 MTCs (128 families) were analyzed by Sanger sequencing to screen for the <i>STK11</i> c.1062&#xa0;C &gt; 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 <i>STK11</i> c.1062&#xa0;C &gt; 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.</p> Results <p>The <i>STK11</i> c.1062&#xa0;C &gt; 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 <i>STK11</i> c.1062&#xa0;C &gt; G showed a mutational spectrum predominantly involving <i>RET</i>, 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 (<i>P</i> = 0.54). In vitro, the <i>STK11</i> c.1062&#xa0;C &gt; G variant was associated with reduced AMPKα phosphorylation compared with wild-type <i>STK11</i>.</p> Conclusion <p>Given the population frequency and ClinVar benign/likely benign classification of this variant, our data do not support <i>STK11</i> c.1062&#xa0;C &gt; 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.</p>

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STK11 c.1062 C > G germline variant in medullary thyroid carcinoma: implications for familial predisposition and genetic counseling

  • 期刊论文

  • 发表日期：

    2026年8月3日

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  • Weimao Kong,
  • Longnv Bao,
  • Meili Wang,
  • Xiangzhong Zhao,
  • Haiyan Gu,
  • Xingzhu Pan,
  • Xinyi Zhang,
  • Tingling Zhang,
  • Xiaoming Xing,
  • Jigang Wang

摘要

Purpose

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.

Methods

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.

Results

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.

Conclusion

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.