STK11Mutation

STK11 mutation refers to alterations in the STK11 gene, which encodes the serine/threonine kinase 11 enzyme, also known as LKB1. STK11 functions as a tumor suppressor and is a central regulator of cellular energy homeostasis and metabolism through activation of the AMPK family of kinases. Mutations can disrupt these pathways and contribute to tumor development.

Germline STK11 mutations cause Peutz-Jeghers syndrome, an inherited disorder characterized by mucocutaneous pigmentation and hamartomatous polyps in the gastrointestinal tract. Individuals with this syndrome have an increased lifetime risk of several cancers, including gastrointestinal, pancreatic, breast, and gynecologic cancers. Somatic STK11 mutations occur in a variety of cancers and are not inherited.

The loss of STK11/LKB1 function impairs the energy-sensing AMPK pathway, leading to unchecked anabolic growth, altered metabolism, disrupted cell polarity, and genomic instability. These changes can promote tumor initiation and progression. In tumors, STK11 mutations often coexist with other genetic alterations and can influence tumor behavior and responses to therapy.

Clinical significance varies by cancer type. In non-small cell lung cancer, STK11 mutations are associated with poorer prognosis and, in some settings, reduced responsiveness to immune checkpoint inhibitors. STK11 alterations are also observed in pancreatic ductal adenocarcinoma and other malignancies, where their presence may inform prognosis and treatment considerations.

Diagnosis is typically through DNA sequencing of tumor tissue to detect somatic mutations, with germline testing considered when hereditary syndromes like Peutz-Jeghers are suspected. Additional testing, including family history assessment and targeted germline analyses, may be appropriate. Treatment implications are evolving, with research exploring metabolic vulnerabilities and combination strategies in STK11-mutant cancers.