STK11LKB1mutation

STK11/LKB1 mutation refers to genetic alterations in the STK11 gene, which encodes the serine/threonine kinase LKB1. STK11 is also known as LKB1; mutations can be inherited or acquired. Germline STK11 mutations cause Peutz-Jeghers syndrome (PJS) and are transmitted in an autosomal dominant pattern.

LKB1 is a tumor suppressor that activates a family of kinases related to AMPK. It forms a complex with STRAD and MO25 to become active and phosphorylates AMPK and other downstream kinases, thereby regulating cellular energy metabolism, cell polarity, growth, and apoptosis. This signaling network helps cells respond to energy stress and coordinate growth with available nutrients.

In Peutz-Jeghers syndrome, germline mutations lead to mucocutaneous pigmented spots and hamartomatous gastrointestinal polyps, with an increased lifetime risk of various cancers, including those of the gastrointestinal tract, pancreas, breast, gynecologic organs, and others. Management involves regular surveillance and polyp management, along with cancer risk-reduction strategies guided by clinical guidelines.

Somatic STK11 mutations occur in multiple sporadic cancers, most notably non-small cell lung cancer, pancreatic ductal adenocarcinoma, colorectal cancer, cervical cancer, and breast cancer. In lung cancer, LKB1 inactivation often co-occurs with KRAS mutations and smoking exposure and is associated with poorer prognosis and may influence therapeutic responses.

Mechanistically, loss of LKB1 impairs AMPK activation and energy-sensing pathways, promoting metabolic reprogramming and unchecked growth, as well as defects in cell polarity. This can contribute to tumor progression and impact responses to certain therapies.

Diagnosis is typically by sequencing STK11; testing may be prompted by family history or cancer risk. Management combines genetic counseling with surveillance for PJS and standard oncologic treatments for cancers, while ongoing research explores metabolic vulnerabilities for targeted approaches.