What are the implications and treatment options for STK2 (Serine/Threonine Kinase 2) gene mutations?

STK11 Gene Mutations: Implications and Treatment Options

STK11 (Serine/Threonine Kinase 11) gene mutations are primarily associated with Peutz-Jeghers Syndrome (PJS), which requires comprehensive cancer surveillance and management due to significantly increased cancer risks across multiple organs.

Genetic Background and Clinical Implications

STK11 (also known as LKB1) is a tumor suppressor gene located on chromosome 19p13.3 that encodes a serine/threonine kinase acting as a regulator of cell-cycle metabolism and cell polarity 1. Mutations in this gene are found in:

• 70% of PJS patients with a family history
• 30-70% of sporadic PJS cases 1

The STK11 gene functions as a tumor suppressor, and its loss leads to dysregulation of the AKT-mTOR signaling pathway 1. Most mutations (approximately 65%) affect the protein structure through nonsense deletions, insertions, and rearrangements leading to null alleles 1.

Clinical Manifestations

PJS patients typically present with:

• Characteristic mucocutaneous pigmentation (lips, buccal mucosa, periorbital region)
• Hamartomatous polyps throughout the gastrointestinal tract
• Onset of symptoms between ages 10-30 years 1
• Common presenting complaints:
  • Intestinal obstruction (43%)
  • Abdominal pain (23%)
  • Blood in stool (14%)
  • Anal extrusion of polyp (7%)
  • Melanin pigmentation (13%) 1

Cancer Risk Profile

PJS patients have a dramatically increased cancer risk:

• Overall relative risk for all cancers: 15.2 times the general population
• Lifetime risk of any cancer: 93% 1

Specific cancer risks include:

• Gastrointestinal cancers (esophagus, stomach, small intestine, colon, pancreas)
• Breast cancer (risk comparable to BRCA1/2 carriers)
• Gynecological cancers
• Lung cancer 1

Surveillance and Management Recommendations

Genetic Testing

1. Who should be tested:

   • Individuals with clinical features of PJS
   • First-degree relatives of confirmed PJS patients 2
   • Individuals with multiple family members with PJS-related tumors 2

2. Testing approach:

   • Complete sequencing of the STK11 gene coding area 1
   • Testing costs approximately $975-$1400 for proband identification 1
   • Targeted testing for relatives once a mutation is identified 2

Cancer Surveillance

Gastrointestinal Surveillance

• Upper endoscopy and colonoscopy: Begin at age 8-10 years, repeat every 2-3 years 1, 2
• Small bowel surveillance: Begin at age 8-10 years using video capsule endoscopy or MRI enterography 1
• Pancreatic cancer screening: Begin at age 30-35 or 10 years younger than earliest pancreatic cancer in family 2
  • Annual endoscopic ultrasound (EUS) and/or MRI/MRCP 2

Non-Gastrointestinal Surveillance

• Breast cancer screening: Begin at age 25-30 with annual mammography and breast MRI 1, 2
• Gynecologic cancer screening: Begin at age 25-30 with annual pelvic examination, transvaginal ultrasound, and CA-125 1
• Testicular examination: Annual beginning at age 10 1

Treatment Approaches

1. Polyp Management:

   • Endoscopic removal of symptomatic polyps or polyps >1.5 cm 1
   • Intraoperative endoscopy during laparotomy for small bowel polyps 1

2. Cancer Treatment:

   • Standard cancer treatments based on cancer type and stage
   • Consider mTOR inhibitors for STK11-related tumors 1
   • Note: STK11-mutated tumors may have reduced response to PD-1 axis inhibitors (immune checkpoint inhibitors) 3

3. Preventive Measures:

   • Consider prophylactic mastectomy for women with very high breast cancer risk
   • Consider prophylactic hysterectomy and oophorectomy after childbearing is complete 1

Special Considerations

Genotype-Phenotype Correlations

• Patients with missense mutations may have later onset of symptoms compared to those with truncating mutations 1
• STK11 mutations may affect response to immunotherapy in cancer treatment 1, 3

Pediatric Considerations

• First symptoms often appear in the first decade of life
• Intussusception is a common complication (47% of patients) 1
• Early screening is essential to prevent complications

Follow-up and Long-term Management

• Lifelong surveillance is required due to the high lifetime cancer risk
• Genetic counseling should be offered to all patients with PJS who are considering having children 1
• Genetic counseling should address the high degree of intrafamilial variability in disease severity 1

By implementing comprehensive surveillance and management strategies, the morbidity and mortality associated with STK11 mutations can be significantly reduced through early detection and intervention.