What is the role of CDKN2A (Cyclin-Dependent Kinase Inhibitor 2A) and TERT (Telomerase Reverse Transcriptase) promoter alterations in cancer management?

Role of CDKN2A and TERT Promoter Alterations in Cancer Management

CDKN2A and TERT promoter alterations are critical molecular markers that significantly impact cancer prognosis and should be routinely tested in specific cancer types to guide treatment decisions and risk stratification. 1

CDKN2A Alterations

Diagnostic and Prognostic Significance

• CDKN2A (Cyclin-Dependent Kinase Inhibitor 2A) alterations, particularly homozygous or heterozygous deletions, are significant prognostic markers in multiple cancer types:
  • In meningiomas: CDKN2A/B deletions are associated with high risk of recurrence and dramatically shorter progression-free intervals 1
  • In peripheral nerve sheath tumors: CDKN2A/B inactivation is a key diagnostic marker for atypical neurofibromatous neoplasms of uncertain biologic potential (ANNUBP) 1

Testing Recommendations

• CDKN2A/B testing should be performed in:
  • CNS WHO grade 2 (atypical) and grade 3 (anaplastic) meningiomas 1
  • Clinically or radiologically worrisome noncutaneous lesions in patients with NF1 1
  • Diffuse astrocytic gliomas without microvascular proliferation or necrosis 1

Cancer Predisposition

• Germline CDKN2A mutations are associated with:
  • Melanoma-astrocytoma syndrome (mutations involving both CDKN2A and p14ARF) 1
  • Hereditary melanoma/familial atypical mole and malignant melanoma syndrome 1
  • Increased risk for pancreatic cancer (17% risk by age 75) 1

TERT Promoter Alterations

Diagnostic and Prognostic Significance

• TERT (Telomerase Reverse Transcriptase) promoter mutations:
  • Are among the most prevalent genetic aberrations in cancer (14.4% of diverse cancers) 2
  • Are particularly common in brain cancers (48%) and melanomas (56%) 2
  • Associated with dramatically shorter progression-free intervals in meningiomas 1
  • Warrant a CNS WHO grade 3 designation in meningiomas regardless of other histological features 1

Testing Recommendations

• TERT promoter mutation testing should be performed in:
  • CNS WHO grade 2 and grade 3 meningiomas 1
  • IDH-wild-type diffuse astrocytic gliomas to identify molecular characteristics of glioblastomas 1
  • Rare CNS WHO grade 1 meningiomas with unexpectedly rapid growth or recurrence 1

Testing Methods

• For TERT promoter:
  • Targeted DNA sequencing covering the 2 hotspots (C228T and C250T)
  • More comprehensive sequencing approaches that adequately cover this region 1
• For CDKN2A/B:
  • Comprehensive next-generation sequencing panel that includes copy number and zygosity assessment 1
  • Array comparative genomic hybridization for copy number analysis 1

Clinical Implementation

When to Test

1. Brain tumors:

   • All CNS WHO grade 2 and 3 meningiomas
   • Diffuse gliomas with atypical features
   • Gliomas with unexpectedly aggressive clinical course

2. Skin cancers:

   • Melanomas, especially with family history
   • Multiple melanocytic nevi (>50)

3. Peripheral nerve sheath tumors:

   • Clinically or radiologically worrisome lesions in NF1 patients

Interpretation Considerations

• TERT promoter mutations and CDKN2A/B alterations frequently coexist with other genetic aberrations 2
• Higher number of genetic alterations correlates with poorer overall survival 2
• Tissue selection is critical - prioritize the most malignant-appearing regions for DNA extraction 1
• Consider tumor cellularity when interpreting CDKN2A/B and aneuploidy results 1

Pitfalls and Caveats

• False negatives/positives can occur when using immunohistochemistry alone as surrogate markers (e.g., H3K27me3, p16) - molecular testing is recommended 1
• CDKN2A/B and TERT alterations can arise during tumor progression, necessitating testing of recurrent tumors 1
• Sensitivity for detecting copy number alterations varies across different assays - results should be interpreted in context of tumor cellularity and viability 1
• Even subclonal frequency mutations in these genes may be clinically significant 1

Future Directions

• TERT promoter mutations may make tumors particularly immunogenic and potentially more responsive to immunotherapy 3
• Therapeutic options targeting tumors with TERT promoter mutations are currently limited but under development 2
• Both markers hold potential for future applications in diagnosis, prognosis, and therapeutic decision-making across multiple cancer types 3