NRAS Mutations Detection (Exon 2 & 3), FFPE Tissue

Cancer

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Molecular oncology test.

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NRAS Mutations Detection (Exon 2 & 3) FFPE Tissue - Comprehensive Test Guide

Why is it done?
- Detects mutations in the NRAS gene (exons 2 and 3) in formalin-fixed, paraffin-embedded (FFPE) tissue samples to identify oncogenic alterations associated with cancer development and progression
- Assists in diagnosis and classification of melanoma, colorectal cancer, ovarian cancer, and other solid tumors with potential NRAS involvement
- Guides targeted therapy selection and predicts treatment response to specific therapeutic agents
- Provides prognostic information regarding patient outcomes and potential clinical course
- Typically performed at the time of initial tissue diagnosis or when specific therapeutic targeting is being considered
- May be ordered as part of comprehensive genomic profiling or as a standalone targeted mutation analysis
Normal Range
- Negative Result (No Mutation Detected): Indicates absence of NRAS mutations in exons 2 and 3; represents the normal/reference finding
- Detection Method: Sensitivity typically 95-99%; able to detect mutations at 1-5% allelic frequency depending on the specific methodology used
- Positive Result (Mutation Detected): Indicates presence of NRAS mutation; reported with specific variant nomenclature (e.g., NRAS c.34G>T p.G12C or NRAS c.181C>A p.Q61K)
- Variants of Uncertain Significance (VUS): Rare variants with unclear clinical significance may require further investigation or interpretation by molecular genetics specialists
- Sample Quality Parameters: Adequate DNA extraction (>100 ng), minimal fixation artifacts, preserved tumor cellularity (>20% recommended)
Interpretation
- Negative NRAS Mutation Status: No pathogenic NRAS mutations detected in exons 2 or 3; does not exclude malignancy or disease but indicates absence of these specific molecular alterations; may suggest alternative oncogenic drivers should be investigated
- Positive NRAS G12 Mutations (Exon 2): Most common NRAS mutations (40-45% of NRAS alterations); includes G12A, G12C, G12D, G12R, G12S, G12V; associated with constitutive NRAS protein activity and oncogenic signaling
- Positive NRAS Q61 Mutations (Exon 3): Most frequent NRAS mutations (55-60% of NRAS alterations); includes Q61K, Q61R, Q61L, Q61H; impairs GTPase activity leading to persistent RAS activation; particularly common in cutaneous melanoma
- Clinical Significance of Mutations: NRAS mutations indicate activated RAS signaling pathway; affect prognosis, treatment selection, and potential resistance to conventional BRAF inhibitors; may confer sensitivity to MEK inhibitors and newer NRAS-targeted therapies
- Factors Affecting Interpretation:
  - Tumor cellularity and heterogeneity - may affect mutation detection sensitivity
  - Specimen fixation quality and age - prolonged formalin exposure may degrade DNA
  - Presence of other concurrent mutations - may influence therapeutic response patterns
  - Allelic frequency of mutation - may indicate clonal vs subclonal involvement
- Therapeutic Implications:
  - MEK inhibitors (e.g., trametinib, cobimetinib) - approved and effective for NRAS-mutant melanoma
  - Newer NRAS-targeted therapies - sotorasib, adagrasib (KRAS inhibitors with potential NRAS activity)
  - Combination immunotherapy - may be considered depending on tumor type and stage
Associated Organs
- Primary Organ Systems Involved:
  - Skin (cutaneous melanoma - most common NRAS-associated malignancy)
  - Colon and rectum (colorectal cancer - 15-25% of cases)
  - Ovaries (ovarian cancer - 5-10% of cases)
  - Lungs (non-small cell lung cancer - 3-5% of cases)
- Diseases Associated with NRAS Mutations:
  - Cutaneous melanoma - 20-30% of all melanomas carry NRAS mutations
  - Colorectal adenocarcinoma - independent prognostic factor for treatment response
  - Epithelial ovarian cancer - associated with worse prognosis in some studies
  - Mucinous ovarian tumors - higher prevalence of NRAS mutations
  - Various other solid tumors - appendiceal, pancreatic, gastric, and biliary tract cancers
- Clinical Consequences of NRAS Mutations:
  - Constitutive activation of MAPK/ERK signaling pathway
  - Resistance to BRAF inhibitors in NRAS wild-type tumors (indirect effect through pathway activation)
  - Altered drug metabolism and potential resistance patterns
  - Enhanced metastatic potential and aggressive tumor behavior
  - Potential for early treatment failure with conventional therapies
Follow-up Tests
- Additional Molecular Testing Based on Results:
  - BRAF mutation testing - to identify alternate driver mutations if NRAS negative
  - KIT mutation analysis - particularly relevant for acral and mucosal melanomas
  - KRAS mutation testing - for colorectal and other solid tumors
  - Comprehensive genomic profiling (CGP) - panel testing for multiple oncogenes and tumor suppressors
- Recommended Tests if NRAS Mutation Positive:
  - Extended RAS pathway analysis - additional exons and codons if clinical assessment warrants
  - Programmed Death Ligand 1 (PD-L1) immunohistochemistry - for immunotherapy selection in melanoma
  - Tumor mutational burden (TMB) assessment - if available through broader genomic profiling
  - Microsatellite instability (MSI) testing - for certain cancer types
- Clinical and Imaging Follow-up:
  - Baseline imaging (CT, MRI, PET-CT) - to stage disease and identify metastases
  - Periodic surveillance imaging - frequency depends on stage and treatment regimen
  - Systemic therapy initiation - prompt treatment with MEK inhibitors or alternative options based on mutation status
- Monitoring During Treatment:
  - Response assessment imaging - every 8-12 weeks during active MEK inhibitor therapy
  - Circulating tumor DNA (ctDNA) testing - emerging modality for monitoring treatment response and detecting recurrence
  - Repeat tumor biopsy - if considering resistance mechanisms or therapy adjustment
- Post-Treatment Surveillance:
  - Regular clinical examination - every 3-6 months initially, then as clinically indicated
  - Long-term imaging surveillance - to detect late recurrence or development of new primary malignancies
Fasting Required?
- Fasting Required: No. This is a tissue-based molecular test performed on previously collected archival FFPE tissue samples; not a blood test and does not require patient fasting
- Sample Collection Requirements:
  - FFPE tissue block or unstained slides with sufficient material for DNA extraction
  - Minimum 10-20 unstained formalin-fixed slides (10 microns thickness) or equivalent tissue material
  - Tissue should be confirmed to contain adequate tumor cellularity (>20% recommended) by pathology review
  - Specimen should be collected per institution standards for tissue preservation
- Special Instructions and Preparation:
  - No medications to avoid - as this is a tissue test, not a blood test
  - Patient does not need to discontinue any medications prior to testing
  - Specimen should be sent to laboratory in designated, labeled containers with proper chain of custody documentation
  - Proper identification with patient name, medical record number, specimen source, and collection date required
  - Room temperature storage acceptable for tissue blocks and slides; protect from direct sunlight and extreme temperatures
- Turnaround Time: Typically 5-14 business days after receipt of adequate tissue sample, depending on laboratory and testing methodology

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