D-WS3-001A
SCF Mutation Catalog (MCAT)
PROJECT HELIX-HTT | Huntington’s-Adjacent Neuro-Oncology Vaccine Program
DOCUMENT CONTROL HEADER
Program Code: SCF-ARGEN-HTT-NO-01
Workflow Stage: Discovery Phase
Deliverable: Core Deliverable #2
Document Code: SCF-MCAT-NO-0001
Purpose: Comprehensive catalog of all tumor-associated genomic alterations for downstream antigen discovery and vaccine prioritization.
1. PURPOSE OF THE MUTATION CATALOG
The Mutation Catalog serves as the master genomic inventory of all tumor-associated sequence alterations that may generate:
- Neoantigens
- Tumor-associated antigens
- Immunogenic fusion peptides
- Repeat-instability peptides
- Stress-associated SCF antigens
The MCAT is the first filtering layer used to identify candidate vaccine targets.
2. GENOMIC ALTERATION CLASSIFICATION FRAMEWORK
All mutations are classified into six major categories.
Class | Mutation Type | Vaccine Relevance |
MC-1 | Single Nucleotide Variants (SNVs) | High |
MC-2 | Insertions / Deletions (Indels) | Very High |
MC-3 | Structural Variants (SVs) | High |
MC-4 | Gene Fusions | Very High |
MC-5 | Alternative Splice Events | Moderate–High |
MC-6 | Repeat Instability Events | Experimental SCF Priority |
3. MUTATION INVENTORY TABLE
MASTER MCAT TEMPLATE
Mutation ID | Gene | Mutation Type | Chromosome | Protein Change | VAF | Clonality | Neoantigen Potential |
MCAT-0001 | Example | SNV | ChrX | p.X123Y | 0.45 | Clonal | High |
MCAT-0002 | Example | Fusion | ChrX | Fusion peptide | 0.38 | Clonal | Very High |
MCAT-0003 | Example | Indel | ChrX | Frameshift | 0.52 | Clonal | Very High |
4. SINGLE NUCLEOTIDE VARIANT (SNV) CATALOG
Purpose
Identify amino acid substitutions capable of generating novel peptides.
Inclusion Criteria
- Non-synonymous
- Somatic
- Tumor-specific
- Confirmed by matched normal subtraction
Priority Ranking
Tier | Criteria |
Tier A | Clonal + expressed |
Tier B | Subclonal + expressed |
Tier C | Unexpressed |
5. INSERTION / DELETION (INDEL) CATALOG
Purpose
Identify frameshift-derived neoantigens.
Scientific Importance
Frameshift mutations often generate:
- Highly foreign peptides
- Strong T-cell responses
- Reduced immune tolerance
Priority
Very High
6. STRUCTURAL VARIANT CATALOG
Includes
- Inversions
- Duplications
- Translocations
- Complex rearrangements
Vaccine Importance
Structural variants may create:
- Novel open reading frames
- Unique peptide junctions
- Tumor-specific antigens
7. GENE FUSION CATALOG
Purpose
Identify fusion-derived neoantigens.
Priority Level
Highest
Scientific Rationale
Fusion junctions are:
- Tumor specific
- Non-self
- Often highly immunogenic
8. ALTERNATIVE SPLICING CATALOG
Purpose
Identify abnormal transcript isoforms.
Examples
- Exon skipping
- Cryptic exon insertion
- Intron retention
SCF Significance
Represents adaptive tumor evolution.
9. REPEAT INSTABILITY CATALOG
SCF EXPERIMENTAL MODULE
Purpose
Identify genomic instability signatures associated with:
- Repeat expansion
- Repeat contraction
- DNA repair stress
Candidate Categories
Category | Description |
RI-1 | CAG instability |
RI-2 | Microsatellite instability |
RI-3 | Repair-associated repeat drift |
RI-4 | Repeat-derived neoepitopes |
10. CLONALITY ANALYSIS
Objective
Determine tumor-wide coverage.
Categories
Class | Definition |
Clonal | Present in majority of tumor cells |
Subclonal | Restricted population |
Rare | Low-frequency population |
SCF Rule
Prioritize:
Clonal > Subclonal > Rare
11. VARIANT ALLELE FRACTION (VAF)
Interpretation
VAF Range | Interpretation |
>40% | Strong candidate |
20–40% | Moderate |
<20% | Exploratory |
12. MUTATION TO ANTIGEN CONVERSION PIPELINE
Mutation
↓
Protein Change
↓
Peptide Generation
↓
HLA Prediction
↓
Expression Validation
↓
Immunopeptidomics Validation
↓
Antigen Ranking13. SCF SAFETY FILTERS
Reject:
- Germline variants
- Normal-brain dominant proteins
- Autoimmunity-associated peptides
- Essential neuronal self-antigens
14. MCAT PRIORITY SCORING
Mutation Priority Score (MPS)
Formula:
MPS =
Clonality
+
Expression Potential
+
Immunogenic Potential
+
Tumor Specificity
CNS Cross-Reactivity Risk
15. OUTPUT FILES
MCAT-01
Raw Variant Catalog
MCAT-02
Annotated Variant Catalog
MCAT-03
Neoantigen Candidate Mutation List
MCAT-04
SCF Repeat Instability Catalog
MCAT-05
High-Priority Vaccine Mutation Set
16. DELIVERABLE SUMMARY
The Mutation Catalog provides:
- Complete genomic alteration inventory
- Neoantigen source identification
- Repeat-instability mapping
- Tumor evolution characterization
- Foundation for the Expression Atlas
DECISION GATE
Advance to Expression Atlas generation if:
✓ Somatic mutation calling complete
✓ Germline subtraction complete
✓ Variant annotation complete
✓ Candidate neoantigen source genes identified
STATUS
Core Deliverable #2: COMPLETE
NEXT DELIVERABLE: Core Deliverable #3 — Expression Atlas (EXAT)
Reply NEXT to generate Core Deliverable #3: Expression Atlas (EXAT).