Monarch Initiative Dismech Cancer Curator

Cancer Curation Skill

Overview

Curate cancer and neoplastic disease entries in the dismech knowledge base with a focus on:

• Genetic drivers (oncogenes, tumor suppressors, fusion genes)
• Pathophysiology with causal chains
• Histopathology findings
• Targeted therapies and their molecular targets
• NCIT terms for biomarkers, gene products, and histologic findings

When to Use

• Creating new cancer/neoplasm entries
• Adding genetic driver information (BCR-ABL, KIT, RET, RB1, etc.)
• Structuring pathophysiology as atomic processes with causal links
• Adding histopathology findings (grades, patterns, rosettes)
• Linking treatments to their molecular targets
• Adding CHEBI terms for chemotherapy drugs
• Adding NCIT terms for biomarkers and fusion proteins

Cancer-Specific Schema Features

Disease Stages (not Subtypes)

For cancers with disease phases (chronic → accelerated → blast crisis), use stages not has_subtypes:

stages:
- name: Chronic Phase
  description: >-
    Initial indolent phase with <10% blasts. Most patients diagnosed here.
- name: Accelerated Phase
  description: >-
    Transitional phase with 10-19% blasts, additional cytogenetic abnormalities.
- name: Blast Crisis
  description: >-
    Terminal phase resembling acute leukemia with ≥20% blasts.

Use has_subtypes for true molecular/histologic subtypes (KIT-mutant vs PDGFRA-mutant GIST).

Pathophysiology: Atomic Processes with Causal Chains

Split bundled pathway descriptions into atomic processes linked by downstream edges:

pathophysiology:
- name: BCR-ABL1 Fusion Oncogene Formation
  description: >-
    The t(9;22) translocation creates the Philadelphia chromosome with
    constitutively active BCR-ABL1 tyrosine kinase.
  cell_types:
  - preferred_term: hematopoietic stem cell
    term:
      id: CL:0000037
      label: hematopoietic stem cell
  gene_products:
  - preferred_term: BCR-ABL1 fusion protein
    term:
      id: NCIT:C16325
      label: BCR/ABL1 Fusion Protein
  downstream:
  - target: Constitutive Tyrosine Kinase Activation
    description: BCR-ABL1 exhibits ligand-independent kinase activity

- name: Constitutive Tyrosine Kinase Activation
  description: >-
    BCR-ABL1 activates RAS-MAPK, PI3K-AKT, and JAK-STAT pathways.
  biological_processes:
  - preferred_term: protein tyrosine kinase activity
    modifier: INCREASED
    term:
      id: GO:0004713
      label: protein tyrosine kinase activity
  downstream:
  - target: Uncontrolled Myeloid Proliferation
    description: Activated signaling drives excessive myeloid expansion

Key principles:

1. One mechanism per entry (not "Oncogenic Signaling" combining MAPK + PI3K)
2. Use downstream to connect cause → effect
3. Include cell_types, biological_processes, locations as appropriate
4. Add gene_products for fusion proteins/oncoproteins (NCIT terms)

Histopathology Section

Use the dedicated histopathology section for microscopic findings:

histopathology:
- name: Flexner-Wintersteiner Rosettes
  finding_term:
    preferred_term: Flexner-Wintersteiner rosette
    term:
      id: HP:0031927
      label: Flexner-Wintersteiner rosette
  frequency: FREQUENT
  diagnostic: true
  description: >-
    Characteristic rosettes with central lumen surrounded by tumor cells
    showing photoreceptor differentiation. Pathognomonic for retinoblastoma.

- name: Spindle Cell Morphology
  finding_term:
    preferred_term: Spindle Cell Pattern
    term:
      id: NCIT:C53643
      label: Spindle Cell Pattern
  frequency: VERY_FREQUENT
  description: >-
    Elongated cells arranged in fascicles. Typical of KIT-mutant GIST.

Histopathology term sources:

• NCIT:C35867 (Morphologic Finding) - patterns, dysplasia, necrosis
• NCIT:C18000 (Histologic Grade) - Fuhrman, Nottingham, GIST grades
• HP:0025461 (Abnormal cell morphology) - rosettes, inclusion bodies

Biomarkers (NCIT)

Add biomarker_term to biochemical entries:

biochemical:
- name: BCR-ABL1 Fusion Transcript
  biomarker_term:
    preferred_term: BCR-ABL1 fusion protein
    term:
      id: NCIT:C36715
      label: BCR-ABL1 Fusion Protein Expression
  notes: >-
    RT-PCR or FISH detection is diagnostic and used for molecular monitoring.

Gene Products (NCIT)

Add gene_products to pathophysiology for fusion proteins and oncoproteins:

gene_products:
- preferred_term: BCR-ABL1 fusion protein
  term:
    id: NCIT:C16325
    label: BCR/ABL1 Fusion Protein

Look up NCIT gene product terms:

uv run runoak -i sqlite:obo:ncit descendants NCIT:C26548 --predicates rdfs:subClassOf | grep -i "fusion\|kinase"

Therapeutic Agents (CHEBI)

Add therapeutic_agent to treatments with CHEBI terms:

treatments:
- name: Imatinib
  description: First-generation TKI targeting BCR-ABL1.
  treatment_term:
    preferred_term: pharmacotherapy
    term:
      id: MAXO:0000058
      label: pharmacotherapy
    therapeutic_agent:
    - preferred_term: imatinib
      term:
        id: CHEBI:45783
        label: imatinib

Ontology Lookups

NCIT Gene Products

# Search for fusion proteins
uv run runoak -i sqlite:obo:ncit search "fusion protein"

# Check specific term
uv run runoak -i sqlite:obo:ncit info NCIT:C16325

# Get descendants of Gene Product
uv run runoak -i sqlite:obo:ncit descendants NCIT:C26548 --predicates rdfs:subClassOf | head -50

NCIT Histopathology

# Morphologic findings
uv run runoak -i sqlite:obo:ncit descendants NCIT:C35867 --predicates rdfs:subClassOf | head -50

# Histologic grades
uv run runoak -i sqlite:obo:ncit descendants NCIT:C18000 --predicates rdfs:subClassOf | head -50

CHEBI Drugs

uv run runoak -i sqlite:obo:chebi search "imatinib"
uv run runoak -i sqlite:obo:chebi info CHEBI:45783

HP Rosettes and Cell Morphology

uv run runoak -i sqlite:obo:hp descendants HP:0025461 --predicates rdfs:subClassOf | grep -i rosette

Common NCIT Terms

Fusion Proteins

Biomarkers

Histologic Grades

Morphologic Findings

Common CHEBI Drug Terms

TKIs

Chemotherapy

Cancer Tiers (from CANCER.md project)

Tier 1: Paradigmatic Single-Gene Drivers

Clear driver mutations with targeted therapies:

• CML (BCR-ABL1) → imatinib
• GIST (KIT/PDGFRA) → imatinib/avapritinib
• MTC (RET) → selpercatinib
• ccRCC (VHL) → belzutifan
• Retinoblastoma (RB1) → two-hit paradigm
• Ewing Sarcoma (EWS-FLI1) → fusion transcription factor

Tier 2: Hereditary Cancer Syndromes

Germline mutations with defined progression:

• Li-Fraumeni (TP53)
• FAP (APC)
• VHL disease
• MEN2 (RET)
• HBOC (BRCA1/2)
• NF1

Tier 3: Molecular Subtype Cancers

• AML (FLT3, NPM1, IDH1/2)
• Colorectal (CMS subtypes)
• Breast (HER2+)
• Melanoma (BRAF)
• Glioblastoma (IDH-mutant vs wildtype)

Validation Workflow

# 1. Schema validation
just validate kb/disorders/MyCancer.yaml

# 2. Term validation (NCIT, CHEBI, HP, CL, GO)
just validate-terms kb/disorders/MyCancer.yaml

# 3. Reference validation (if evidence added)
just validate-references kb/disorders/MyCancer.yaml

# 4. Full QC
just qc

Example: Creating a New Cancer Entry

1. Start with deep research (if available):

   # Check for existing research
   ls research/*MyCancer*.md
   

2. Create YAML structure:

   • name, description, categories, parents
   • disease_term (MONDO)
   • has_subtypes or stages (as appropriate)
   • pathophysiology (atomic, with causal chains)
   • histopathology (if relevant)
   • phenotypes
   • biochemical (with biomarker_term)
   • genetic
   • treatments (with treatment_term + therapeutic_agent)

3. Add evidence for key claims (PMID references)

4. Validate all term bindings

Integration with Other Skills

• dismech-terms: For general ontology term lookups (HP, CL, GO, MONDO)
• dismech-references: For evidence validation and PMID snippet checking
• dismech-compliance: For checking field coverage

Project Tracking

Cancer curation is tracked in projects/CANCER.md. Update status after completing entries.

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