Cancer Classification via OncoTree

Standardize cancer type nomenclature using the OncoTree ontology. Resolves free-text tumor descriptions to structured codes with UMLS/NCI cross-references, enabling downstream use in OncoKB variant annotation and GDC cohort selection.

When to Use

Apply when researcher asks about:

• "What is the OncoTree code for [tumor description]?"
• "Find all subtypes of [cancer type]"
• "What cancers originate in [tissue]?"
• "I need the tumor type code for OncoKB annotation"
• "What is the TCGA/COSMIC code for [cancer]?"
• "List all CNS/Brain cancer subtypes"
• "What NCI code corresponds to glioblastoma?"

Key Tools

Tool	Purpose	Key Params
OncoTree_search	Free-text search for cancer types	query (tumor name or description)
OncoTree_get_type	Full details for a known OncoTree code	code (e.g., "LUAD", "AML")
OncoTree_list_tissues	List all 32 tissue categories	(no params)
OncoKB_annotate_variant	Variant annotation using OncoTree code	gene, variant, tumor_type
GDC_get_mutation_frequency	Pan-cancer mutation frequency (TCGA)	gene_symbol

Workflow

Phase 1: Cancer Type Discovery

Start with free-text search to find matching OncoTree codes:

OncoTree_search(query="breast cancer")
-> Returns list: code, name, main_type, tissue, parent, level, external_references

Key response fields:

• code: OncoTree code (e.g., "BRCA", "IBC") — use this in OncoKB calls
• level: hierarchy depth (1=tissue, 2=main type, 3-5=subtypes)
• parent: parent node code for navigating the hierarchy
• external_references.UMLS: UMLS CUI list
• external_references.NCI: NCI thesaurus code list

Search tips:

• Broad terms ("lung cancer") return many results; narrow by tissue or level
• Use tissue-specific terms ("invasive breast carcinoma") for precise matching
• Acronyms work: query="GBM" finds glioblastoma, query="AML" finds leukemia types

Phase 2: Code Validation and Detail Retrieval

Once you have a candidate code, retrieve full details:

OncoTree_get_type(code="LUAD")
-> Returns: name, main_type, tissue, color, parent, level, history, external_references

Note: Not all codes are valid. "GBM" returns 404 — correct code is "GB" (Glioblastoma, IDH-Wildtype). Always validate via OncoTree_get_type before using in downstream tools.

Phase 3: Tissue-Level Exploration

When the user wants all cancers in a tissue category:

OncoTree_list_tissues()
-> Returns 32 tissue names: "Breast", "CNS/Brain", "Lung", "Myeloid", ...

OncoTree_search(query="CNS/Brain")
-> All cancer types with tissue="CNS/Brain"

Phase 4: Downstream Use in Variant Annotation

Pass validated OncoTree code to OncoKB for cancer-type-specific therapeutic levels:

OncoKB_annotate_variant(gene="EGFR", variant="L858R", tumor_type="LUAD")
-> highestSensitiveLevel: "1" (FDA-approved therapy for this tumor+variant)

Without tumor_type, OncoKB returns pan-cancer levels which may be less specific.

Tool Parameter Reference

Tool	Required	Optional	Notes
OncoTree_search	query	—	Free text; returns list sorted by relevance
OncoTree_get_type	code	—	Case-sensitive; "BRCA" not "brca". Returns 404 for invalid codes
OncoTree_list_tissues	—	—	No params; returns list of 32 tissue strings
OncoKB_annotate_variant	gene, variant	tumor_type	tumor_type is OncoTree code; omit for pan-cancer
GDC_get_mutation_frequency	gene_symbol	—	Pan-cancer TCGA only; no per-subtype breakdown

Common OncoTree Codes (verified working)

Code	Name	Tissue
BRCA	Invasive Breast Carcinoma	Breast
LUAD	Lung Adenocarcinoma	Lung
LUSC	Lung Squamous Cell Carcinoma	Lung
MEL	Melanoma	Skin
CRC	Colorectal Cancer	Bowel
PAAD	Pancreatic Adenocarcinoma	Pancreas
GBM	(invalid — use GB)	CNS/Brain
GB	Glioblastoma, IDH-Wildtype	CNS/Brain
AML	Acute Myeloid Leukemia	Myeloid
PRAD	Prostate Adenocarcinoma	Prostate

Common Patterns

# Pattern: Resolve free-text to OncoTree code
results = OncoTree_search(query="pancreatic ductal adenocarcinoma")
# Pick result with lowest level number (most specific match)
code = results["data"][0]["code"]  # e.g., "PAAD"

# Pattern: Get all subtypes within a main type
results = OncoTree_search(query="Glioma")
subtypes = [r for r in results["data"] if r["main_type"] == "Glioma"]

# Pattern: Validate code before OncoKB call
detail = OncoTree_get_type(code="GB")
if detail["status"] == "success":
    OncoKB_annotate_variant(gene="IDH1", variant="R132H", tumor_type="GB")

Tumor Classification Reasoning (CRITICAL)

LOOK UP DON'T GUESS -- tumor classification determines treatment. Always verify codes and biomarker interpretation via tools rather than relying on memory.

Histological vs Molecular Classification

Tumors are classified on TWO axes -- both matter for treatment selection:

• Histological (what it looks like under microscope): adenocarcinoma, squamous, small cell, etc. This determines the OncoTree hierarchy level 3+.
• Molecular (what mutations/alterations drive it): EGFR-mutant, HER2-amplified, MSI-high, etc. This determines OncoKB therapeutic levels.

A tumor can be histologically identical to another but molecularly different, requiring different treatment. Example: two lung adenocarcinomas (both LUAD) but one is EGFR-mutant (targeted therapy) and another is KRAS-mutant (different targeted therapy). Always check both axes.

Biomarker Interpretation Strategy

When interpreting cancer biomarkers, use OncoKB for actionability:

• HER2: Positive = IHC 3+ or FISH-amplified. Use OncoKB_annotate_variant(gene="ERBB2", variant="Amplification", tumor_type="BRCA") for therapeutic level
• ER/PR: Positive = hormone-receptor positive breast cancer. Changes treatment class (endocrine therapy)
• Ki67: Proliferation index. High (>20%) suggests aggressive biology; used in breast cancer grading (Luminal A vs B)
• TMB (Tumor Mutational Burden): High TMB (>10 mut/Mb) predicts immunotherapy response across tumor types. Use OncoKB_annotate_variant(gene="Other Biomarkers", variant="TMB-H")
• MSI (Microsatellite Instability): MSI-High is FDA-approved biomarker for pembrolizumab pan-cancer. Use OncoKB_annotate_variant(gene="Other Biomarkers", variant="MSI-H")

Staging vs Grading -- Different Concepts

• Stage (TNM): How far has it spread? T=tumor size, N=lymph nodes, M=metastasis. Stage I-IV. Determines prognosis and surgery eligibility.
• Grade: How abnormal do the cells look? Grade 1 (well-differentiated, slow) to Grade 3 (poorly-differentiated, aggressive). Determines aggressiveness.
• A Stage I, Grade 3 tumor (small but aggressive) has different implications than Stage III, Grade 1 (spread but slow-growing).

Actionability Assessment

After classifying the tumor, assess whether findings are clinically actionable:

1. Level 1 (FDA-approved, specific tumor type): Immediate treatment implication. Example: EGFR L858R in LUAD
2. Level 2 (Standard care): Strong evidence but context-dependent
3. Level 3 (Compelling evidence): Clinical trial candidates
4. Level 4 (Biological evidence): Research-stage only
5. Always provide the OncoTree code to OncoKB -- without it, you get pan-cancer levels which may understate or overstate actionability for the specific tumor type

Reasoning Framework for Result Interpretation

Evidence Grading

Grade	Criteria	Example
Confirmed	Exact OncoTree code validated via OncoTree_get_type, UMLS + NCI cross-refs present	LUAD: validated, UMLS C0152013, NCI C3512
Probable	OncoTree search returns match, but code not yet validated or missing cross-refs	Search for "cholangiocarcinoma" returns CHOL with partial external refs
Ambiguous	Multiple OncoTree codes match the description at different hierarchy levels	"Breast cancer" matches BRCA (invasive), BREAST (tissue), IBC (inflammatory)
Unresolved	No OncoTree match; tumor type too rare or novel for the ontology	Ultra-rare sarcoma subtype not in OncoTree

Interpretation Guidance

• OncoTree code confidence: Always validate candidate codes with OncoTree_get_type before downstream use. Some common acronyms (e.g., "GBM") are NOT valid OncoTree codes (correct code is "GB"). A validated code with UMLS and NCI cross-references is highest confidence.
• UMLS/NCI cross-reference priority: For standardized reporting, NCI Thesaurus codes are preferred for cancer-specific contexts (used by caDSR, GDC). UMLS CUIs are broader (cross-disease) and useful for literature mining. When both are available, report both; when only one exists, NCI is preferred for oncology workflows.
• Tissue hierarchy interpretation: OncoTree levels represent specificity: Level 1 = tissue of origin (e.g., "Lung"), Level 2 = main cancer type (e.g., "Non-Small Cell Lung Cancer"), Level 3+ = histological subtypes (e.g., "Lung Adenocarcinoma"). For OncoKB variant annotation, use the most specific (deepest) level that accurately describes the tumor. For cohort-level analysis (e.g., TCGA), the Level 2-3 code is typically appropriate.
• OncoKB tumor type impact: Providing a tumor type code to OncoKB can change the therapeutic level (e.g., EGFR L858R is Level 1 in LUAD but Level 3B pan-cancer). Always use the validated OncoTree code for the patient's specific tumor type.
• Deprecated or renamed codes: OncoTree evolves across versions. The history field in OncoTree_get_type response shows prior names. Always use the current code.

Synthesis Questions

1. Does the chosen OncoTree code represent the most specific histological subtype, or could a more precise code provide better therapeutic annotation in OncoKB?
2. When the free-text tumor description maps to multiple OncoTree codes, which hierarchy level best balances specificity and coverage for the analysis goal (variant annotation vs cohort selection)?
3. Are the UMLS/NCI cross-references consistent with external classifications (WHO, ICD-O), or are there discrepancies that need resolution?

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Fallback Chains

Primary	Fallback	When
OncoTree_get_type(code="GBM")	OncoTree_search(query="glioblastoma")	404 for common aliases
OncoTree_search (no results)	OncoTree_list_tissues + tissue-level search	Very rare/novel tumor types
OncoTree code for OncoKB	Omit tumor_type param	Code not recognized by OncoKB