Skill: erisonbarros/erobeng-master (version 1.0.0)

--- name: depmap description: Query the Cancer Dependency Map (DepMap) for cancer cell line gene dependency scores (CRISPR Chronos), drug sensitivity data, and gene effect profiles. Use for identifying cancer-specific vulnerabilities, synthetic lethal interactions, and validating oncology drug targets. license: CC-BY-4.0 metadata: skill-author: Kuan-lin Huang --- # DepMap — Cancer Dependency Map ## Overview The Cancer Dependency Map (DepMap) project, run by the Broad Institute, systematically characterizes genetic dependencies across hundreds of cancer cell lines using genome-wide CRISPR knockout screens (DepMap CRISPR), RNA interference (RNAi), and compound sensitivity assays (PRISM). DepMap data is essential for: - Identifying which genes are essential for specific cancer types - Finding cancer-selective dependencies (therapeutic targets) - Validating oncology drug targets - Discovering synthetic lethal interactions **Key resources:** - DepMap Portal: https://depmap.org/portal/ - DepMap data downloads: https://depmap.org/portal/download/all/ - Python package: `depmap` (or access via API/downloads) - API: https://depmap.org/portal/api/ ## When to Use This Skill Use DepMap when: - **Target validation**: Is a gene essential for survival in cancer cell lines with a specific mutation (e.g., KRAS-mutant)? - **Biomarker discovery**: What genomic features predict sensitivity to knockout of a gene? - **Synthetic lethality**: Find genes that are selectively essential when another gene is mutated/deleted - **Drug sensitivity**: What cell line features predict response to a compound? - **Pan-cancer essentiality**: Is a gene broadly essential across all cancer types (bad target) or selectively essential? - **Correlation analysis**: Which pairs of genes have correlated dependency profiles (co-essentiality)? ## Core Concepts ### Dependency Scores | Score | Range | Meaning | |-------|-------|---------| | **Chronos** (CRISPR) | ~ -3 to 0+ | More negative = more essential. Common essential threshold: −1. Pan-essential genes ~−1 to −2 | | **RNAi DEMETER2** | ~ -3 to 0+ | Similar scale to Chronos | | **Gene Effect** | normalized | Normalized Chronos; −1 = median effect of common essential genes | **Key thresholds:** - Chronos ≤ −0.5: likely dependent - Chronos ≤ −1: strongly dependent (common essential range) ### Cell Line Annotations Each cell line has: - `DepMap_ID`: unique identifier (e.g., `ACH-000001`) - `cell_line_name`: human-readable name - `primary_disease`: cancer type - `lineage`: broad tissue lineage - `lineage_subtype`: specific subtype ## Core Capabilities ### 1. DepMap API ```python import requests import pandas as pd BASE_URL = "https://depmap.org/portal/api" def depmap_get(endpoint, params=None): url = f"{BASE_URL}/{endpoint}" response = requests.get(url, params=params) response.raise_for_status() return response.json() ``` ### 2. Gene Dependency Scores ```python def get_gene_dependency(gene_symbol, dataset="Chronos_Combined"): """Get CRISPR dependency scores for a gene across all cell lines.""" url = f"{BASE_URL}/gene" params = { "gene_id": gene_symbol, "dataset": dataset } response = requests.get(url, params=params) return response.json() # Alternatively, use the /data endpoint: def get_dependencies_slice(gene_symbol, dataset_name="CRISPRGeneEffect"): """Get a gene's dependency slice from a dataset.""" url = f"{BASE_URL}/data/gene_dependency" params = {"gene_name": gene_symbol, "dataset_name": dataset_name} response = requests.get(url, params=params) data = response.json() return data ``` ### 3. Download-Based Analysis (Recommended for Large Queries) For large-scale analysis, download DepMap data files and analyze locally: ```python import pandas as pd import requests, os def download_depmap_data(url, output_path): """Download a DepMap data file.""" response = requests.get(url, stream=True) with open(output_path, 'wb') as f: for chunk in response.iter_content(chunk_size=8192): f.write(chunk) # DepMap 24Q4 data files (update version as needed) FILES = { "crispr_gene_effect": "https://figshare.com/ndownloader/files/...", # OR download from: https://depmap.org/portal/download/all/ # Files available: # CRISPRGeneEffect.csv - Chronos gene effect scores # OmicsExpressionProteinCodingGenesTPMLogp1.csv - mRNA expression # OmicsSomaticMutationsMatrixDamaging.csv - mutation binary matrix # OmicsCNGene.csv - copy number # sample_info.csv - cell line metadata } def load_depmap_gene_effect(filepath="CRISPRGeneEffect.csv"): """ Load DepMap CRISPR gene effect matrix. Rows = cell lines (DepMap_ID), Columns = genes (Symbol (EntrezID)) """ df = pd.read_csv(filepath, index_col=0) # Rename columns to gene symbols only df.columns = [col.split(" ")[0] for col in df.columns] return df def load_cell_line_info(filepath="sample_info.csv"): """Load cell line metadata.""" return pd.read_csv(filepath) ``` ### 4. Identifying Selective Dependencies ```python import numpy as np import pandas as pd def find_selective_dependencies(gene_effect_df, cell_line_info, target_gene, cancer_type=None, threshold=-0.5): """Find cell lines selectively dependent on a gene.""" # Get scores for target gene if target_gene not in gene_effect_df.columns: return None scores = gene_effect_df[target_gene].dropna() dependent = scores[scores <= threshold] # Add cell line info result = pd.DataFrame({ "DepMap_ID": dependent.index, "gene_effect": dependent.values }).merge(cell_line_info[["DepMap_ID", "cell_line_name", "primary_disease", "lineage"]]) if cancer_type: result = result[result["primary_disease"].str.contains(cancer_type, case=False, na=False)] return result.sort_values("gene_effect") # Example usage (after loading data) # df_effect = load_depmap_gene_effect("CRISPRGeneEffect.csv") # cell_info = load_cell_line_info("sample_info.csv") # deps = find_selective_dependencies(df_effect, cell_info, "KRAS", cancer_type="Lung") ``` ### 5. Biomarker Analysis (Gene Effect vs. Mutation) ```python import pandas as pd from scipy import stats def biomarker_analysis(gene_effect_df, mutation_df, target_gene, biomarker_gene): """ Test if mutation in biomarker_gene predicts dependency on target_gene. Args: gene_effect_df: CRISPR gene effect DataFrame mutation_df: Binary mutation DataFrame (1 = mutated) target_gene: Gene to assess dependency of biomarker_gene: Gene whose mutation may predict dependency """ if target_gene not in gene_effect_df.columns or biomarker_gene not in mutation_df.columns: return None # Align cell lines common_lines = gene_effect_df.index.intersection(mutation_df.index) scores = gene_effect_df.loc[common_lines, target_gene].dropna() mutations = mutation_df.loc[scores.index, biomarker_gene] mutated = scores[mutations == 1] wt = scores[mutations == 0] stat, pval = stats.mannwhitneyu(mutated, wt, alternative='less') return { "target_gene": target_gene, "biomarker_gene": biomarker_gene, "n_mutated": len(mutated), "n_wt": len(wt), "mean_effect_mutated": mutated.mean(), "mean_effect_wt": wt.mean(), "pval": pval, "significant": pval < 0.05 } ``` ### 6. Co-Essentiality Analysis ```python import pandas as pd def co_essentiality(gene_effect_df, target_gene, top_n=20): """Find genes with most correlated dependency profiles (co-essential partners).""" if target_gene not in gene_effect_df.columns: return None target_scores = gene_effect_df[target_gene].dropna() correlations = {} for gene in gene_effect_df.columns: if gene == target_gene: continue other_scores = gene_effect_df[gene].dropna() common = target_scores.index.intersection(other_scores.index) if len(common) < 50: continue r = target_scores[common].corr(other_scores[common]) if not pd.isna(r): correlations[gene] = r corr_series = pd.Series(correlations).sort_values(ascending=False) return corr_series.head(top_n) # Co-essential genes often share biological complexes or pathways ``` ## Query Workflows ### Workflow 1: Target Validation for a Cancer Type 1. Download `CRISPRGeneEffect.csv` and `sample_info.csv` 2. Filter cell lines by cancer type 3. Compute mean gene effect for target gene in cancer vs. all others 4. Calculate selectivity: how specific is the dependency to your cancer type? 5. Cross-reference with mutation, expression, or CNA data as biomarkers ### Workflow 2: Synthetic Lethality Screen 1. Identify cell lines with mutation/deletion in gene of interest (e.g., BRCA1-mutant) 2. Compute gene effect scores for all genes in mutant vs. WT lines 3. Identify genes significantly more essential in mutant lines (synthetic lethal partners) 4. Filter by selectivity and effect size ### Workflow 3: Compound Sensitivity Analysis 1. Download PRISM compound sensitivity data (`primary-screen-replicate-treatment-info.csv`) 2. Correlate compound AUC/log2(fold-change) with genomic features 3. Identify predictive biomarkers for compound sensitivity ## DepMap Data Files Reference | File | Description | |------|-------------| | `CRISPRGeneEffect.csv` | CRISPR Chronos gene effect (primary dependency data) | | `CRISPRGeneEffectUnscaled.csv` | Unscaled CRISPR scores | | `RNAi_merged.csv` | DEMETER2 RNAi dependency | | `sample_info.csv` | Cell line metadata (lineage, disease, etc.) | | `OmicsExpressionProteinCodingGenesTPMLogp1.csv` | mRNA expression | | `OmicsSomaticMutationsMatrixDamaging.csv` | Damaging somatic mutations (binary) | | `OmicsCNGene.csv` | Copy number per gene | | `PRISM_Repurposing_Primary_Screens_Data.csv` | Drug sensitivity (repurposing library) | Download all files from: https://depmap.org/portal/download/all/ ## Best Practices - **Use Chronos scores** (not DEMETER2) for current CRISPR analyses — better controlled for cutting efficiency - **Distinguish pan-essential from cancer-selective**: Target genes with low variance (essential in all lines) are poor drug targets - **Validate with expression data**: A gene not expressed in a cell line will score as non-essential regardless of actual function - **Use DepMap ID** for cell line identification — cell_line_name can be ambiguous - **Account for copy number**: Amplified genes may appear essential due to copy number effect (junk DNA hypothesis) - **Multiple testing correction**: When computing biomarker associations genome-wide, apply FDR correction ## Additional Resources - **DepMap Portal**: https://depmap.org/portal/ - **Data downloads**: https://depmap.org/portal/download/all/ - **DepMap paper**: Behan FM et al. (2019) Nature. PMID: 30971826 - **Chronos paper**: Dempster JM et al. (2021) Nature Methods. PMID: 34349281 - **GitHub**: https://github.com/broadinstitute/depmap-portal - **Figshare**: https://figshare.com/articles/dataset/DepMap_24Q4_Public/27993966

path: references/dependency_analysis.md
content: # DepMap Dependency Analysis Guide

## Understanding Chronos Scores

Chronos is the current (v5+) algorithm for computing gene dependency scores from CRISPR screen data. It addresses systematic biases including:
- Copy number effects (high-copy genes appear essential due to DNA cutting)
- Guide RNA efficiency variation
- Cell line growth rates

### Score Interpretation

| Score Range | Interpretation |
|------------|----------------|
| > 0 | Likely growth-promoting when knocked out (some noise) |
| 0 to −0.3 | Non-essential: minimal fitness effect |
| −0.3 to −0.5 | Mild dependency |
| −0.5 to −1.0 | Significant dependency |
| < −1.0 | Strong dependency (common essential range) |
| ≈ −1.0 | Median of pan-essential genes (e.g., proteasome subunits) |

### Common Essential Genes (Controls)

Genes that are essential in nearly all cell lines (score ~−1 to −2):
- Ribosomal proteins: RPL..., RPS...
- Proteasome: PSMA..., PSMB...
- Spliceosome: SNRPD1, SNRNP70
- DNA replication: MCM2, PCNA
- Transcription: POLR2A, TAF...

These can be used as positive controls for screen quality.

### Non-Essential Controls

Genes with negligible fitness effect (score ~ 0):
- Non-expressed genes (tissue-specific)
- Safe harbor loci

## Selectivity Assessment

To determine if a dependency is cancer-selective:

```python
import pandas as pd
import numpy as np

def compute_selectivity(gene_effect_df, target_gene, cancer_lineage):
    """Compute selectivity score for a cancer lineage."""
    scores = gene_effect_df[target_gene].dropna()

    # Get cell line metadata
    from depmap_utils import load_cell_line_info
    cell_info = load_cell_line_info()
    scores_df = scores.reset_index()
    scores_df.columns = ["DepMap_ID", "score"]
    scores_df = scores_df.merge(cell_info[["DepMap_ID", "lineage"]])

    cancer_scores = scores_df[scores_df["lineage"] == cancer_lineage]["score"]
    other_scores = scores_df[scores_df["lineage"] != cancer_lineage]["score"]

    # Selectivity: lower mean in cancer lineage vs others
    selectivity = other_scores.mean() - cancer_scores.mean()
    return {
        "target_gene": target_gene,
        "cancer_lineage": cancer_lineage,
        "cancer_mean": cancer_scores.mean(),
        "other_mean": other_scores.mean(),
        "selectivity_score": selectivity,
        "n_cancer": len(cancer_scores),
        "fraction_dependent": (cancer_scores < -0.5).mean()
    }
```

## CRISPR Dataset Versions

| Dataset | Description | Recommended |
|---------|-------------|-------------|
| `CRISPRGeneEffect` | Chronos-corrected gene effect | Yes (current) |
| `Achilles_gene_effect` | Older CERES algorithm | Legacy only |
| `RNAi_merged` | DEMETER2 RNAi | For cross-validation |

## Quality Metrics

DepMap reports quality control metrics per screen:
- **Skewness**: Pan-essential genes should show negative skew
- **AUC**: Area under ROC for pan-essential vs non-essential controls

Good screens: skewness < −1, AUC > 0.85

## Cancer Lineage Codes

Common values for `lineage` field in `sample_info.csv`:

| Lineage | Description |
|---------|-------------|
| `lung` | Lung cancer |
| `breast` | Breast cancer |
| `colorectal` | Colorectal cancer |
| `brain_cancer` | Brain cancer (GBM, etc.) |
| `leukemia` | Leukemia |
| `lymphoma` | Lymphoma |
| `prostate` | Prostate cancer |
| `ovarian` | Ovarian cancer |
| `pancreatic` | Pancreatic cancer |
| `skin` | Melanoma and other skin |
| `liver` | Liver cancer |
| `kidney` | Kidney cancer |

## Synthetic Lethality Analysis

```python
import pandas as pd
import numpy as np
from scipy import stats

def find_synthetic_lethal(gene_effect_df, mutation_df, biomarker_gene,
                           fdr_threshold=0.1):
    """
    Find synthetic lethal partners for a loss-of-function mutation.

    For each gene, tests if cell lines mutant in biomarker_gene
    are more dependent on that gene vs. WT lines.
    """
    if biomarker_gene not in mutation_df.columns:
        return pd.DataFrame()

    # Get mutant vs WT cell lines
    common = gene_effect_df.index.intersection(mutation_df.index)
    is_mutant = mutation_df.loc[common, biomarker_gene] == 1

    mutant_lines = common[is_mutant]
    wt_lines = common[~is_mutant]

    results = []
    for gene in gene_effect_df.columns:
        mut_scores = gene_effect_df.loc[mutant_lines, gene].dropna()
        wt_scores = gene_effect_df.loc[wt_lines, gene].dropna()

        if len(mut_scores) < 5 or len(wt_scores) < 10:
            continue

        stat, pval = stats.mannwhitneyu(mut_scores, wt_scores, alternative='less')
        results.append({
            "gene": gene,
            "mean_mutant": mut_scores.mean(),
            "mean_wt": wt_scores.mean(),
            "effect_size": wt_scores.mean() - mut_scores.mean(),
            "pval": pval,
            "n_mutant": len(mut_scores),
            "n_wt": len(wt_scores)
        })

    df = pd.DataFrame(results)
    # FDR correction
    from scipy.stats import false_discovery_control
    df["qval"] = false_discovery_control(df["pval"], method="bh")
    df = df[df["qval"] < fdr_threshold].sort_values("effect_size", ascending=False)
    return df
```

## Drug Sensitivity (PRISM)

DepMap also contains compound sensitivity data from the PRISM assay:

```python
import pandas as pd

def load_prism_data(filepath="primary-screen-replicate-collapsed-logfold-change.csv"):
    """
    Load PRISM drug sensitivity data.
    Rows = cell lines, Columns = compounds (broad_id::name::dose)
    Values = log2 fold change (more negative = more sensitive)
    """
    return pd.read_csv(filepath, index_col=0)

# Available datasets:
# primary-screen: 4,518 compounds at single dose
# secondary-screen: ~8,000 compounds at multiple doses (AUC available)
```


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