Q (haiku): List the top 20 mutated genes in study nbl_msk_2023.

▶ read_guide
{
 "uri": "cbioportal://mutation-frequency-guide"
}

▶ clickhouse_list_tables
{}

◀ result
# Mutation Frequency Analysis Guide

## IMPORTANT: Reporting Mutation Frequencies
- **ALWAYS report frequencies as percentages**, not raw counts: `frequency = (altered_samples / total_profiled_samples) × 100`
- For quick frequency lookups, **prefer the TCGA Pan-Cancer Atlas study first**, then offer to expand to other studies
- When reporting across multiple studies, show **ranges** (e.g., "TP53 is mutated in 30–60% of samples") rather than a single average
- **NEVER** sum mutation events across studies to compute an aggregate frequency — this can exceed 100% due to double-counting
- Warn users that samples may overlap across cohorts (e.g., MSK studies may share patients)
- **Choose and state the counting unit**: use patient-level frequencies for prevalence/rate questions unless the user explicitly asks for samples; use sample-level frequencies when the user asks about samples.
- **For "across cancer types" questions**, jump to the [Cross-Cancer-Type Mutation Frequency](#cross-cancer-type-mutation-frequency) section below — there is one correct recipe and several common wrong ones.

## Counting Unit: Samples vs Patients

Before answering any mutation count or frequency question, decide whether the unit is samples or patients and state that choice in the answer.

| User wording | Counting unit |
|--------------|---------------|
| "prevalence", "rate", "fraction of patients", "patients with", "how common is" | Patient-level: `COUNT(DISTINCT patient_unique_id)` |
| "samples", "specimens", "biopsies", sample-level cohort composition | Sample-level: `COUNT(DISTINCT sample_unique_id)` |
| Ambiguous | Ask, or default to patient-level for prevalence/rate language and say so |

### Cross-study sample-count caveat

When an answer touches more than one study and reports a sample count, prepend a one-line caveat:

> Sample IDs are unique within cBioPortal study prefixes, not guaranteed biological-sample identifiers across studies; overlapping cohorts can count the same patient/sample more than once.

Prefer one of these safer approaches:

- Use a shipped `cancer_study_query_preferences` cohort such as `pan_cancer_tcga` or `all_studies_non_redundant`.
- Restrict to one named study.
- Aggregate by `patient_unique_id` when the biological question is patient prevalence.

## STOP rule: a frequency above 100% means your query is wrong

If your query returns a frequency over 100%, **do not try to debug or explain the data inconsistency to the user**. The cause is always one of these query bugs:

- Summing mutation events instead of `COUNT(DISTINCT sample_unique_id)` for the numerator
- Using a study-wide sample count as the denominator instead of the gene-specific profiled count
- Cross-study aggregation where the same biological sample appears under multiple `sample_unique_id` values (e.g., MSK-IMPACT and MSK-CHORD share patients)
- **Joining the profiled CTE through `gene_panel` / `gene_panel_list` without a WES branch.** `gene_panel_id = 'WES'` is *not* a row in … (35166 more chars)

◀ result
{"tables":[{"name":"allele_specific_copy_number"},{"name":"alteration_driver_annotation"},{"name":"cancer_study"},{"name":"cancer_study_query_preferences"},{"name":"cancer_study_tags"},{"name":"cbioportal_sequence_state"},{"name":"clinical_attribute_counts"},{"name":"clinical_attribute_meta"},{"name":"clinical_data_derived"},{"name":"clinical_event"},{"name":"clinical_event_data"},{"name":"clinical_event_data_derived"},{"name":"clinical_event_derived"},{"name":"clinical_patient"},{"name":"clinical_sample"},{"name":"cna_event"},{"name":"cna_panel_gene_coverage"},{"name":"cna_wes_coverage"},{"name":"co_altered_genes_in_study"},{"name":"copy_number_seg"},{"name":"copy_number_seg_file"},{"name":"gene"},{"name":"gene_alias"},{"name":"gene_alteration_frequency_by_cancer_type"},{"name":"gene_cna_distribution_in_study"},{"name":"gene_mutation_frequency_by_cancer_type"},{"name":"gene_mutation_frequency_in_studies"},{"name":"gene_mutation_frequency_in_study"},{"name":"gene_mutation_variants_in_study"},{"name":"gene_pair_coexpression"},{"name":"gene_panel"},{"name":"gene_panel_list"},{"name":"gene_panel_to_gene_derived"},{"name":"generic_assay_data_derived"},{"name":"generic_assay_meta_derived"},{"name":"generic_assay_profile_entity_derived"},{"name":"generic_entity_properties"},{"name":"geneset"},{"name":"geneset_gene"},{"name":"geneset_hierarchy_leaf"},{"name":"geneset_hierarchy_node"},{"name":"genetic_alteration"},{"name":"genetic_alteration_derived"},{"name":"genetic_entity"},{"name":"genetic_profile"},{"name":"genetic_profile_link"},{"name":"genetic_profile_samples"},{"name":"genomic_event_derived"},{"name":"gistic"},{"name":"gistic_to_gene"},{"name":"info"},{"name":"mut_sig"},{"name":"mutation"},{"name":"mutation_count_by_keyword"},{"name":"mutation_derived"},{"name":"mutation_event"},{"name":"mutation_panel_gene_coverage"},{"name":"mutation_wes_coverage"},{"name":"patient"},{"name":"reference_genome"},{"name":"reference_genome_gene"},{"name":"resource_definition"},{"name":"resource_patient"},{"name":"resource_sample"},{"name":"resource_study"},{"name":"sample"},{"name":"sample_cna_event"},{"name":"sample_derived"},{"name":"sample_list"},{"name":"sample_list_list"},{"name":"sample_profile"},{"name":"sample_to_gene_panel_derived"},{"name":"structural_variant"},{"name":"sv_panel_gene_coverage"},{"name":"sv_wes_coverage"},{"name":"top_cna_genes_in_study"},{"name":"top_mutated_genes_in_cohort"},{"name":"top_mutated_genes_in_study"},{"name":"top_sv_genes_in_study"},{"name":"treatment_counts_in_study"},{"name":"treatment_regimens_in_study"},{"name":"type_of_cancer"}]}

▶ clickhouse_run_select_query
{
 "query": "SELECT *
FROM top_mutated_genes_in_study(study = 'nbl_msk_2023', top_n = 20);",
 "max_rows": 20
}

◀ result
{"rows":[{"hugo_gene_symbol":"ALK","altered_samples":33,"profiled_samples":223,"frequency_pct":14.8,"total_mutation_events":34},{"hugo_gene_symbol":"ATRX","altered_samples":24,"profiled_samples":223,"frequency_pct":10.8,"total_mutation_events":24},{"hugo_gene_symbol":"SMARCA4","altered_samples":9,"profiled_samples":223,"frequency_pct":4,"total_mutation_events":9},{"hugo_gene_symbol":"BRAF","altered_samples":8,"profiled_samples":223,"frequency_pct":3.6,"total_mutation_events":8},{"hugo_gene_symbol":"BRCA2","altered_samples":8,"profiled_samples":223,"frequency_pct":3.6,"total_mutation_events":8},{"hugo_gene_symbol":"TERT","altered_samples":7,"profiled_samples":223,"frequency_pct":3.1,"total_mutation_events":7},{"hugo_gene_symbol":"CREBBP","altered_samples":6,"profiled_samples":223,"frequency_pct":2.7,"total_mutation_events":8},{"hugo_gene_symbol":"FAT1","altered_samples":6,"profiled_samples":223,"frequency_pct":2.7,"total_mutation_events":6},{"hugo_gene_symbol":"KMT2D","altered_samples":6,"profiled_samples":223,"frequency_pct":2.7,"total_mutation_events":9},{"hugo_gene_symbol":"KRAS","altered_samples":6,"profiled_samples":223,"frequency_pct":2.7,"total_mutation_events":6},{"hugo_gene_symbol":"PTPN11","altered_samples":6,"profiled_samples":223,"frequency_pct":2.7,"total_mutation_events":6},{"hugo_gene_symbol":"ROS1","altered_samples":6,"profiled_samples":223,"frequency_pct":2.7,"total_mutation_events":6},{"hugo_gene_symbol":"CD79B","altered_samples":5,"profiled_samples":223,"frequency_pct":2.2,"total_mutation_events":5},{"hugo_gene_symbol":"IRS2","altered_samples":5,"profiled_samples":223,"frequency_pct":2.2,"total_mutation_events":5},{"hugo_gene_symbol":"KMT2B","altered_samples":5,"profiled_samples":168,"frequency_pct":3,"total_mutation_events":5},{"hugo_gene_symbol":"NCOR1","altered_samples":5,"profiled_samples":223,"frequency_pct":2.2,"total_mutation_events":5},{"hugo_gene_symbol":"NF1","altered_samples":5,"profiled_samples":223,"frequency_pct":2.2,"total_mutation_events":6},{"hugo_gene_symbol":"PDGFRA","altered_samples":5,"profiled_samples":223,"frequency_pct":2.2,"total_mutation_events":5},{"hugo_gene_symbol":"ARID1A","altered_samples":4,"profiled_samples":223,"frequency_pct":1.8,"total_mutation_events":4},{"hugo_gene_symbol":"AXL","altered_samples":4,"profiled_samples":223,"frequency_pct":1.8,"total_mutation_events":4}]}

═ answer (success)
Perfect! Here are the **top 20 mutated genes in the nbl_msk_2023 study**:

| Gene | Altered Samples | Profiled Samples | Frequency (%) | Total Mutation Events |
|------|-----------------|-----------------|---------------|-----------------------|
| ALK | 33 | 223 | 14.8% | 34 |
| ATRX | 24 | 223 | 10.8% | 24 |
| SMARCA4 | 9 | 223 | 4.0% | 9 |
| BRAF | 8 | 223 | 3.6% | 8 |
| BRCA2 | 8 | 223 | 3.6% | 8 |
| TERT | 7 | 223 | 3.1% | 7 |
| CREBBP | 6 | 223 | 2.7% | 8 |
| FAT1 | 6 | 223 | 2.7% | 6 |
| KMT2D | 6 | 223 | 2.7% | 9 |
| KRAS | 6 | 223 | 2.7% | 6 |
| PTPN11 | 6 | 223 | 2.7% | 6 |
| ROS1 | 6 | 223 | 2.7% | 6 |
| CD79B | 5 | 223 | 2.2% | 5 |
| IRS2 | 5 | 223 | 2.2% | 5 |
| KMT2B | 5 | 168 | 3.0% | 5 |
| NCOR1 | 5 | 223 | 2.2% | 5 |
| NF1 | 5 | 223 | 2.2% | 6 |
| PDGFRA | 5 | 223 | 2.2% | 5 |
| ARID1A | 4 | 223 | 1.8% | 4 |
| AXL | 4 | 223 | 1.8% | 4 |

**Key findings:**
- **ALK** is the most frequently mutated gene, present in 14.8% of neuroblastoma samples—consistent with ALK's well-known role in pediatric neuroblastoma
- **ATRX** is the second most common at 10.8%, a frequent mutation in neural tumors
- Most other genes are mutated in 2–4% of samples
- All genes shown (except KMT2B, which has 168 profiled samples) were sequenced in 223 profiled samples