Q (haiku): What are the most mutated genes in lung cancer?

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

◀ 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 … (36467 more chars)

▶ resolve_and_route
{
 "studyKeywords": [
  "lung"
 ]
}

◀ result
{"success":true,"message":"Found 43 matching studies (top 5 with full metadata, rest with basic info). Pick the best match (prefer TCGA → prefer PanCancer Atlas), use its metadata to call the appropriate navigation tool(s) and generate URLs immediately. Present other studies as alternatives.","data":{"totalCount":43,"studiesWithMetadata":[{"studyId":"msk_met_2021","name":"MSK MetTropism (MSK, Cell 2021)","sampleCount":25775,"studyViewUrl":"https://www.cbioportal.org/study?id=msk_met_2021","metadata":{"clinicalAttributeIds":["AGE_AT_DEATH","AGE_AT_EVIDENCE_OF_METS","AGE_AT_LAST_CONTACT","AGE_AT_SEQUENCING","AGE_AT_SURGERY","CANCER_TYPE","CANCER_TYPE_DETAILED","DMETS_DX_ADRENAL_GLAND","DMETS_DX_BILIARY_TRACT","DMETS_DX_BLADDER_UT","DMETS_DX_BONE","DMETS_DX_BOWEL","DMETS_DX_BREAST","DMETS_DX_CNS_BRAIN","DMETS_DX_DIST_LN","DMETS_DX_FEMALE_GENITAL","DMETS_DX_HEAD_NECK","DMETS_DX_INTRA_ABDOMINAL","DMETS_DX_KIDNEY","DMETS_DX_LIVER","DMETS_DX_LUNG","DMETS_DX_MALE_GENITAL","DMETS_DX_MEDIASTINUM","DMETS_DX_OVARY","DMETS_DX_PLEURA","DMETS_DX_PNS","DMETS_DX_SKIN","DMETS_DX_UNSPECIFIED","FGA","FRACTION_GENOME_ALTERED","GENE_PANEL","IS_DIST_MET_MAPPED","METASTATIC_SITE","MET_COUNT","MET_SITE_COUNT","MSI_SCORE","MSI_TYPE","MUTATION_COUNT","ONCOTREE_CODE","ORGAN_SYSTEM","OS_MONTHS","OS_STATUS","PRIMARY_SITE","RACE","SAMPLE_COUNT","SAMPLE_COVERAGE","SAMPLE_TYPE","SEX","SUBTYPE","SUBTYPE_ABBREVIATION","TMB_NONSYNONYMOUS","TUMOR_PURITY"],"molecularProfileIds":["msk_met_2021_cna","msk_met_2021_mutations","msk_met_2021_structural_variants"],"availableComparisonTabs":["overlap","clinical","survival","alterations","mutations"]}},{"studyId":"luad_mskcc_2023_met_organotropism","name":"Lung Adenocarcinoma Met Organotropism (MSK, Cancer Cell 2023)","sampleCount":2653,"studyViewUrl":"https://www.cbioportal.org/study?id=luad_mskcc_2023_met_organotropism","metadata":{"clinicalAttributeIds":["ADJUVANT","ADJUVANT_CHEMOTHERAPY","ADJUVANT_IMMUNOTHERAPY","ADJUVANT_TARGETED","ADJUVANT_THERAPY","ADJUVANT_XRT","ADRENAL_MONTHS","ADRENAL_STATUS","AGE_AT_DOS_BX","BONE_MONTHS","BONE_STATUS","CANCER_TYPE","CANCER_TYPE_DETAILED","CELL_CYCLE","CIGARETTE_HX","CNS_MONTHS","CNS_STATUS","CSTAGE","DEATH","EVER_MET_SITE_ADRENAL","EVER_MET_SITE_BONE","EVER_MET_SITE_CNS","EVER_MET_SITE_LIVER_BILIARY_TRACT","EVER_MET_SITE_LN","EVER_MET_SITE_LUNG","EVER_MET_SITE_PLEURA","FGA","FRACTION_GENOME_ALTERED","FU_2YRS","GENE_PANEL","GROUP_NO","HAD_SURGERY","HIPPO","IMPACT_METASTATIC_LESION","IMPACT_PRIMARY_GROUP","INSTITUTE","IN_MATCHED","IS_WGD","LIVER_MONTHS","LIVER_STATUS","LN_MONTHS","LN_STATUS","LUNG_MONTHS","LUNG_STATUS","METASTATIC_BURDEN","METASTATIC_SITE","MONTHS_FROM_MATCHED_PRIM","MSI_SCORE","MSI_TYPE","MUTATION_COUNT","MYC_PATH","NEOADJUVANT","NEOADJUVANT_CHEMOTHERAPY","NEOADJUVANT_IMMUNOTHERAPY","NEOADJUVANT_TARGETED","NEOADJUVANT_XRT","NOTCH","NRF2","ONCOTREE_CODE","OS_MONTHS","OS_STATUS","PI3K","PLEURA_MONTHS","PLEURA_STATUS","PLOIDY","POST_SAMPLE_CHEMOTHERAPY","POST_SAMPLE_IMMUNOTHERAPY","POS … (12605 more chars)

▶ clickhouse_run_select_query
{
 "query": "SELECT * FROM top_mutated_genes_in_cohort(preference = 'pan_cancer_tcga', top_n = 20);",
 "max_rows": "25"
}

✗ error
<tool_use_error>Error: No such tool available: mcp__clickhouse_run_select_query</tool_use_error>

▶ clickhouse_run_select_query
{
 "query": "SELECT * FROM top_mutated_genes_in_cohort(preference = 'pan_cancer_tcga', top_n = 20);",
 "max_rows": 25
}

◀ result
{"rows":[{"hugo_gene_symbol":"TP53","altered_samples":3839,"profiled_samples":10443,"frequency_pct":36.8,"total_mutation_events":4225},{"hugo_gene_symbol":"TTN","altered_samples":3131,"profiled_samples":10443,"frequency_pct":30,"total_mutation_events":9629},{"hugo_gene_symbol":"MUC16","altered_samples":2014,"profiled_samples":10443,"frequency_pct":19.3,"total_mutation_events":4708},{"hugo_gene_symbol":"PIK3CA","altered_samples":1371,"profiled_samples":10443,"frequency_pct":13.1,"total_mutation_events":1619},{"hugo_gene_symbol":"CSMD3","altered_samples":1350,"profiled_samples":10443,"frequency_pct":12.9,"total_mutation_events":2304},{"hugo_gene_symbol":"RYR2","altered_samples":1320,"profiled_samples":10443,"frequency_pct":12.6,"total_mutation_events":2196},{"hugo_gene_symbol":"LRP1B","altered_samples":1297,"profiled_samples":10443,"frequency_pct":12.4,"total_mutation_events":2247},{"hugo_gene_symbol":"SYNE1","altered_samples":1251,"profiled_samples":10443,"frequency_pct":12,"total_mutation_events":2175},{"hugo_gene_symbol":"FLG","altered_samples":1170,"profiled_samples":10443,"frequency_pct":11.2,"total_mutation_events":1753},{"hugo_gene_symbol":"USH2A","altered_samples":1130,"profiled_samples":10443,"frequency_pct":10.8,"total_mutation_events":1824},{"hugo_gene_symbol":"PCLO","altered_samples":1087,"profiled_samples":10443,"frequency_pct":10.4,"total_mutation_events":1851},{"hugo_gene_symbol":"ZFHX4","altered_samples":1029,"profiled_samples":10443,"frequency_pct":9.9,"total_mutation_events":1610},{"hugo_gene_symbol":"DNAH5","altered_samples":1011,"profiled_samples":10443,"frequency_pct":9.7,"total_mutation_events":1839},{"hugo_gene_symbol":"KMT2D","altered_samples":972,"profiled_samples":10443,"frequency_pct":9.3,"total_mutation_events":1356},{"hugo_gene_symbol":"CSMD1","altered_samples":944,"profiled_samples":10443,"frequency_pct":9,"total_mutation_events":1493},{"hugo_gene_symbol":"FAT4","altered_samples":934,"profiled_samples":10443,"frequency_pct":8.9,"total_mutation_events":1617},{"hugo_gene_symbol":"SPTA1","altered_samples":928,"profiled_samples":10443,"frequency_pct":8.9,"total_mutation_events":1293},{"hugo_gene_symbol":"HMCN1","altered_samples":913,"profiled_samples":10443,"frequency_pct":8.7,"total_mutation_events":1423},{"hugo_gene_symbol":"OBSCN","altered_samples":905,"profiled_samples":10443,"frequency_pct":8.7,"total_mutation_events":1413},{"hugo_gene_symbol":"KMT2C","altered_samples":904,"profiled_samples":10443,"frequency_pct":8.7,"total_mutation_events":1287}]}

▶ clickhouse_run_select_query
{
 "query": "SELECT * FROM top_mutated_genes_in_study(study = 'luad_tcga_pan_can_atlas_2018', top_n = 20);",
 "max_rows": 25
}

▶ clickhouse_run_select_query
{
 "query": "SELECT * FROM top_mutated_genes_in_study(study = 'lusc_tcga_pan_can_atlas_2018', top_n = 20);",
 "max_rows": 25
}

◀ result
{"rows":[{"hugo_gene_symbol":"TP53","altered_samples":295,"profiled_samples":566,"frequency_pct":52.1,"total_mutation_events":314},{"hugo_gene_symbol":"TTN","altered_samples":272,"profiled_samples":566,"frequency_pct":48.1,"total_mutation_events":679},{"hugo_gene_symbol":"MUC16","altered_samples":242,"profiled_samples":566,"frequency_pct":42.8,"total_mutation_events":424},{"hugo_gene_symbol":"CSMD3","altered_samples":226,"profiled_samples":566,"frequency_pct":39.9,"total_mutation_events":394},{"hugo_gene_symbol":"RYR2","altered_samples":217,"profiled_samples":566,"frequency_pct":38.3,"total_mutation_events":395},{"hugo_gene_symbol":"LRP1B","altered_samples":201,"profiled_samples":566,"frequency_pct":35.5,"total_mutation_events":338},{"hugo_gene_symbol":"ZFHX4","altered_samples":185,"profiled_samples":566,"frequency_pct":32.7,"total_mutation_events":276},{"hugo_gene_symbol":"USH2A","altered_samples":177,"profiled_samples":566,"frequency_pct":31.3,"total_mutation_events":286},{"hugo_gene_symbol":"KRAS","altered_samples":168,"profiled_samples":566,"frequency_pct":29.7,"total_mutation_events":172},{"hugo_gene_symbol":"XIRP2","altered_samples":150,"profiled_samples":566,"frequency_pct":26.5,"total_mutation_events":202},{"hugo_gene_symbol":"SPTA1","altered_samples":148,"profiled_samples":566,"frequency_pct":26.1,"total_mutation_events":198},{"hugo_gene_symbol":"FLG","altered_samples":145,"profiled_samples":566,"frequency_pct":25.6,"total_mutation_events":229},{"hugo_gene_symbol":"CSMD1","altered_samples":125,"profiled_samples":566,"frequency_pct":22.1,"total_mutation_events":164},{"hugo_gene_symbol":"NAV3","altered_samples":123,"profiled_samples":566,"frequency_pct":21.7,"total_mutation_events":155},{"hugo_gene_symbol":"FAT3","altered_samples":121,"profiled_samples":566,"frequency_pct":21.4,"total_mutation_events":171},{"hugo_gene_symbol":"COL11A1","altered_samples":120,"profiled_samples":566,"frequency_pct":21.2,"total_mutation_events":161},{"hugo_gene_symbol":"PCDH15","altered_samples":118,"profiled_samples":566,"frequency_pct":20.8,"total_mutation_events":172},{"hugo_gene_symbol":"ZNF536","altered_samples":117,"profiled_samples":566,"frequency_pct":20.7,"total_mutation_events":157},{"hugo_gene_symbol":"ANK2","altered_samples":111,"profiled_samples":566,"frequency_pct":19.6,"total_mutation_events":139},{"hugo_gene_symbol":"MUC17","altered_samples":111,"profiled_samples":566,"frequency_pct":19.6,"total_mutation_events":152}]}

◀ result
{"rows":[{"hugo_gene_symbol":"TP53","altered_samples":404,"profiled_samples":484,"frequency_pct":83.5,"total_mutation_events":430},{"hugo_gene_symbol":"TTN","altered_samples":345,"profiled_samples":484,"frequency_pct":71.3,"total_mutation_events":810},{"hugo_gene_symbol":"CSMD3","altered_samples":209,"profiled_samples":484,"frequency_pct":43.2,"total_mutation_events":314},{"hugo_gene_symbol":"RYR2","altered_samples":192,"profiled_samples":484,"frequency_pct":39.7,"total_mutation_events":277},{"hugo_gene_symbol":"MUC16","altered_samples":188,"profiled_samples":484,"frequency_pct":38.8,"total_mutation_events":317},{"hugo_gene_symbol":"LRP1B","altered_samples":171,"profiled_samples":484,"frequency_pct":35.3,"total_mutation_events":251},{"hugo_gene_symbol":"USH2A","altered_samples":160,"profiled_samples":484,"frequency_pct":33.1,"total_mutation_events":212},{"hugo_gene_symbol":"SYNE1","altered_samples":151,"profiled_samples":484,"frequency_pct":31.2,"total_mutation_events":202},{"hugo_gene_symbol":"ZFHX4","altered_samples":143,"profiled_samples":484,"frequency_pct":29.5,"total_mutation_events":194},{"hugo_gene_symbol":"FAM135B","altered_samples":118,"profiled_samples":484,"frequency_pct":24.4,"total_mutation_events":155},{"hugo_gene_symbol":"KMT2D","altered_samples":111,"profiled_samples":484,"frequency_pct":22.9,"total_mutation_events":132},{"hugo_gene_symbol":"NAV3","altered_samples":104,"profiled_samples":484,"frequency_pct":21.5,"total_mutation_events":124},{"hugo_gene_symbol":"RYR3","altered_samples":99,"profiled_samples":484,"frequency_pct":20.5,"total_mutation_events":134},{"hugo_gene_symbol":"CDH10","altered_samples":97,"profiled_samples":484,"frequency_pct":20,"total_mutation_events":120},{"hugo_gene_symbol":"SPTA1","altered_samples":97,"profiled_samples":484,"frequency_pct":20,"total_mutation_events":127},{"hugo_gene_symbol":"DNAH5","altered_samples":93,"profiled_samples":484,"frequency_pct":19.2,"total_mutation_events":126},{"hugo_gene_symbol":"PCDH15","altered_samples":93,"profiled_samples":484,"frequency_pct":19.2,"total_mutation_events":123},{"hugo_gene_symbol":"XIRP2","altered_samples":93,"profiled_samples":484,"frequency_pct":19.2,"total_mutation_events":113},{"hugo_gene_symbol":"PKHD1L1","altered_samples":91,"profiled_samples":484,"frequency_pct":18.8,"total_mutation_events":106},{"hugo_gene_symbol":"PAPPA2","altered_samples":89,"profiled_samples":484,"frequency_pct":18.4,"total_mutation_events":101}]}

▶ navigate_to_results_view
{
 "studyIds": [
  "luad_tcga_pan_can_atlas_2018",
  "lusc_tcga_pan_can_atlas_2018"
 ],
 "genes": [
  "TP53",
  "KRAS",
  "EGFR"
 ],
 "tab": "oncoprint"
}

◀ result
{"success":true,"message":"Navigating to https://www.cbioportal.org/results/oncoprint?cancer_study_list=luad_tcga_pan_can_atlas_2018%2Clusc_tcga_pan_can_atlas_2018&gene_list=TP53%0AKRAS%0AEGFR&case_set_id=all","url":"https://www.cbioportal.org/results/oncoprint?cancer_study_list=luad_tcga_pan_can_atlas_2018%2Clusc_tcga_pan_can_atlas_2018&gene_list=TP53%0AKRAS%0AEGFR&case_set_id=all","data":{"studyIds":["luad_tcga_pan_can_atlas_2018","lusc_tcga_pan_can_atlas_2018"],"studies":[{"studyId":"luad_tcga_pan_can_atlas_2018","name":"Lung Adenocarcinoma (TCGA, PanCancer Atlas)","sampleCount":566},{"studyId":"lusc_tcga_pan_can_atlas_2018","name":"Lung Squamous Cell Carcinoma (TCGA, PanCancer Atlas)","sampleCount":487}],"genes":["TP53","KRAS","EGFR"],"caseSetId":"all","pageDescription":"Visual summary of alterations in queried genes across samples."}}

═ answer (success)
## Most Mutated Genes in Lung Cancer

Based on **TCGA PanCancer Atlas** lung cancer data, here are the top 20 most frequently mutated genes:

### **Lung Adenocarcinoma** (LUAD, *n* = 566 samples):

| Gene | # Samples | % of Profiled | Mutations |
|------|-----------|---------------|-----------|
| **TP53** | 295 | 52.1% | 314 |
| **TTN** | 272 | 48.1% | 679 |
| **MUC16** | 242 | 42.8% | 424 |
| **CSMD3** | 226 | 39.9% | 394 |
| **RYR2** | 217 | 38.3% | 395 |
| **LRP1B** | 201 | 35.5% | 338 |
| **ZFHX4** | 185 | 32.7% | 276 |
| **USH2A** | 177 | 31.3% | 286 |
| **KRAS** | 168 | 29.7% | 172 |
| MUC17 | 111 | 19.6% | 152 |

### **Lung Squamous Cell Carcinoma** (LUSC, *n* = 484 samples):

| Gene | # Samples | % of Profiled | Mutations |
|------|-----------|---------------|-----------|
| **TP53** | 404 | 83.5% | 430 |
| **TTN** | 345 | 71.3% | 810 |
| **CSMD3** | 209 | 43.2% | 314 |
| **RYR2** | 192 | 39.7% | 277 |
| **MUC16** | 188 | 38.8% | 317 |
| **LRP1B** | 171 | 35.3% | 251 |
| **USH2A** | 160 | 33.1% | 212 |
| **SYNE1** | 151 | 31.2% | 202 |
| **ZFHX4** | 143 | 29.5% | 194 |
| **KMT2D** | 111 | 22.9% | 132 |

### Key Findings:

- **TP53** is the most clinically significant — mutated in **52% of LUAD** and **84% of LUSC**. This tumor suppressor is nearly universal in squamous cell carcinoma.
- **KRAS** ranks 9th in adenocarcinoma (29.7%) — a critical driver of LUAD.
- **TTN** and **MUC16** are large, mutation-prone genes with many events but likely represent passenger mutations rather than oncogenic drivers.
- LUSC shows substantially higher TP53 mutation burden than LUAD (84% vs. 52%), reflecting greater genomic instability.

[View TCGA Lung Cancer OncoPrint](https://www.cbioportal.org/results/oncoprint?cancer_study_list=luad_tcga_pan_can_atlas_2018%2Clusc_tcga_pan_can_atlas_2018&gene_list=TP53%0AKRAS%0AEGFR&case_set_id=all) — includes EGFR (often mutated in LUAD) and compare both histologies side-by-side.