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

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

▶ search_oncotree
{
 "search_term": "lung"
}

◀ 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
{"result":[{"code":"LUNG","name":"Lung","score":100,"mainType":"Lung Cancer","tissue":"Lung","hierarchy":"LUNG"},{"code":"LAIS","name":"Lung Adenocarcinoma In Situ","score":60,"mainType":"Non-Small Cell Lung Cancer","tissue":"Lung","hierarchy":"LUNG > LAIS"},{"code":"LNET","name":"Lung Neuroendocrine Tumor","score":60,"mainType":"Non-Small Cell Lung Cancer","tissue":"Lung","hierarchy":"LUNG > LNET"},{"code":"LUAD","name":"Lung Adenocarcinoma","score":60,"mainType":"Non-Small Cell Lung Cancer","tissue":"Lung","hierarchy":"LUNG > NSCLC > LUAD"},{"code":"LUAS","name":"Lung Adenosquamous Carcinoma","score":60,"mainType":"Non-Small Cell Lung Cancer","tissue":"Lung","hierarchy":"LUNG > NSCLC > LUAS"},{"code":"LUCA","name":"Lung Carcinoid","score":60,"mainType":"Non-Small Cell Lung Cancer","tissue":"Lung","hierarchy":"LUNG > LNET > LUCA"},{"code":"LUSC","name":"Lung Squamous Cell Carcinoma","score":60,"mainType":"Non-Small Cell Lung Cancer","tissue":"Lung","hierarchy":"LUNG > NSCLC > LUSC"},{"code":"ALUCA","name":"Atypical Lung Carcinoid","score":50,"mainType":"Non-Small Cell Lung Cancer","tissue":"Lung","hierarchy":"LUNG > LNET > ALUCA"},{"code":"BLCLC","name":"Basaloid Large Cell Carcinoma of the Lung","score":50,"mainType":"Non-Small Cell Lung Cancer","tissue":"Lung","hierarchy":"LUNG > NSCLC > LCLC > BLCLC"},{"code":"CCLC","name":"Clear Cell Carcinoma of the Lung","score":50,"mainType":"Non-Small Cell Lung Cancer","tissue":"Lung","hierarchy":"LUNG > NSCLC > LCLC > CCLC"},{"code":"CMPT","name":"Ciliated Muconodular Papillary Tumor of the Lung","score":50,"mainType":"Non-Small Cell Lung Cancer","tissue":"Lung","hierarchy":"LUNG > NSCLC > CMPT"},{"code":"CSCLC","name":"Combined Small Cell Lung Carcinoma","score":50,"mainType":"Small Cell Lung Cancer","tissue":"Lung","hierarchy":"LUNG > CSCLC"},{"code":"GCLC","name":"Giant Cell Carcinoma of the Lung","score":50,"mainType":"Non-Small Cell Lung Cancer","tissue":"Lung","hierarchy":"LUNG > NSCLC > LCLC > GCLC"},{"code":"IMTL","name":"Inflammatory Myofibroblastic Lung Tumor","score":50,"mainType":"Non-Small Cell Lung Cancer","tissue":"Lung","hierarchy":"LUNG > IMTL"},{"code":"LCLC","name":"Large Cell Lung Carcinoma","score":50,"mainType":"Non-Small Cell Lung Cancer","tissue":"Lung","hierarchy":"LUNG > NSCLC > LCLC"},{"code":"LECLC","name":"Lymphoepithelioma-like Carcinoma of the Lung","score":50,"mainType":"Non-Small Cell Lung Cancer","tissue":"Lung","hierarchy":"LUNG > NSCLC > LCLC > LECLC"},{"code":"LUACC","name":"Adenoid Cystic Carcinoma of the Lung","score":50,"mainType":"Non-Small Cell Lung Cancer","tissue":"Lung","hierarchy":"LUNG > NSCLC > SGTTL > LUACC"},{"code":"LUMEC","name":"Mucoepidermoid Carcinoma of the Lung","score":50,"mainType":"Non-Small Cell Lung Cancer","tissue":"Lung","hierarchy":"LUNG > NSCLC > SGTTL > LUMEC"},{"code":"LUPC","name":"Pleomorphic Carcinoma of the Lung","score":50,"mainType":"Non-Small Cell Lung Cancer","tissue":"Lung","hierarchy":"LUNG > NSCLC > LUPC"},{"code":"NSCLC","na … (947 more chars)

▶ list_studies
{
 "search": "lung TCGA",
 "limit": 10
}

◀ result
{"result":[{"cancer_study_identifier":"nsclc_tcga_broad_2016","name":"Pan-Lung Cancer (TCGA, Nat Genet 2016)","type_of_cancer_id":"nsclc","sample_count":1144,"has_guide":false,"url":"https://www.cbioportal.org/study/summary?id=nsclc_tcga_broad_2016"},{"cancer_study_identifier":"luad_tcga","name":"Lung Adenocarcinoma (TCGA, Firehose Legacy)","type_of_cancer_id":"luad","sample_count":586,"has_guide":false,"url":"https://www.cbioportal.org/study/summary?id=luad_tcga"},{"cancer_study_identifier":"luad_tcga_gdc","name":"Lung Adenocarcinoma (TCGA GDC, 2025)","type_of_cancer_id":"luad","sample_count":571,"has_guide":false,"url":"https://www.cbioportal.org/study/summary?id=luad_tcga_gdc"},{"cancer_study_identifier":"luad_tcga_pan_can_atlas_2018","name":"Lung Adenocarcinoma (TCGA, PanCancer Atlas)","type_of_cancer_id":"luad","sample_count":566,"has_guide":true,"url":"https://www.cbioportal.org/study/summary?id=luad_tcga_pan_can_atlas_2018"},{"cancer_study_identifier":"lusc_tcga","name":"Lung Squamous Cell Carcinoma (TCGA, Firehose Legacy)","type_of_cancer_id":"lusc","sample_count":511,"has_guide":false,"url":"https://www.cbioportal.org/study/summary?id=lusc_tcga"},{"cancer_study_identifier":"lusc_tcga_gdc","name":"Lung Squamous Cell Carcinoma (TCGA GDC, 2025)","type_of_cancer_id":"lusc","sample_count":503,"has_guide":false,"url":"https://www.cbioportal.org/study/summary?id=lusc_tcga_gdc"},{"cancer_study_identifier":"lusc_tcga_pan_can_atlas_2018","name":"Lung Squamous Cell Carcinoma (TCGA, PanCancer Atlas)","type_of_cancer_id":"lusc","sample_count":487,"has_guide":false,"url":"https://www.cbioportal.org/study/summary?id=lusc_tcga_pan_can_atlas_2018"},{"cancer_study_identifier":"luad_tcga_pub","name":"Lung Adenocarcinoma (TCGA, Nature 2014)","type_of_cancer_id":"luad","sample_count":230,"has_guide":false,"url":"https://www.cbioportal.org/study/summary?id=luad_tcga_pub"},{"cancer_study_identifier":"lusc_tcga_pub","name":"Lung Squamous Cell Carcinoma (TCGA, Nature 2012)","type_of_cancer_id":"lusc","sample_count":178,"has_guide":false,"url":"https://www.cbioportal.org/study/summary?id=lusc_tcga_pub"}]}

▶ clickhouse_run_select_query
{
 "query": "
SELECT hugo_gene_symbol, 
       altered_samples, 
       profiled_samples, 
       frequency_pct,
       total_mutation_events
FROM top_mutated_genes_in_study(study = 'nsclc_tcga_broad_2016', top_n = 20)
ORDER BY frequency_pct DESC
",
 "max_rows": 20
}

◀ result
{"rows":[{"hugo_gene_symbol":"TP53","altered_samples":775,"profiled_samples":1144,"frequency_pct":67.7,"total_mutation_events":814},{"hugo_gene_symbol":"TTN","altered_samples":682,"profiled_samples":1144,"frequency_pct":59.6,"total_mutation_events":1676},{"hugo_gene_symbol":"CSMD3","altered_samples":477,"profiled_samples":1144,"frequency_pct":41.7,"total_mutation_events":775},{"hugo_gene_symbol":"MUC16","altered_samples":463,"profiled_samples":1144,"frequency_pct":40.5,"total_mutation_events":808},{"hugo_gene_symbol":"RYR2","altered_samples":448,"profiled_samples":1144,"frequency_pct":39.2,"total_mutation_events":732},{"hugo_gene_symbol":"LRP1B","altered_samples":402,"profiled_samples":1144,"frequency_pct":35.1,"total_mutation_events":633},{"hugo_gene_symbol":"USH2A","altered_samples":390,"profiled_samples":1144,"frequency_pct":34.1,"total_mutation_events":570},{"hugo_gene_symbol":"ZFHX4","altered_samples":356,"profiled_samples":1144,"frequency_pct":31.1,"total_mutation_events":512},{"hugo_gene_symbol":"SPTA1","altered_samples":284,"profiled_samples":1144,"frequency_pct":24.8,"total_mutation_events":377},{"hugo_gene_symbol":"XIRP2","altered_samples":268,"profiled_samples":1144,"frequency_pct":23.4,"total_mutation_events":360},{"hugo_gene_symbol":"FLG","altered_samples":253,"profiled_samples":1144,"frequency_pct":22.1,"total_mutation_events":358},{"hugo_gene_symbol":"SYNE1","altered_samples":253,"profiled_samples":1144,"frequency_pct":22.1,"total_mutation_events":318},{"hugo_gene_symbol":"NAV3","altered_samples":234,"profiled_samples":1144,"frequency_pct":20.5,"total_mutation_events":285},{"hugo_gene_symbol":"PCDH15","altered_samples":230,"profiled_samples":1144,"frequency_pct":20.1,"total_mutation_events":315},{"hugo_gene_symbol":"CSMD1","altered_samples":225,"profiled_samples":1144,"frequency_pct":19.7,"total_mutation_events":300},{"hugo_gene_symbol":"FAM135B","altered_samples":223,"profiled_samples":1144,"frequency_pct":19.5,"total_mutation_events":276},{"hugo_gene_symbol":"FAT3","altered_samples":222,"profiled_samples":1144,"frequency_pct":19.4,"total_mutation_events":309},{"hugo_gene_symbol":"KRAS","altered_samples":222,"profiled_samples":1144,"frequency_pct":19.4,"total_mutation_events":224},{"hugo_gene_symbol":"MUC17","altered_samples":219,"profiled_samples":1144,"frequency_pct":19.1,"total_mutation_events":280},{"hugo_gene_symbol":"PCLO","altered_samples":219,"profiled_samples":1144,"frequency_pct":19.1,"total_mutation_events":287}]}

▶ resolve_and_route
{
 "studyIds": [
  "nsclc_tcga_broad_2016"
 ]
}

◀ result
{"success":true,"message":"Found 1 study. Use the metadata to call the appropriate navigation tool(s).","data":{"totalCount":1,"studiesWithMetadata":[{"studyId":"nsclc_tcga_broad_2016","name":"Pan-Lung Cancer (TCGA, Nat Genet 2016)","sampleCount":1144,"studyViewUrl":"https://www.cbioportal.org/study?id=nsclc_tcga_broad_2016","metadata":{"clinicalAttributeIds":["AGE","AGE_AT_SURGERY","CANCER_TYPE","CANCER_TYPE_DETAILED","DAYS_TO_DEATH","DAYS_TO_LAST_FOLLOWUP","FRACTION_GENOME_ALTERED","HISTORY_NEOADJUVANT_TRTYN","HISTORY_OTHER_MALIGNANCY","MUTATION_COUNT","M_STAGE","N_STAGE","ONCOTREE_CODE","OS_MONTHS","OS_STATUS","SAMPLE_COUNT","SEX","SMOKING_HISTORY","SMOKING_PACK_YEARS","SOMATIC_STATUS","STAGE","TMB_NONSYNONYMOUS","T_STAGE"],"molecularProfileIds":["nsclc_tcga_broad_2016_cna","nsclc_tcga_broad_2016_mutations","nsclc_tcga_broad_2016_structural_variants"],"availableComparisonTabs":["overlap","clinical","survival","alterations","mutations"]}}]}}

▶ navigate_to_results_view
{
 "studyIds": [
  "nsclc_tcga_broad_2016"
 ],
 "genes": [
  "TP53",
  "TTN",
  "CSMD3",
  "MUC16",
  "RYR2",
  "KRAS"
 ],
 "tab": "mutations"
}

◀ result
{"success":true,"message":"Navigating to https://www.cbioportal.org/results/mutations?cancer_study_list=nsclc_tcga_broad_2016&gene_list=TP53%0ATTN%0ACSMD3%0AMUC16%0ARYR2%0AKRAS&case_set_id=nsclc_tcga_broad_2016_all","url":"https://www.cbioportal.org/results/mutations?cancer_study_list=nsclc_tcga_broad_2016&gene_list=TP53%0ATTN%0ACSMD3%0AMUC16%0ARYR2%0AKRAS&case_set_id=nsclc_tcga_broad_2016_all","data":{"studyIds":["nsclc_tcga_broad_2016"],"studies":[{"studyId":"nsclc_tcga_broad_2016","name":"Pan-Lung Cancer (TCGA, Nat Genet 2016)","sampleCount":1144}],"genes":["TP53","TTN","CSMD3","MUC16","RYR2","KRAS"],"caseSetId":"nsclc_tcga_broad_2016_all","pageDescription":"Detailed mutation table with lollipop plot showing mutation positions, types, and frequencies for queried genes."}}

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

I queried the **Pan-Lung Cancer TCGA dataset** (1,144 samples, including adenocarcinoma and squamous cell carcinoma), which is the most comprehensive lung cancer cohort available. Here are the **top 20 most frequently mutated genes**:

| Gene | Altered Samples | Frequency | Mutation Events |
|------|-----------------|-----------|-----------------|
| **TP53** | 775 | **67.7%** | 814 |
| **TTN** | 682 | **59.6%** | 1,676 |
| **CSMD3** | 477 | **41.7%** | 775 |
| **MUC16** | 463 | **40.5%** | 808 |
| **RYR2** | 448 | **39.2%** | 732 |
| **LRP1B** | 402 | **35.1%** | 633 |
| **USH2A** | 390 | **34.1%** | 570 |
| **ZFHX4** | 356 | **31.1%** | 512 |
| **SPTA1** | 284 | 24.8% | 377 |
| **XIRP2** | 268 | 23.4% | 360 |
| **FLG** | 253 | 22.1% | 358 |
| **SYNE1** | 253 | 22.1% | 318 |
| **NAV3** | 234 | 20.5% | 285 |
| **PCDH15** | 230 | 20.1% | 315 |
| **CSMD1** | 225 | 19.7% | 300 |
| **FAM135B** | 223 | 19.5% | 276 |
| **FAT3** | 222 | 19.4% | 309 |
| **KRAS** | 222 | **19.4%** | 224 |
| **MUC17** | 219 | 19.1% | 280 |
| **PCLO** | 219 | 19.1% | 287 |

### Key Findings

**Driver genes** (clinically significant):
- **TP53**: The tumor suppressor is mutated in ~68% of lung cancers, making it the most frequently altered gene.
- **KRAS**: An oncogenic driver, mutated in ~19% of lung cancers, particularly enriched in adenocarcinomas.

**Large/passenger genes**: TTN, MUC16, and CSMD3 are among the most frequently mutated in all cancer types due to their large genomic size. Their high mutation frequencies reflect sample size rather than functional driver status.

### Explore the Data
[View detailed mutation analysis in cBioPortal](https://www.cbioportal.org/results/mutations?cancer_study_list=nsclc_tcga_broad_2016&gene_list=TP53%0ATTN%0ACSMD3%0AMUC16%0ARYR2%0AKRAS&case_set_id=nsclc_tcga_broad_2016_all) – includes OncoPrint visualization, mutation types, and protein change details for each gene.