Q (sonnet-5.5): What are the most mutated genes in lung cancer?

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

▶ list_studies
{
 "search": "lung",
 "limit": 50
}

◀ 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)

◀ result
{"result":[{"cancer_study_identifier":"msk_met_2021","name":"MSK MetTropism (MSK, Cell 2021)","type_of_cancer_id":"mixed","sample_count":25775,"has_guide":false,"url":"https://www.cbioportal.org/study/summary?id=msk_met_2021"},{"cancer_study_identifier":"luad_mskcc_2023_met_organotropism","name":"Lung Adenocarcinoma Met Organotropism (MSK, Cancer Cell 2023)","type_of_cancer_id":"luad","sample_count":2653,"has_guide":false,"url":"https://www.cbioportal.org/study/summary?id=luad_mskcc_2023_met_organotropism"},{"cancer_study_identifier":"nsclc_ctdx_msk_2022","name":"Metastatic Non-Small Cell Lung Cancer (MSK, Nature Medicine 2022)","type_of_cancer_id":"nsclc","sample_count":2621,"has_guide":false,"url":"https://www.cbioportal.org/study/summary?id=nsclc_ctdx_msk_2022"},{"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":"lung_msk_2017","name":"Non-Small Cell Cancer (MSK, Cancer Discov 2017)","type_of_cancer_id":"luad","sample_count":915,"has_guide":false,"url":"https://www.cbioportal.org/study/summary?id=lung_msk_2017"},{"cancer_study_identifier":"luad_mskcc_2020","name":"Lung Adenocarcinoma (MSK, J Thorac Oncol 2020)","type_of_cancer_id":"luad","sample_count":604,"has_guide":false,"url":"https://www.cbioportal.org/study/summary?id=luad_mskcc_2020"},{"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":"nsclc_tracerx_2017","name":"Non-Small Cell Lung Cancer (TRACERx, NEJM & N … (7167 more chars)

▶ clickhouse_run_select_query
{
 "query": "SELECT 'LUAD' AS study, * FROM top_mutated_genes_in_study(study='luad_tcga_pan_can_atlas_2018', top_n=10)
UNION ALL
SELECT 'LUSC' AS study, * FROM top_mutated_genes_in_study(study='lusc_tcga_pan_can_atlas_2018', top_n=10)"
}

▶ resolve_and_route
{
 "studyIds": [
  "luad_tcga_pan_can_atlas_2018",
  "lusc_tcga_pan_can_atlas_2018"
 ]
}

◀ result
{"rows":[{"study":"LUAD","hugo_gene_symbol":"TP53","altered_samples":295,"profiled_samples":566,"frequency_pct":52.1,"total_mutation_events":314},{"study":"LUAD","hugo_gene_symbol":"TTN","altered_samples":272,"profiled_samples":566,"frequency_pct":48.1,"total_mutation_events":679},{"study":"LUAD","hugo_gene_symbol":"MUC16","altered_samples":242,"profiled_samples":566,"frequency_pct":42.8,"total_mutation_events":424},{"study":"LUAD","hugo_gene_symbol":"CSMD3","altered_samples":226,"profiled_samples":566,"frequency_pct":39.9,"total_mutation_events":394},{"study":"LUAD","hugo_gene_symbol":"RYR2","altered_samples":217,"profiled_samples":566,"frequency_pct":38.3,"total_mutation_events":395},{"study":"LUAD","hugo_gene_symbol":"LRP1B","altered_samples":201,"profiled_samples":566,"frequency_pct":35.5,"total_mutation_events":338},{"study":"LUAD","hugo_gene_symbol":"ZFHX4","altered_samples":185,"profiled_samples":566,"frequency_pct":32.7,"total_mutation_events":276},{"study":"LUAD","hugo_gene_symbol":"USH2A","altered_samples":177,"profiled_samples":566,"frequency_pct":31.3,"total_mutation_events":286},{"study":"LUAD","hugo_gene_symbol":"KRAS","altered_samples":168,"profiled_samples":566,"frequency_pct":29.7,"total_mutation_events":172},{"study":"LUAD","hugo_gene_symbol":"XIRP2","altered_samples":150,"profiled_samples":566,"frequency_pct":26.5,"total_mutation_events":202},{"study":"LUSC","hugo_gene_symbol":"TP53","altered_samples":404,"profiled_samples":484,"frequency_pct":83.5,"total_mutation_events":430},{"study":"LUSC","hugo_gene_symbol":"TTN","altered_samples":345,"profiled_samples":484,"frequency_pct":71.3,"total_mutation_events":810},{"study":"LUSC","hugo_gene_symbol":"CSMD3","altered_samples":209,"profiled_samples":484,"frequency_pct":43.2,"total_mutation_events":314},{"study":"LUSC","hugo_gene_symbol":"RYR2","altered_samples":192,"profiled_samples":484,"frequency_pct":39.7,"total_mutation_events":277},{"study":"LUSC","hugo_gene_symbol":"MUC16","altered_samples":188,"profiled_samples":484,"frequency_pct":38.8,"total_mutation_events":317},{"study":"LUSC","hugo_gene_symbol":"LRP1B","altered_samples":171,"profiled_samples":484,"frequency_pct":35.3,"total_mutation_events":251},{"study":"LUSC","hugo_gene_symbol":"USH2A","altered_samples":160,"profiled_samples":484,"frequency_pct":33.1,"total_mutation_events":212},{"study":"LUSC","hugo_gene_symbol":"SYNE1","altered_samples":151,"profiled_samples":484,"frequency_pct":31.2,"total_mutation_events":202},{"study":"LUSC","hugo_gene_symbol":"ZFHX4","altered_samples":143,"profiled_samples":484,"frequency_pct":29.5,"total_mutation_events":194},{"study":"LUSC","hugo_gene_symbol":"FAM135B","altered_samples":118,"profiled_samples":484,"frequency_pct":24.4,"total_mutation_events":155}]}

◀ result
{"success":true,"message":"Found 2 matching studies. 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":2,"studiesWithMetadata":[{"studyId":"luad_tcga_pan_can_atlas_2018","name":"Lung Adenocarcinoma (TCGA, PanCancer Atlas)","sampleCount":566,"studyViewUrl":"https://www.cbioportal.org/study?id=luad_tcga_pan_can_atlas_2018","metadata":{"clinicalAttributeIds":["AGE","AJCC_PATHOLOGIC_TUMOR_STAGE","AJCC_STAGING_EDITION","ANEUPLOIDY_SCORE","BUFFA_HYPOXIA_SCORE","CANCER_TYPE","CANCER_TYPE_ACRONYM","CANCER_TYPE_DETAILED","DAYS_LAST_FOLLOWUP","DAYS_TO_BIRTH","DAYS_TO_INITIAL_PATHOLOGIC_DIAGNOSIS","DFS_MONTHS","DFS_STATUS","DSS_MONTHS","DSS_STATUS","ETHNICITY","FORM_COMPLETION_DATE","FRACTION_GENOME_ALTERED","GENETIC_ANCESTRY_LABEL","GRADE","HISTORY_NEOADJUVANT_TRTYN","ICD_10","ICD_O_3_HISTOLOGY","ICD_O_3_SITE","INFORMED_CONSENT_VERIFIED","IN_PANCANPATHWAYS_FREEZE","MSI_SCORE_MANTIS","MSI_SENSOR_SCORE","MUTATION_COUNT","NEW_TUMOR_EVENT_AFTER_INITIAL_TREATMENT","ONCOTREE_CODE","OS_MONTHS","OS_STATUS","OTHER_PATIENT_ID","PATH_M_STAGE","PATH_N_STAGE","PATH_T_STAGE","PERSON_NEOPLASM_CANCER_STATUS","PFS_MONTHS","PFS_STATUS","PRIMARY_LYMPH_NODE_PRESENTATION_ASSESSMENT","PRIOR_DX","RACE","RADIATION_THERAPY","RAGNUM_HYPOXIA_SCORE","SAMPLE_COUNT","SAMPLE_TYPE","SEX","SOMATIC_STATUS","SUBTYPE","TBL_SCORE","TISSUE_PROSPECTIVE_COLLECTION_INDICATOR","TISSUE_RETROSPECTIVE_COLLECTION_INDICATOR","TISSUE_SOURCE_SITE","TISSUE_SOURCE_SITE_CODE","TMB_NONSYNONYMOUS","TUMOR_TISSUE_SITE","TUMOR_TYPE","WEIGHT","WINTER_HYPOXIA_SCORE"],"molecularProfileIds":["luad_tcga_pan_can_atlas_2018_gistic","luad_tcga_pan_can_atlas_2018_log2CNA","luad_tcga_pan_can_atlas_2018_mutations","luad_tcga_pan_can_atlas_2018_rna_seq_v2_mrna","luad_tcga_pan_can_atlas_2018_rna_seq_v2_mrna_median_Zscores","luad_tcga_pan_can_atlas_2018_rna_seq_v2_mrna_median_all_sample_Zscores","luad_tcga_pan_can_atlas_2018_rna_seq_v2_mrna_median_all_sample_ref_normal_Zscores","luad_tcga_pan_can_atlas_2018_rppa","luad_tcga_pan_can_atlas_2018_rppa_Zscores","luad_tcga_pan_can_atlas_2018_structural_variants"],"genericAssayProfiles":["luad_tcga_pan_can_atlas_2018_armlevel_cna","luad_tcga_pan_can_atlas_2018_genetic_ancestry","luad_tcga_pan_can_atlas_2018_methylation_hm27_hm450_merge","luad_tcga_pan_can_atlas_2018_methylation_hm450"],"heatmapProfileIds":["luad_tcga_pan_can_atlas_2018_rna_seq_v2_mrna_median_Zscores","luad_tcga_pan_can_atlas_2018_rna_seq_v2_mrna_median_all_sample_Zscores","luad_tcga_pan_can_atlas_2018_rna_seq_v2_mrna_median_all_sample_ref_normal_Zscores","luad_tcga_pan_can_atlas_2018_rppa_Zscores"],"availableComparisonTabs":["overlap","clinical","survival","alterations","mutations","mrna","protein","generic_assay_armlevel_cna","generic_assay_genetic_ancestry","generic_assay_methylation"]}},{"studyId":"lusc_tcga_pan_can_atlas_2018","name":"Lung Squamous Cell … (2585 more chars)

▶ navigate_to_study_view
{
 "studyIds": [
  "luad_tcga_pan_can_atlas_2018",
  "lusc_tcga_pan_can_atlas_2018"
 ]
}

◀ result
{"success":true,"message":"Navigating to https://www.cbioportal.org/study/summary?id=luad_tcga_pan_can_atlas_2018%2Clusc_tcga_pan_can_atlas_2018","url":"https://www.cbioportal.org/study/summary?id=luad_tcga_pan_can_atlas_2018%2Clusc_tcga_pan_can_atlas_2018","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}],"tab":"summary","hasFilters":false,"hasPlotsConfig":false,"pageDescription":"Overview of all study data displayed as interactive charts summarizing available clinical and genomic data. Click within a chart to filter. Additional charts may be available in the Charts menu."}}

═ answer (success)
I used the TCGA PanCancer Atlas cohorts, which are the standard reference for this question. Lung cancer has many other studies in cBioPortal, so I can rerun this on a different cohort if you prefer. Percentages are samples with a mutation divided by samples profiled, and all samples were whole-exome sequenced.

**Lung adenocarcinoma (LUAD): 566 samples**

| Gene | Mutated samples | Frequency |
|---|---|---|
| TP53 | 295 | 52.1% |
| TTN | 272 | 48.1% |
| MUC16 | 242 | 42.8% |
| CSMD3 | 226 | 39.9% |
| RYR2 | 217 | 38.3% |
| LRP1B | 201 | 35.5% |
| ZFHX4 | 185 | 32.7% |
| USH2A | 177 | 31.3% |
| KRAS | 168 | 29.7% |
| XIRP2 | 150 | 26.5% |

**Lung squamous cell carcinoma (LUSC): 484 profiled samples**

| Gene | Mutated samples | Frequency |
|---|---|---|
| TP53 | 404 | 83.5% |
| TTN | 345 | 71.3% |
| CSMD3 | 209 | 43.2% |
| RYR2 | 192 | 39.7% |
| MUC16 | 188 | 38.8% |
| LRP1B | 171 | 35.3% |
| USH2A | 160 | 33.1% |
| SYNE1 | 151 | 31.2% |
| ZFHX4 | 143 | 29.5% |
| FAM135B | 118 | 24.4% |

- **TP53** is the most frequently mutated gene in both subtypes. It is mutated in about 52% of LUAD and 84% of LUSC.
- **KRAS** is the only well-known cancer gene in the LUAD top 10, at about 30%. It doesn't appear in the LUSC top 10.
- **Large genes:** TTN, MUC16, CSMD3, RYR2 and LRP1B are very large genes. They are often mutated by chance in tumors with high mutation burdens, so being frequently mutated doesn't mean they drive the cancer. I didn't check driver annotation for these results.

I didn't run the small cell lung cancer studies. These are separate cohorts, and I can pull them if you want.

[View both cohorts in cBioPortal](https://www.cbioportal.org/study/summary?id=luad_tcga_pan_can_atlas_2018%2Clusc_tcga_pan_can_atlas_2018)