Q (sonnet): What are the most mutated genes in lung cancer? ▶ list_guides {} ◀ result {"result":[{"uri":"cbioportal://mutation-frequency-guide","description":"Comprehensive guide for calculating gene mutation frequencies with gene-specific profiling denominators"},{"uri":"cbioportal://clinical-data-guide","description":"Guide for querying clinical data including patient vs sample level considerations"},{"uri":"cbioportal://sample-filtering-guide","description":"Guide for filtering samples and studies in cBioPortal queries"},{"uri":"cbioportal://common-pitfalls","description":"Guide to avoid common mistakes when querying cBioPortal data. If you already know which numbered pitfall applies, fetch just that section via read_guide(\"cbioportal://common-pitfalls#\") (e.g. #16) instead of the full guide"},{"uri":"cbioportal://treatment-guide","description":"Guide for querying treatment/clinical event data including drug agents, timelines, and linking to genomic data"},{"uri":"cbioportal://faq-guide","description":"General cBioPortal FAQ: history, how to cite, data types, reference genome, abbreviations, GISTIC thresholds, API access"},{"uri":"cbioportal://statistical-tests-guide","description":"Statistical test selection guide — decision matrix for choosing Fisher's exact, Wilcoxon, chi-squared, t-test, ANOVA, etc. based on data type and group count"},{"uri":"cbioportal://gene-expression-guide","description":"Gene expression / copy-number / methylation analysis. Covers genetic_alteration_derived, profile_type discovery, and the gene_pair_coexpression view for Spearman correlation between two genes"},{"uri":"cbioportal://external-resources-guide","description":"Guide for finding external linked resources such as imaging, pathology, Minerva, HTAN, or other resource_* table links before declaring data unavailable"},{"uri":"cbioportal://gene-resolution-guide","description":"Guide for resolving ambiguous gene symbols, aliases, gene families, and shorthand such as CD3 before querying expression or alteration data"},{"uri":"cbioportal://study-resolution-guide","description":"Guide for resolving requested studies, avoiding silent substitute cohorts, and redirecting to known external cBioPortal instances when data is not in this deployment"},{"uri":"cbioportal://germline-guide","description":"Guide for querying germline variant data — storage columns, study discovery, query patterns, and somatic vs germline considerations"},{"uri":"cbioportal://study-guide/{study_id}","description":"Dynamic study-specific guide - use get_study_guide(study_id) tool to generate"}]} ▶ read_guide { "uri": "cbioportal://mutation-frequency-guide" } ▶ search_oncotree { "search_term": "lung cancer" } ◀ 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":65,"mainType":"Lung Cancer","tissue":"Lung","hierarchy":"LUNG"},{"code":"NSCLC","name":"Non-Small Cell Lung Cancer","score":50,"mainType":"Non-Small Cell Lung Cancer","tissue":"Lung","hierarchy":"LUNG > NSCLC"},{"code":"NSCLCPD","name":"Poorly Differentiated Non-Small Cell Lung Cancer","score":50,"mainType":"Non-Small Cell Lung Cancer","tissue":"Lung","hierarchy":"LUNG > NSCLC > NSCLCPD"},{"code":"SCLC","name":"Small Cell Lung Cancer","score":50,"mainType":"Small Cell Lung Cancer","tissue":"Lung","hierarchy":"LUNG > LNET > SCLC"},{"code":"ALUCA","name":"Atypical Lung Carcinoid","score":45,"mainType":"Non-Small Cell Lung Cancer","tissue":"Lung","hierarchy":"LUNG > LNET > ALUCA"},{"code":"BLCLC","name":"Basaloid Large Cell Carcinoma of the Lung","score":45,"mainType":"Non-Small Cell Lung Cancer","tissue":"Lung","hierarchy":"LUNG > NSCLC > LCLC > BLCLC"},{"code":"CCLC","name":"Clear Cell Carcinoma of the Lung","score":45,"mainType":"Non-Small Cell Lung Cancer","tissue":"Lung","hierarchy":"LUNG > NSCLC > LCLC > CCLC"},{"code":"CMPT","name":"Ciliated Muconodular Papillary Tumor of the Lung","score":45,"mainType":"Non-Small Cell Lung Cancer","tissue":"Lung","hierarchy":"LUNG > NSCLC > CMPT"},{"code":"CSCLC","name":"Combined Small Cell Lung Carcinoma","score":45,"mainType":"Small Cell Lung Cancer","tissue":"Lung","hierarchy":"LUNG > CSCLC"},{"code":"GCLC","name":"Giant Cell Carcinoma of the Lung","score":45,"mainType":"Non-Small Cell Lung Cancer","tissue":"Lung","hierarchy":"LUNG > NSCLC > LCLC > GCLC"},{"code":"IMTL","name":"Inflammatory Myofibroblastic Lung Tumor","score":45,"mainType":"Non-Small Cell Lung Cancer","tissue":"Lung","hierarchy":"LUNG > IMTL"},{"code":"LAIS","name":"Lung Adenocarcinoma In Situ","score":45,"mainType":"Non-Small Cell Lung Cancer","tissue":"Lung","hierarchy":"LUNG > LAIS"},{"code":"LAM","name":"Pulmonary Lymphangiomyomatosis","score":45,"mainType":"Non-Small Cell Lung Cancer","tissue":"Lung","hierarchy":"LUNG > LAM"},{"code":"LCLC","name":"Large Cell Lung Carcinoma","score":45,"mainType":"Non-Small Cell Lung Cancer","tissue":"Lung","hierarchy":"LUNG > NSCLC > LCLC"},{"code":"LECLC","name":"Lymphoepithelioma-like Carcinoma of the Lung","score":45,"mainType":"Non-Small Cell Lung Cancer","tissue":"Lung","hierarchy":"LUNG > NSCLC > LCLC > LECLC"},{"code":"LNET","name":"Lung Neuroendocrine Tumor","score":45,"mainType":"Non-Small Cell Lung Cancer","tissue":"Lung","hierarchy":"LUNG > LNET"},{"code":"LUACC","name":"Adenoid Cystic Carcinoma of the Lung","score":45,"mainType":"Non-Small Cell Lung Cancer","tissue":"Lung","hierarchy":"LUNG > NSCLC > SGTTL > LUACC"},{"code":"LUAD","name":"Lung Adenocarcinoma","score":45,"mainType":"Non-Small Cell Lung Cancer","tissue":"Lung","hierarchy":"LUNG > NSCLC > LUAD"},{"code":"LUAS","name":"Lung Adenosquamous Carcinoma","score":45,"mainType":"Non-Small Cell Lung Cancer","tissue":"Lung","hierarchy":"LUNG > NSCLC > LUAS"},{"code":"LUCA","name":"Lung C … (915 more chars) ▶ clickhouse_run_select_query { "query": "SELECT * FROM top_mutated_genes_in_study(study = 'luad_tcga_pan_can_atlas_2018', top_n = 10)" } ▶ clickhouse_run_select_query { "query": "SELECT * FROM top_mutated_genes_in_study(study = 'lusc_tcga_pan_can_atlas_2018', top_n = 10)" } ◀ 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}]} ◀ 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}]} ▶ resolve_and_route { "studyIds": [ "luad_tcga_pan_can_atlas_2018", "lusc_tcga_pan_can_atlas_2018" ] } ◀ 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_results_view { "studyIds": [ "luad_tcga_pan_can_atlas_2018" ], "genes": [ "TP53", "TTN", "MUC16", "CSMD3", "RYR2", "LRP1B", "ZFHX4", "USH2A", "KRAS", "XIRP2" ], "tab": "oncoprint" } ◀ result {"success":true,"message":"Navigating to https://www.cbioportal.org/results/oncoprint?cancer_study_list=luad_tcga_pan_can_atlas_2018&gene_list=TP53%0ATTN%0AMUC16%0ACSMD3%0ARYR2%0ALRP1B%0AZFHX4%0AUSH2A%0AKRAS%0AXIRP2&case_set_id=luad_tcga_pan_can_atlas_2018_all","url":"https://www.cbioportal.org/results/oncoprint?cancer_study_list=luad_tcga_pan_can_atlas_2018&gene_list=TP53%0ATTN%0AMUC16%0ACSMD3%0ARYR2%0ALRP1B%0AZFHX4%0AUSH2A%0AKRAS%0AXIRP2&case_set_id=luad_tcga_pan_can_atlas_2018_all","data":{"studyIds":["luad_tcga_pan_can_atlas_2018"],"studies":[{"studyId":"luad_tcga_pan_can_atlas_2018","name":"Lung Adenocarcinoma (TCGA, PanCancer Atlas)","sampleCount":566}],"genes":["TP53","TTN","MUC16","CSMD3","RYR2","LRP1B","ZFHX4","USH2A","KRAS","XIRP2"],"caseSetId":"luad_tcga_pan_can_atlas_2018_all","pageDescription":"Visual summary of alterations in queried genes across samples."}} ▶ navigate_to_results_view { "studyIds": [ "lusc_tcga_pan_can_atlas_2018" ], "genes": [ "TP53", "TTN", "CSMD3", "RYR2", "MUC16", "LRP1B", "USH2A", "SYNE1", "ZFHX4", "FAM135B" ], "tab": "oncoprint" } ◀ result {"success":true,"message":"Navigating to https://www.cbioportal.org/results/oncoprint?cancer_study_list=lusc_tcga_pan_can_atlas_2018&gene_list=TP53%0ATTN%0ACSMD3%0ARYR2%0AMUC16%0ALRP1B%0AUSH2A%0ASYNE1%0AZFHX4%0AFAM135B&case_set_id=lusc_tcga_pan_can_atlas_2018_all","url":"https://www.cbioportal.org/results/oncoprint?cancer_study_list=lusc_tcga_pan_can_atlas_2018&gene_list=TP53%0ATTN%0ACSMD3%0ARYR2%0AMUC16%0ALRP1B%0AUSH2A%0ASYNE1%0AZFHX4%0AFAM135B&case_set_id=lusc_tcga_pan_can_atlas_2018_all","data":{"studyIds":["lusc_tcga_pan_can_atlas_2018"],"studies":[{"studyId":"lusc_tcga_pan_can_atlas_2018","name":"Lung Squamous Cell Carcinoma (TCGA, PanCancer Atlas)","sampleCount":487}],"genes":["TP53","TTN","CSMD3","RYR2","MUC16","LRP1B","USH2A","SYNE1","ZFHX4","FAM135B"],"caseSetId":"lusc_tcga_pan_can_atlas_2018_all","pageDescription":"Visual summary of alterations in queried genes across samples."}} ═ answer (success) "Lung cancer" spans multiple histologies; I queried the two major TCGA PanCancer Atlas lung cohorts (WES-based, so denominators = all profiled samples). Frequencies are sample-level (% of samples with ≥1 mutation in the gene). ## Lung Adenocarcinoma (LUAD, TCGA PanCancer Atlas, n=566 profiled) | Gene | Altered Samples | Frequency | |------|-----------------|-----------| | TP53 | 295/566 | 52.1% | | TTN | 272/566 | 48.1% | | MUC16 | 242/566 | 42.8% | | CSMD3 | 226/566 | 39.9% | | RYR2 | 217/566 | 38.3% | | LRP1B | 201/566 | 35.5% | | ZFHX4 | 185/566 | 32.7% | | USH2A | 177/566 | 31.3% | | KRAS | 168/566 | 29.7% | | XIRP2 | 150/566 | 26.5% | ## Lung Squamous Cell Carcinoma (LUSC, TCGA PanCancer Atlas, n=484 profiled) | Gene | Altered Samples | Frequency | |------|-----------------|-----------| | TP53 | 404/484 | 83.5% | | TTN | 345/484 | 71.3% | | CSMD3 | 209/484 | 43.2% | | RYR2 | 192/484 | 39.7% | | MUC16 | 188/484 | 38.8% | | LRP1B | 171/484 | 35.3% | | USH2A | 160/484 | 33.1% | | SYNE1 | 151/484 | 31.2% | | ZFHX4 | 143/484 | 29.5% | | FAM135B | 118/484 | 24.4% | **Notes:** - TP53 dominates both subtypes, especially LUSC (83.5% vs. 52.1% in LUAD) — a well-known histology distinction. - KRAS mutations (29.7%) are prominent in LUAD but do not reach the LUSC top-10, another classic LUAD/LUSC divergence. - TTN, MUC16, CSMD3, RYR2, LRP1B, USH2A, ZFHX4 are very large genes; high mutation frequency partly reflects gene size/passenger mutation burden, not necessarily oncogenic driver status. High mutation frequency ≠ oncogenicity — I have not queried driver/OncoKB annotations here. - These are two separate cohorts (LUAD and LUSC) — frequencies are not summed or pooled together. ## Explore Further [LUAD Top Mutated Genes — OncoPrint](https://www.cbioportal.org/results/oncoprint?cancer_study_list=luad_tcga_pan_can_atlas_2018&gene_list=TP53%0ATTN%0AMUC16%0ACSMD3%0ARYR2%0ALRP1B%0AZFHX4%0AUSH2A%0AKRAS%0AXIRP2&case_set_id=luad_tcga_pan_can_atlas_2018_all) [LUSC Top Mutated Genes — OncoPrint](https://www.cbioportal.org/results/oncoprint?cancer_study_list=lusc_tcga_pan_can_atlas_2018&gene_list=TP53%0ATTN%0ACSMD3%0ARYR2%0AMUC16%0ALRP1B%0AUSH2A%0ASYNE1%0AZFHX4%0AFAM135B&case_set_id=lusc_tcga_pan_can_atlas_2018_all) If you'd like, I can also pull Small Cell Lung Cancer (SCLC) or run a pooled "Non-Small Cell Lung Cancer" view merging LUAD+LUSC via `CANCER_TYPE`.